Advances in Autism Research
compiled by Teresa Binstock for
Autism Research Institute
April 2008
Autism, Pollution, and Nutrients: a Unifying Relationship
Commentary by Teresa Binstock
Thus far, every study that has screened for pollutants within the human body has found numerous pollutants in the blood of every individual so tested (reviewed in 4). Oxidative stress is associated with autism and with pollutants (5-6). Nutrients participate in detoxification and immunity. When a human embryo, fetus, infant, or toddler has a large number of intra-body toxins (ie, “pollutants”), then he or she is at risk of experiencing and of living with adverse sequelae. Effects may appear as PDD, language problems, autism, or other autism-spectrum disorders - or as non-Hodgkin's lympoma, Parkinson's disease, etc.
Why intra-body pollutants affect some children more than other children brings forth findings related to susceptibility. Why do some children have increased susceptibility? Let us ask again, for this is a most important question: Why do some individuals have increased susceptibility for developing one or more pathologies associated with pollutants and other toxic molecules?
Answering this question leads us into various domains of medicine. For instance, weak alleles of glutathione-related genes impair detoxification and immunity. An illness may induce suboptimal, intra-body nutritional-status. Nutrients are crucial to the proper functioning of mitochondria.
An answer is becoming elucidated in peer-reviewed studies: nutrient depletion.
Each pollutant that becomes an intra-body toxin induces process of detoxification and thereby draws upon the body's reserves of nutrients needed for detoxification and for immunity. When the rate of acquiring pollutants within the human body (eg, pregnant woman, embryo, fetus, infant, toddler) exceeds that individual's intra-body reserves of nutrients needed for detoxification, adverse sequlae within one or more body systems (eg, brain, lungs, kidneys, pancreas) are likely to occur. This tendency towards depletion of nutrients needed for detoxification and for immunity is exacerbated (a) by the individual having one or more weak alleles related to nutrition, detoxification, and/or immunity, (b) by an illness or recent illness, and/or (c) by other other reason for supoptimal nutritional status.
Ramifications blossom forth.
A. Years ago, the official policy was that sick children ought not be vaccinated. However, so as to increase rewards for vaccination coverage, that policy was changed in ways encouraging the vaccinating of sick or recently sick children. The ethylmercury, aluminum, and other pollutants (8-12) present in vaccines are more likely to induce adverse effects in an infant or toddler who is sick or who was recently sick and thus who has suboptimal levels of intra-body nutrients.
B. Studies that focus upon single pollutants may miss or underestimate adverse effects induced by the fact of myriad pollutants within the human body, within breast milk and cord blood, etc. Pollutant-induced depletion of nutrients ought become a focus as important (and will be as likely to be ignored) as are additive, cumulative, synergistic, and hormetic effects of so-called “low dose” exposures.
Conclusion: Many factors contributing to why some individuals have increased susceptibility for adverse effects from pollutants, whether injected or obtained by other means. Many of these factors have been identified. Proper nutritional status of pregnant women, infants, and toddlers is important and ought be re-delineated in relation to the individual's level of environmental pollutants, oxididative stress, and weak alleles related to detoxification and immunity.
Warning: Many of the abstracts herein call attention to positive benefits of sulfur-containing supplements. Importantly, a subgroup of individuals is hyper-reactive to sulfur-containing molecules. More information is available from long-time Autism Research Institute colleague Susan Owens (13).
References:
Data and overviews by physicians who are have experience with autistic children.
1. Parent Ratings of behavioral effects of biomedical interventions
Pharmaceuticals, diets, supplements, etc.
http://www.autismwebsite.com/ARI/treatment/form34q.htm
2. Changing the Course of Autism
by Bryan Jepson, M.D., autism parent,
with Jane Johnson, autism parent.
http://www.thoughtfulhouse.org/pr/jepson_book.htm
3. Healing the New Childhood Epidemics: Autism, ADHD, Asthma, and Allergies:
The Groundbreaking Program for the 4-A Disorders
by Kenneth Bock, M.D., with Cameron Stauth
http://www.amazon.com/Healing-New-Childhood-Epidemics-Groundbreaking/dp/0345494504
4. Children with Starving Brains: A Medical Treatment Guide for Autism Spectrum Disorder, 3rd edition 2007.
by Jaquelyn McCandless, M.D., with contributions by Jack Zimmerman, Ph.D., and Teresa Binstock, Independent Researcher with Asperger's Disorder.
http://autismstore.dyndns.org/Books-Children_with_Starving_Brains.html
6. Pollutants and oxidative stress
7. Oxidative stress and autism:
8. Mercury content of vaccines exceed recommended limits
Reputation Of Vaccines And The People Who Defend Them
Michael F. Wagnitz
Senior Chemist, Toxicology Section, Wisconsin State Lab of Hygiene
http://pediatrics.aappublications.org/cgi/eletters/121/3/621#36839
9. Is Aluminum the New Thimerosal?
By Robert W. Sears Issue 146, January/February 2008
http://www.mothering.com/articles/growing_child/vaccines/aluminum-new-thimerosal.html
10. Vaccines, Neurodevelopment and Autism Spectrum Disorders
The Danger of Excessive Vaccination During Brain Development: The Case for a Link to Autism Spectrum Disorders
Russell L. Blaylock, M.D.
http://tinyurl.com/2mqksl
http://web.mac.com/rblaylock/Russell_Blaylock_M.D./Information/Entries/2008/3/12_Vaccines%2C_Neurodevelopment_and_Autism_Spectrum_Disorders.html
11. CDC: Vaccine Excipient & Media Summary, Part 1
http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/B/excipient-table-1.pdf
12. CDC: Vaccine Excipient & Media Summary, Part 2: Excipients Included in U.S. Vaccines, by Vaccine
http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/B/excipient-table-2.pdf
[overview of ingredients]
13. Sulfur Stories: A discussion and research group moderated by Susan Owens
http://health.groups.yahoo.com/group/sulfurstories/
From the peer-reviewed literature
14. Diet, genetic polymorphisms, detoxification, and health risks
Lampe JW.
Altern Ther Health Med. 2007 Mar-Apr;13(2):S108-11.
Modulation of detoxification enzymes is one mechanism by which diet may influence risk of cancer and other diseases. However, genetic differences in taste preference, food tolerance, nutrient absorption, and metabolism and response of target tissues all potentially influence the effect of diet on disease risk. Thus, disease prevention at the individual and population level needs to be evaluated in the context of the totality of genetic background and exposures to both causative agents and chemopreventive compounds. Polymorphisms in the detoxification enzymes that alter protein expression and/or function can modify risk in individuals exposed to the relevant substrates. Diet is a mixture of carcinogens, mutagens, and protective agents that are all metabolized by detoxification enzymes. Genotypes associated with more favorable handling of carcinogens may be associated with less favorable handling of phytochemicals. For example, glutathione S-transferases (GST) detoxify polycyclic aromatic hydrocarbons present in grilled meats. GSTs also conjugate isothiocyanates, the chemopreventive compounds found in cruciferous vegetables. Polymorphisms in the GSTM1 and GSTT1 genes result in complete lack of GSTM1-1 and GSTT1-1 proteins, respectively. In some observational studies of cancer, cruciferous vegetable intake confers greater protection in individuals with these polymorphisms; however, in other studies, the converse is observed. A recent study of sulforaphane pharmacokinetics suggests that lack of the GSTM1 enzyme is associated with more rapid excretion of sulforaphane. Many phytochemicals are also conjugated with glucuronide and sulfate moieties, and are excreted in urine and bile. Polymorphisms in UDP-glucuronosyltransferases (UGT) and sulfotransferases (SULT) may contribute to the variability in phytochemical clearance and efficacy. The effects of UGT polymorphisms on flavonoid clearance have not been examined, but UGT polymorphisms affect glucuronidation of several drugs and steroid hormones. Genetic polymorphisms in detoxification enzymes may account in part for individual variation in disease risk but have to be considered in the context of other aspects of human genetics, gut bacterial genetics, and environmental exposures.
PMID: 17405687
15. Amino acids and immune function
Li P, Yin YL, Li D, Kim SW, Wu G.
Br J Nutr. 2007 Aug;98(2):237-52. Epub 2007 Apr 3.
http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=1208236
A deficiency of dietary protein or amino acids has long been known to impair immune function and increase the susceptibility of animals and humans to infectious disease. However, only in the past 15 years have the underlying cellular and molecular mechanisms begun to unfold. Protein malnutrition reduces concentrations of most amino acids in plasma. Findings from recent studies indicate an important role for amino acids in immune responses by regulating: (1) the activation of T lymphocytes, B lymphocytes, natural killer cells and macrophages; (2) cellular redox state, gene expression and lymphocyte proliferation; and (3) the production of antibodies, cytokines and other cytotoxic substances. Increasing evidence shows that dietary supplementation of specific amino acids to animals and humans with malnutrition and infectious disease enhances the immune status, thereby reducing morbidity and mortality. Arginine, glutamine and cysteine precursors are the best prototypes. Because of a negative impact of imbalance and antagonism among amino acids on nutrient intake and utilisation, care should be exercised in developing effective strategies of enteral or parenteral provision for maximum health benefits. Such measures should be based on knowledge about the biochemistry and physiology of amino acids, their roles in immune responses, nutritional and pathological states of individuals and expected treatment outcomes. New knowledge about the metabolism of amino acids in leucocytes is critical for the development of effective means to prevent and treat immunodeficient diseases. These nutrients hold great promise in improving health and preventing infectious diseases in animals and humans.
PMID: 17403271
16. Metabolic learning in the intestine: adaptation to nutrition and luminal factors
Schmitz G, Langmann T.
Horm Metab Res. 2006 Jul;38(7):452-4.
There is increasing evidence that the magnitude and potential of intestinal nutrient absorption (sugars, fatty acids, cholesterol and triglycerides) and intestinal defense function are regulated by metabolic learning phenomena, and are influenced by dietary energy content and exercise. Metabolic overload syndromes, mainly obesity, and chronic malabsorption disorders such as inflammatory bowel disease and celiac disease have been defined as extreme phenotypes. Metabolic learning processes depend on developmental and transcriptional control systems of intestinal epithelial cell differentiation. The physiological differentiation zone of enterocytes is linked to the beta-catenin system, apolipoprotein apoA-IV and the master transcription factors Cdx2, HNF1alpha, and GATA4. In addition to these developmental regulatory transcription factors, nuclear receptors including RXR, LXR, PPAR, PXR, and CAR have been implicated in the generation of more absorptive enterocytes with a more differentiated phenotype on the one hand, and dedifferentiated cells with reduced capacity of detoxification and defense causing loss of junction control and barrier defects on the other. Large-scale analysis of gene expression profiles and identification of key pathways and master regulatory transcription factors will help dissect the role of nutritional and environmental factors as well as pharmacological intervention on mucosal homeostasis and disease, with potential applications for diagnosis and therapy.
PMID: 16933181
17. Exposures to airborne particulate matter and adverse perinatal outcomes: a biologically plausible mechanistic framework for exploring potential effect modification by nutrition
Kannan S, Misra DP, Dvonch JT, Krishnakumar A.
Environ Health Perspect. 2006 Nov;114(11):1636-42.
http://www.ehponline.org/members/2006/9081/9081.html
OBJECTIVES: The specific objectives are threefold: to describe the biologically plausible mechanistic pathways by which exposure to particulate matter (PM) may lead to the adverse perinatal outcomes of low birth weight (LBW), intrauterine growth retardation (IUGR), and preterm delivery (PTD); review the evidence showing that nutrition affects the biologic pathways; and explain the mechanisms by which nutrition may modify the impact of PM exposure on perinatal outcomes. METHODS: We propose an interdisciplinary conceptual framework that brings together maternal and infant nutrition, air pollution exposure assessment, and cardiopulmonary and perinatal epidemiology. Five possible albeit not exclusive biologic mechanisms have been put forth in the emerging environmental sciences literature and provide corollaries for the proposed framework. CONCLUSIONS: Protecting the environmental health of mothers and infants remains a top global priority. The existing literature indicates that the effects of PM on LBW, PTD, and IUGR may manifest through the cardiovascular mechanisms of oxidative stress, inflammation, coagulation, endothelial function, and hemodynamic responses. PM exposure studies relating mechanistic pathways to perinatal outcomes should consider the likelihood that biologic responses and adverse birth outcomes may be derived from both PM and non-PM sources (e.g., nutrition). In the concluding section, we present strategies for empirically testing the proposed model and developing future research efforts.
PMID: 17107846
18. Autism spectrum disorders in relation to distribution of hazardous air pollutants in the san francisco bay area
Windham GC, Zhang L, Gunier R, Croen LA, Grether JK.
Environ Health Perspect. 2006 Sep;114(9):1438-44.
http://www.ehponline.org/members/2006/9120/9120.html
OBJECTIVE: To explore possible associations between autism spectrum disorders (ASD) and environmental exposures, we linked the California autism surveillance system to estimated hazardous air pollutant (HAP) concentrations compiled by the U.S. Environmental Protection Agency. METHODS: Subjects included 284 children with ASD and 657 controls, born in 1994 in the San Francisco Bay area. We assigned exposure level by census tract of birth residence for 19 chemicals we identified as potential neurotoxicants, developmental toxicants, and/or endocrine disruptors from the 1996 HAPs database. Because concentrations of many of these were highly correlated, we combined the chemicals into mechanistic and structural groups, calculating summary index scores. We calculated ASD risk in the upper quartiles of these group scores or individual chemical concentrations compared with below the median, adjusting for demographic factors. RESULTS: The adjusted odds ratios (AORs) were elevated by 50% in the top quartile of chlorinated solvents and heavy metals [95% confidence intervals (CIs) , 1.1-2.1], but not for aromatic solvents. Adjusting for these three groups simultaneously led to decreased risks for the solvents and increased risk for metals (AORs for metals: fourth quartile = 1.7 ; 95% CI, 1.0-3.0 ; third quartile = 1.95 ; 95% CI, 1.2-3.1) . The individual compounds that contributed most to these associations included mercury, cadmium, nickel, trichloroethylene, and vinyl chloride. CONCLUSIONS: Our results suggest a potential association between autism and estimated metal concentrations, and possibly solvents, in ambient air around the birth residence, requiring confirmation and more refined exposure assessment in future studies.
PMID: 16966102
19. Environmental mercury release, special education rates, and autism disorder: an ecological study of Texas
Palmer RF, Blanchard S, Stein Z, Mandell D, Miller C.
Health Place. 2006 Jun;12(2):203-9.
The association between environmentally released mercury, special education and autism rates in Texas was investigated using data from the Texas Education Department and the United States Environmental Protection Agency. A Poisson regression analysis adjusted for school district population size, economic and demographic factors was used. There was a significant increase in the rates of special education students and autism rates associated with increases in environmentally released mercury. On average, for each 1,000 lb of environmentally released mercury, there was a 43% increase in the rate of special education services and a 61% increase in the rate of autism. The association between environmentally released mercury and special education rates were fully mediated by increased autism rates. This ecological study suggests the need for further research regarding the association between environmentally released mercury and developmental disorders such as autism. These results have implications for policy planning and cost analysis.
PMID: 16338635
20. Proximity to point sources of environmental mercury release as a predictor of autism prevalence
Palmer RF, Blanchard S, Wood R.
Health Place. 2008 Feb 12 [Epub ahead of print]
The objective of this study was to determine if proximity to sources of mercury pollution in 1998 were related to autism prevalence in 2002. Autism count data from the Texas Educational Agency and environmental mercury release data from the Environmental Protection Agency were used. We found that for every 1000 pounds of industrial release, there was a corresponding 2.6% increase in autism rates (p<.05) and a 3.7% increase associated with power plant emissions(P<.05). Distances to these sources were independent predictors after adjustment for relevant covariates. For every 10 miles from industrial or power plant sources, there was an associated decreased autism Incident Risk of 2.0% and 1.4%, respectively (p<.05). While design limitations preclude interpretation of individual risk, further investigations of environmental risks to child development issues are warranted.
PMID: 18353703
21. Developmental origins of health and disease: new insights
Hanson MA, Gluckman PD.
Basic Clin Pharmacol Toxicol. 2008 Feb;102(2):90-3.
Epidemiological and animal studies show that small changes in the developmental environment can induce phenotypic changes affecting an individual's responses to their later environment. These may alter the risk of chronic disease such as metabolic syndrome or cardiovascular disease. Recent research shows that animals exposed to such a mismatch between prenatal and postnatal environment develop obesity, reduced activity, leptin and insulin resistance, elevated blood pressure and vascular endothelial dysfunction. Epigenetic processes are involved in such effects, targeted to promoter regions of specific genes in specific tissues. Such fine control of gene expression suggests that the mechanisms have been retained through evolution through their adaptive advantage, rather than representing extreme effects of developmental disruption akin to teratogenesis. There may be adaptive advantage in a developmental cue inducing a phenotypic change in generations beyond the immediate pregnancy, and a range of data that support this concept. In animals, epigenetic effects such as DNA methylation can be passed to successive generations. Environmental toxins, including endocrine disruptors, may induce greater risk of chronic disease, even at low exposure levels, if they affect such normal developmental epigenetic processes. Appropriate interventions may have long-term multigenerational effects to reduce the risk of chronic disease.
PMID: 18226060
22. Circadian clocks: regulators of endocrine and metabolic rhythms
Hastings M, O'Neill JS, Maywood ES.
J Endocrinol. 2007 Nov;195(2):187-98.
http://joe.endocrinology-journals.org/cgi/content/full/195/2/187
Daily and seasonal rhythms in the endocrine system are co-ordinated by a hypothalamic pacemaker, the suprachiasmatic nuclei (SCN) that is synchronised to solar time by direct retinal afferents. Individual SCN neurons are circadian clocks, their intrinsic oscillator consisting of a series of interlinked autoregulatory transcriptional/post-translational feedback loops incorporating Period (Per) and Cryptochrome (Cry) genes. Mutations that alter the rate of transcription of Per and Cry genes or the stability of Per and Cry proteins affect clock speed. Molecular timekeeping in SCN neurons is synchronised and sustained by interneuronal neuropeptidergic signals. A molecular clock mechanism comparable to that of the SCN is present in most major organ systems. These tissue clocks are synchronised by endocrine, autonomic and behavioural cues that are dependent on the SCN, and in turn they drive the circadian expression of local transcriptomes, thereby co-ordinating circadian metabolism and physiology. Rhythmic glucocorticoid signalling is a prominent mediator of SCN output and internal synchroniser. The role of local SCN-synchronised clocks in controlling vital processes, including xenobiotic detoxification, cell division and nutrient metabolism, is essential to health, and disturbances to circadian timing arising from modern working schedules are becoming recognised as an increasingly relevant factor in major systemic illness. Moreover, the newly identified molecular components of circadian control systems provide novel avenues for therapeutic intervention.
PMID: 17951531
23. Environmental exposures and gene regulation in disease etiology
Edwards TM, Myers JP.
Environ Health Perspect. 2007 Sep;115(9):1264-70.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1964917&blobtype=pdf
OBJECTIVE: Health or disease is shaped for all individuals by interactions between their genes and environment. Exactly how the environment changes gene expression and how this can lead to disease are being explored in a fruitful new approach to environmental health research, representative studies of which are reviewed here. DATA SOURCES: We searched Web of Science and references of relevant publications to understand the diversity of gene regulatory mechanisms affected by environmental exposures with disease implications. DATA SYNTHESIS: Pharmaceuticals, pesticides, air pollutants, industrial chemicals, heavy metals, hormones, nutrition, and behavior can change gene expression through a broad array of gene regulatory mechanisms. Mechanisms include regulation of gene translocation, histone modifications, DNA methylation, DNA repair, transcription, RNA stability, alternative RNA splicing, protein degradation, gene copy number, and transposon activation. Furthermore, chemically induced changes in gene regulation are associated with serious and complex human diseases, including cancer, diabetes and obesity, infertility, respiratory diseases, allergies, and neurodegenerative disorders such as Parkinson and Alzheimer diseases. One of the best-studied areas of gene regulation is epigenetics, especially DNA methylation. Our examples of environmentally induced changes in DNA methylation are presented in the context of early development, when methylation patterns are initially laid down. This approach highlights the potential role for altered DNA methylation in fetal origins of adult disease and inheritance of acquired genetic change. CONCLUSIONS: The reviewed studies indicate that genetic predisposition for disease is best predicted in the context of environmental exposures. Second, the genetic mechanisms investigated in these studies offer new avenues for risk assessment research. Finally, we are likely to witness dramatic improvements in human health, and reductions in medical costs, if environmental pollution is decreased.
PMID: 17805414
24. Environmental medicine, part one: the human burden of environmental toxins and their common health effects
Crinnion WJ.
Altern Med Rev. 2000 Feb;5(1):52-63.
http://www.thorne.com/media/environmental_medicine_1.pdf
Chemical compounds ubiquitous in our food, air, and water are now found in every person. The bioaccumulation of these compounds in some individuals can lead to a variety of metabolic and systemic dysfunctions, and in some cases outright disease states. The systems most affected by these xenobiotic compounds include the immune, neurological, and endocrine systems. Toxicity in these systems can lead to immune dysfunction, autoimmunity, asthma, allergies, cancers, cognitive deficit, mood changes, neurological illnesses, changes in libido, reproductive dysfunction, and glucose dysregulation. Chemicals and their effects on these systems are reviewed in this article. Subsequent articles in this series will focus on therapeutic regimens to combat the toxic effects of these and other compounds.
PMID: 10696119
25. The detoxification enzyme systems
Liska DJ.
Altern Med Rev. 1998 Jun;3(3):187-98.
http://www.thorne.com/media/detoxificationenzymes.pdf
The human body is exposed to a wide array of xenobiotics in one s lifetime, from food components to environmental toxins to pharmaceuticals, and has developed complex enzymatic mechanisms to detoxify these substances. These mechanisms exhibit significant individual variability, and are affected by environment, lifestyle, and genetic influences. The scientific literature suggests an association between impaired detoxification and certain diseases, including cancer, Parkinson's disease, fibromyalgia, and chronic fatigue/immune dysfunction syndrome. Data regarding these hepatic detoxification enzyme systems and the body s mechanisms of regulating them suggests the ability to efficiently detoxify and remove xenobiotics can affect these and other chronic disease processes. This article reviews the myriad detoxification enzyme systems, their regulatory mechanisms, and the dietary, lifestyle, and genetic factors influencing their activities, as well as laboratory tests available to assess their functioning.
PMID: 9630736
26. Interindividual differences in phytochemical metabolism and disposition
Lampe JW, Chang JL.
Semin Cancer Biol. 2007 Oct;17(5):347-53. Epub 2007 May 13.
Many phytochemicals, the bioactive nonnutrient compounds found in plant foods, possess biologic effects associated with reduced risk of various diseases such as cancer. Genetic variation in pathways affecting absorption, metabolism, and distribution of phytochemicals is likely to influence exposure at the tissue level, thus modifying disease risk in individuals. Few studies have examined these gene-phytochemical interactions in humans. In this review, we discuss the sources of variation in metabolism and disposition of phytochemicals, and focus on two aspects of phytochemical handling that have received some attention: the impact of intestinal bacteria and genetically polymorphic phase II, conjugating enzymes.
PMID: 17588771
27. Environmental toxins and health--the health impact of pesticides
Cohen M.
Aust Fam Physician. 2007 Dec;36(12):1002-4.
BACKGROUND: Pesticides, including insecticides, herbicides and fungicides, are widely used in Australian agriculture. There is growing public concern about their impact on human health. OBJECTIVE: This article reviews the available evidence about the potential chronic health effects of pesticides, particularly relating to children and breastfeeding women, and discusses the potential role of organic food in decreasing risk. DISCUSSION: Exposure to pesticides can occur directly from occupational, agricultural and household use, and indirectly through the diet. Studies suggest that pesticides may be related to various diseases, including cancers, as well as having neurological, mental and reproductive effects. Children may be more susceptible to the effects of pesticides due to increased exposure via food and breast milk, underdeveloped detoxification pathways, and longer life expectancy in which to develop diseases with long latency periods. Some studies suggest that organic food consumption may lead to reduced pesticide exposure, however, there is a lack of direct evidence that organic food is a healthier option. Recommendations to minimise pesticide exposure include avoiding the use of pesticides at home or in the garden, limiting skin exposure to pesticides through the use of appropriate protective gear, and consuming organic food.
PMID: 18075622
28. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions
D'Amelio M et al.
Mol Psychiatry. 2005 Nov;10(11):1006-16.
Organophosphates (OPs) are routinely used as pesticides in agriculture and as insecticides within the household. Our prior work on Reelin and APOE delineated a gene-environment interactive model of autism pathogenesis, whereby genetically vulnerable individuals prenatally exposed to OPs during critical periods in neurodevelopment could undergo altered neuronal migration, resulting in an autistic syndrome. Since household use of OPs is far greater in the USA than in Italy, this model was predicted to hold validity in North America, but not in Europe. Here, we indirectly test this hypothesis by assessing linkage/association between autism and variants of the paraoxonase gene (PON1) encoding paraoxonase, the enzyme responsible for OP detoxification. Three functional single nucleotide polymorphisms, PON1 C-108T, L55M, and Q192R, were assessed in 177 Italian and 107 Caucasian-American complete trios with primary autistic probands. As predicted, Caucasian-American and not Italian families display a significant association between autism and PON1 variants less active in vitro on the OP diazinon (R192), according to case-control contrasts (Q192R: chi2=6.33, 1 df, P<0.025), transmission/disequilibrium tests (Q192R: TDT chi2=5.26, 1 df, P<0.025), family-based association tests (Q192R and L55M: FBAT Z=2.291 and 2.435 respectively, P<0.025), and haplotype-based association tests (L55/R192: HBAT Z=2.430, P<0.025). These results are consistent with our model and provide further support for the hypothesis that concurrent genetic vulnerability and environmental OP exposure may possibly contribute to autism pathogenesis in a sizable subgroup of North American individuals.
PMID: 16027737
29. Dietary Intake and Its Contribution to Longitudinal Organophosphorus Pesticide Exposure in Urban/Suburban Children
Chensheng Lu et al.
Environ Health Perspect 116:537-542 (2008).
http://www.ehponline.org/members/2008/10912/10912.pdf
Background: The widespread use of organophosphorus (OP) pesticides has led to frequent exposure in adults and children. Because such exposure may cause adverse health effects, particularly in children, the sources and patterns of exposure need to be studied further.
Objectives: We assessed young urban/suburban children's longitudinal exposure to OP pesticides in the Children's Pesticide Exposure Study (CPES) conducted in the greater Seattle, Washington, area, and used a novel study design that allowed us to determine the contribution of dietary intake to the overall OP pesticide exposure.
Methods: Twenty-three children 3-11 years of age who consumed only conventional diets were recruited for this 1-year study conducted in 2003-2004. Children switched to organic diets for 5 consecutive days in the summer and fall sampling seasons. We measured specific urinary metabolites for malathion, chlorpyrifos, and other OP pesticides in urine samples collected twice daily for a period of 7, 12, or 15 consecutive days during each of the four seasons.
Results: By substituting organic fresh fruits and vegetables for corresponding conventional food items, the median urinary metabolite concentrations were reduced to nondetected or close to nondetected levels for malathion and chlorpyrifos at the end of the 5-day organic diet intervention period in both summer and fall seasons. We also observed a seasonal effect on the OP urinary metabolite concentrations, and this seasonality corresponds to the consumption of fresh produce throughout the year.
Conclusions: The findings from this study demonstrate that dietary intake of OP pesticides represents the major source of exposure in young children.
30. Organic diets significantly lower children's dietary exposure to organophosphorus pesticides
Lu C et al.
Environ Health Perspect. 2006 Feb;114(2):260-3.
http://www.ehponline.org/members/2005/8418/8418.html
We used a novel study design to measure dietary organophosphorus pesticide exposure in a group of 23 elementary school-age children through urinary biomonitoring. We substituted most of children's conventional diets with organic food items for 5 consecutive days and collected two spot daily urine samples, first-morning and before-bedtime voids, throughout the 15-day study period. We found that the median urinary concentrations of the specific metabolites for malathion and chlorpyrifos decreased to the nondetect levels immediately after the introduction of organic diets and remained nondetectable until the conventional diets were reintroduced. The median concentrations for other organophosphorus pesticide metabolites were also lower in the organic diet consumption days; however, the detection of those metabolites was not frequent enough to show any statistical significance. In conclusion, we were able to demonstrate that an organic diet provides a dramatic and immediate protective effect against exposures to organophosphorus pesticides that are commonly used in agricultural production. We also concluded that these children were most likely exposed to these organophosphorus pesticides exclusively through their diet. To our knowledge, this is the first study to employ a longitudinal design with a dietary intervention to assess children's exposure to pesticides. It provides new and persuasive evidence of the effectiveness of this intervention.
PMID: 16451864
31. Organophosphorus pesticide exposure of urban and suburban preschool children with organic and conventional diets
Curl CL, Fenske RA, Elgethun K.
Environ Health Perspect. 2003 Mar;111(3):377-82.
http://www.ehponline.org/members/2003/5754/5754.html
We assessed organophosphorus (OP) pesticide exposure from diet by biological monitoring among Seattle, Washington, preschool children. Parents kept food diaries for 3 days before urine collection, and they distinguished organic and conventional foods based on label information. Children were then classified as having consumed either organic or conventional diets based on analysis of the diary data. Residential pesticide use was also recorded for each home. We collected 24-hr urine samples from 18 children with organic diets and 21 children with conventional diets and analyzed them for five OP pesticide metabolites. We found significantly higher median concentrations of total dimethyl alkylphosphate metabolites than total diethyl alkylphosphate metabolites (0.06 and 0.02 micro mol/L, respectively; p = 0.0001). The median total dimethyl metabolite concentration was approximately six times higher for children with conventional diets than for children with organic diets (0.17 and 0.03 micro mol/L; p = 0.0003); mean concentrations differed by a factor of nine (0.34 and 0.04 micro mol/L). We calculated dose estimates from urinary dimethyl metabolites and from agricultural pesticide use data, assuming that all exposure came from a single pesticide. The dose estimates suggest that consumption of organic fruits, vegetables, and juice can reduce children's exposure levels from above to below the U.S. Environmental Protection Agency's current guidelines, thereby shifting exposures from a range of uncertain risk to a range of negligible risk. Consumption of organic produce appears to provide a relatively simple way for parents to reduce their children's exposure to OP pesticides.
PMID: 12611667
32. Metals and neurotoxicology
Wright RO, Baccarelli A.
J Nutr. 2007 Dec;137(12):2809-13.
http://jn.nutrition.org/cgi/content/full/137/12/2809
Metals are ubiquitous and play a critical role in neurobiology. Transition metals are important because they alter the redox state of the physical environment. Biologically, transition metals catalyze redox reactions that are critical to cellular respiration, chemical detoxification, metabolism, and even neurotransmitter synthesis. Many metals are both nutrients and neurotoxicants, such as iron, zinc, copper, and manganese. Other metals, such as lead and cadmium, are metabolized similarly to these metals, particularly iron. Iron metabolism and genes that regulate iron metabolism may be the key to understanding metal toxicity. Finally, recent evidence demonstrates that early life exposures may program later life and adult disease phenotypes via processes of epigenetics. Parallel work in metals demonstrates that epigenetics may be a critical pathway by which metals produce health effects.
PMID: 18029504
33. Maternal care, the epigenome and phenotypic differences in behavior
Szyf M, Weaver I, Meaney M.
Reprod Toxicol. 2007 Jul;24(1):9-19. Epub 2007 May 10.
The genome is programmed by the epigenome, which is comprised of chromatin and a covalent modification of DNA by methylation. Epigenetic patterns are sculpted during development to shape the diversity of gene expression programs in the different cell types of the organism. The epigenome of the developing fetus is especially sensitive to maternal nutrition, and exposure to environmental toxins as well as psychological stress. It is postulated here that not only chemicals but also exposure of the young pup to social behavior, such as maternal care, could affect the epigenome. Since epigenetic programming defines the state of expression of genes, epigenetic differences could have the same consequences as genetic polymorphisms. We will propose here a mechanism linking maternal behavior and epigenetic programming and we will discuss the prospect that similar epigenetic variations generated during early life play a role in generating inter-individual differences in human behavior. We speculate that exposures to different environmental toxins, which affect the epigenetic machinery might alter long-established epigenetic programs in the brain.
PMID: 17561370
34. Metal transporters in intestine and brain: their involvement in metal-associated neurotoxicities
Bressler JP et al.
Hum Exp Toxicol. 2007 Mar;26(3):221-9.
http://het.sagepub.com/cgi/reprint/26/3/221
The transport of essential metals and other nutrients across tight membrane barriers such as the gastrointestinal tract and blood-brain barrier is mediated by specific transport mechanisms. Specific transporters take up metals at the apical surface and export them at the basolateral surface, and are involved in their intracellular distribution. Transporters for each of the major essential metals, calcium, iron and zinc, have been identified. These transporters also mediate the transport of non-essential metals across tight membrane barriers. For example, the intestinal iron transporter divalent metal transporter 1 mediates the uptake of lead and cadmium. The levels of essential metals are strictly regulated by transporters. When dietary levels of essential metals are low, levels of the corresponding transporters increase in the intestine, after which there is a greater potential for increased transport of toxic metals. In the brain, the strict regulation of metals prevents injury that potentially would result from oxidative damage induced by the essential metals iron, copper and zinc. Indeed, the oxidative damage found in neurodegenerative diseases is likely to be due to higher levels of these metals. Involvement of intracellular transporters for copper and zinc has been shown in animal models of Alzheimer's disease, raising the possibility that higher levels of iron, zinc and copper might be due to a disruption in the activity of transporters. Accordingly, exposure to toxicants that affect the activity of transporters potentially could contribute to the aetiology/progression of neurodegenerative diseases.
PMID: 17439925
35. The role of thiols, dithiols, nutritional factors and interacting ligands in the toxicology of mercury
Rooney JP.
Toxicology. 2007 May 20;234(3):145-56. Epub 2007 Mar 1.
Mercury has been a known as a toxic substance for centuries. Whilst the clinical features of acute mercury poisoning have been well described, chronic low dose exposure to mercury remains poorly characterised and its potential role in various chronic disease states remains controversial. Low molecular weight thiols, i.e. sulfhydryl containing molecules such as cysteine, are emerging as important factors in the transport and distribution of mercury throughout the body due to the phenomenon of "Molecular Mimicry" and its role in the molecular transport of mercury. Chelation agents such as the dithiols sodium 2,3-dimercaptopropanesulfate (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) are the treatments of choice for mercury toxicity. Alpha-lipoic acid (ALA), a disulfide, and its metabolite dihydrolipoic acid (DHLA), a dithiol, have also been shown to have chelation properties when used in an appropriate manner. Whilst N-acetyl-cysteine (NAC) and glutathione (GSH) have been recommended in the treatment of mercury toxicity in the past, an examination of available evidence suggests these agents may in fact be counterproductive. Zinc and selenium have also been shown to exert protective effects against mercury toxicity, most likely mediated by induction of the metal binding proteins metallothionein and selenoprotein-P. Evidence suggests however that the co-administration of selenium and dithiol chelation agents during treatment may also be counter-productive. Finally, the issue of diagnostic testing for chronic, historical or low dose mercury poisoning is considered including an analysis of the influence of ligand interactions and nutritional factors upon the accuracy of "chelation challenge" tests.
PMID: 17408840
36. Environmental factors and developmental outcomes in the lung
Kajekar R.
Pharmacol Ther. 2007 May;114(2):129-45. Epub 2007 Feb 24.
The developing lung is highly susceptible to damage from exposure to environmental toxicants particularly due to the protracted maturation of the respiratory system, extending from the embryonic phase of development in utero through to adolescence. The functional organization of the lungs requires a coordinated ontogeny of critical developmental processes that include branching morphogenesis, cellular differentiation and proliferation, alveolarization, and maturation of the pulmonary immune, vasculature, and neural systems. Therefore, exposure to environmental pollutants during crucial periods of prenatal and/or postnatal development may determine the course of lung morphogenesis and maturation. Depending on the timing of exposure and pathobiological response of the affected tissue, exposure to environmental pollutants can potentially result in long-term alterations that affect the structure and function of the respiratory system. Besides an immature respiratory system at birth, children possess unique differences in their physiology and behavioral characteristics compared to adults that are believed to augment the vulnerability of their developing lungs to perturbations by environmental toxins. Furthermore, an interaction between genetic predisposition and increased opportunity for exposure to chemical and infectious disease increase the hazards and risks for infants and children. In this article, the evidence for perturbations of lung developmental processes by key ambient pollutants (environmental tobacco smoke [ETS], ozone, and particulate matter [PM]) are discussed in terms of biological factors that are intrinsic to infants and children and that influence exposure-related lung development and respiratory outcomes.
PMID: 17408750
37. Environmental toxicity, nutrition, and gene interactions in the development of atherosclerosis
Hennig B, Oesterling E, Toborek M.
Nutr Metab Cardiovasc Dis. 2007 Feb;17(2):162-9. Epub 2006 Mar 31.
There is substantial evidence from epidemiological studies that the pathology of cardiovascular diseases is linked in part to environmental pollution. Many environmental contaminants, and especially persistent organic pollutants, are risk factors for atherosclerosis because they may exacerbate an underlying disease by altering gene expression patterns. Many mechanisms and signaling pathways associated with the pathology of "modern" diseases are similarly modulated by poor dietary habits and environmental pollutants. Many genes induced in diseases associated with vascular dysfunction such as atherosclerosis are oxidative stress-sensitive, suggesting that an imbalance in cellular oxidative stress and antioxidant status is a critical underlying factor. One of the emerging issues in modern toxicological sciences is the modification of environmental toxicity by nutrients. Evidence is emerging which suggests that antioxidant nutrients and related bioactive compounds common in fruits and vegetables protect against environmental toxic insult to the vascular endothelium by down-regulation of signaling pathways involved in inflammatory responses associated with vascular diseases such as atherosclerosis. Thus, the concept that nutrition may modify or ameliorate the toxicity of environmental chemicals may have implications for understanding the complex interaction of environmental toxicity and disease development.
PMID: 17306736
38. Developmental exposure to environmental endocrine disruptors: consequences within the ovary and on female reproductive function
Uzumcu M, Zachow R.
Reprod Toxicol. 2007 Apr-May;23(3):337-52. Epub 2006 Nov 6.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1950429&blobtype=pdf
Female reproductive function depends upon the exquisite control of ovarian steroidogenesis that enables folliculogenesis, ovulation, and pregnancy. These mechanisms are set during fetal and/or neonatal development and undergo phases of differentiation throughout pre- and post-pubescent life. Ovarian development and function are collectively regulated by a host of endogenous growth factors, cytokines, gonadotropins, and steroid hormones as well as exogenous factors such as nutrients and environmental agents. Endocrine disruptors represent one class of environmental agent that can impact female fertility by altering ovarian development and function, purportedly through estrogenic, anti-estrogenic, and/or anti-androgenic effects. This review discusses ovarian development and function and how these processes are affected by some of the known estrogenic and anti-androgenic endocrine disruptors. Recent information suggests not only that exposure to endocrine disruptors during the developmental period causes reproductive abnormalities in adult life but also that these abnormalities are transgenerational. This latter finding adds another level of importance for identifying and understanding the mechanisms of action of these agents.
PMID: 17140764
39. Human health effects from chronic arsenic poisoning--a review
Kapaj S, Peterson H, Liber K, Bhattacharya P.
J Environ Sci Health A Tox Hazard Subst Environ Eng. 2006;41(10):2399-428.
The ill effects of human exposure to arsenic (As) have recently been reevaluated by government agencies around the world. This has lead to a lowering of As guidelines in drinking water, with Canada decreasing the maximum allowable level from 50 to 25 microg/L and the U.S. from 50 to 10 microg/L. Canada is currently contemplating a further decrease to 5 microg/L. The reason for these regulatory changes is the realization that As can cause deleterious effects at lower concentrations than was previously thought. There is a strong relationship between chronic ingestion of As and deleterious human health effects and here we provide an overview of some of the major effects documented in the scientific literature. As regulatory levels of As have been decreased, an increasing number of water supplies will now require removal of As before the water can be used for human consumption. While As exposure can occur from food, air and water, all major chronic As poisonings have stemmed from water and this is usually the predominant exposure route. Exposure to As leads to an accumulation of As in tissues such as skin, hair and nails, resulting in various clinical symptoms such as hyperpigmentation and keratosis. There is also an increased risk of skin, internal organ, and lung cancers. Cardiovascular disease and neuropathy have also been linked to As consumption. Verbal IQ and long term memory can also be affected, and As can suppress hormone regulation and hormone mediated gene transcription. Increases in fetal loss and premature delivery, and decreased birth weights of infants, can occur even at low (<10 microg/L) exposure levels. Malnourished people have been shown to be more predisposed to As-related skin lesions. A large percentage of the population (30-40%) that is using As-contaminated drinking water can have elevated As levels in urine, hair and nails, while showing no noticeable clinical symptoms, such as skin lesions. It is therefore important to carry out clinical tests of As exposure. Factors combining to increase/decrease the ill effects of As include duration and magnitude of As exposure, source of As exposure, nutrition, age and general health status. Analytical determinations of As poisoning can be made by examining As levels in urine, hair and toenails. Communities and individuals relying on groundwater sources for drinking water need to measure As levels to ensure that their supplies are safe. Communities with water As levels greater than 5 microg/L should consider a program to document As levels in the population.
PMID: 17018421
40. Mitochondrial glutathione: hepatocellular survival-death switch
Garcia-Ruiz C, Fernandez-Checa JC.
J Gastroenterol Hepatol. 2006 Oct;21 Suppl 3:S3-6.
Steatohepatitis represents an advanced stage of fatty liver disease that encompasses alcoholic (ASH) and non-alcoholic steatohepatitis (NASH). The progression from steatosis to steatohepatitis is poorly understood. One of the clues to this progression is the sensitization of hepatocytes to oxidative stress and cytokine-induced cell death. Mitochondrial glutathione (mGSH), which plays a central role in the control of mitochondrial reactive oxygen species (ROS) generation, modulates the sensitivity to cell death pathways. Mitochondrial GSH depletion due to alcohol-mediated alteration in mitochondrial membrane dynamics underlies the susceptibility of hepatocytes from alcohol-fed models to tumor necrosis factor (TNF), and in nutritional and genetic models of hepatic steatosis, mGSH depletion occurs due to the enrichment of mitochondria in free cholesterol, resulting in decreased mitochondrial membrane fluidity. The signaling of TNF through its membrane receptor TNFR1 from complex I to complex II is similar in hepatocytes depleted or not depleted in mGSH, yet hepatocellular susceptibility to TNF occurs if mGSH is depleted. Thus, mGSH is a critical factor in the development of steatohepatitis through sensitization of hepatocytes to inflammatory cytokines, and understanding the homeostasis of cholesterol and its trafficking to mitochondria may be of relevance in the pathophysiology of ASH and NASH.
PMID: 16958667
41. Adequate range for sulfur-containing amino acids and biomarkers for their excess: lessons from enteral and parenteral nutrition
van de Poll MC, Dejong CH, Soeters PB.
J Nutr. 2006 Jun;136(6 Suppl):1694S-1700S.
http://jn.nutrition.org/cgi/content/full/136/6/1694S
The adequacy range of dietary requirements of specific amino acids in disease states is difficult to determine. In health, several techniques are available allowing rather precise quantification of requirements based on growth of the organism, rises in plasma concentration, or increases in the oxidation of marker amino acids during incremental administration of the amino acid under study. Requirements may not be similar in disease with regard to protein synthesis or with regard to specific functions such as scavenging of reactive oxygen species by compounds including glutathione. Requirements for this purpose can be assessed only when such a function can be measured and related to clinical outcome. There is apparent consensus concerning normal sulfur amino acid (SAA) requirements. WHO recommendations amount to 13 mg/kg per 24 h in healthy adults. This amount is roughly doubled in artificial nutrition regimens. In disease or after trauma, requirements may be altered for methionine, cysteine, and taurine. Although in specific cases of congenital enzyme deficiency, prematurity, or diminished liver function, hypermethionemia or hyperhomocysteinemia may occur, SAA supplementation can be considered safe in amounts exceeding 2-3 times the minimal recommended daily intake. Apart from some very specific indications (e.g., acetaminophen poisoning), the usefulness of SAA supplementation is not yet established. There is a growing body of data pointing out the potential importance of oxidative stress and resulting changes in redox state in numerous diseases including sepsis, chronic inflammation, cancer, AIDS/HIV, and aging. These observations warrant continued attention for the potential role of SAA supplementation. In particular, N-acetylcysteine remains promising for these conditions.
PMID: 16702341
42. The in vivo sparing of methionine by cysteine in sulfur amino acid requirements in animal models and adult humans
Ball RO, Courtney-Martin G, Pencharz PB.
J Nutr. 2006 Jun;136(6 Suppl):1682S-1693S.
http://jn.nutrition.org/cgi/content/full/136/6/1682S
Sulfur amino acid metabolism has been receiving increased attention because of the link to chronic diseases such as cardiovascular disease, Alzheimer's disease, and diabetes. In addition, the role of cysteine and optimal intakes for physiological substrates such as glutathione are currently of considerable interest in human health. Although the dietary indispensability of methionine is not in question, the ability of cysteine to substitute for a portion of its requirement has been the topic of much debate. Methionine is often the most limiting amino acid in the diets of the developing world's population because of its low concentration in cereal grains. Therefore, the ability of cysteine to substitute for methionine requirement is not just biologically interesting; it is also of considerable economic and social importance. The primary goal of this review is to discuss the available evidence on the effect of cysteine substitution for methionine to meet the total sulfur amino acid requirement in adult humans, including an assessment of the methodological features of experiments with conflicting results. Assessment of the requirement experiments for amino acids with complex metabolism such as methionine and cysteine must begin with a careful definition of requirements and what substitution means. As a result of these definitions, a set of criteria for the intakes of methionine that will allow demonstration of the substitution effect have been developed. Some recent publications are assessed using these definitions and criteria, and a possible reason for the conflicting results in the literature is proposed. An approach to estimating tolerable upper intakes is also proposed. Research on in vivo sulfur amino acid metabolism in humans is tremendously difficult, and therefore, we do not wish to be overly critical of the high-quality work of the ambitious and highly intelligent men and women who have conducted various studies. Our goal is to objectively review the data for the reader in a logical and comprehensive manner and propose methods that may avoid difficulties in future studies.
PMID: 16702340
43. Functions of sulfur-containing amino acids in lipid metabolism
Oda H.
J Nutr. 2006 Jun;136(6 Suppl):1666S-1669S.
http://jn.nutrition.org/cgi/content/full/136/6/1666S
It is known that plasma lipid levels are controlled not only by dietary fat and carbohydrate but also by dietary protein and amino acids. Although it used to be thought that the source of protein was important, it is known that amino acid composition, amino acids themselves, and peptides from digested protein are more important than the protein source. Sulfur-containing amino acids (SAAs) are recognized to be some of the most potent modulators of lipid metabolism among amino acids. It has been demonstrated that SAAs have an increasing effect on HDL (high-density lipoprotein)-cholesterol and a decreasing effect on VLDL (very low-density lipoprotein)-cholesterol. These data lead us to propose that SAAs have some beneficial functions against atherosclerotic diseases and metabolic syndrome. Relative availability of SAAs (RASAA) as well as the amount of SAAs in dietary protein would determine lipid metabolism. Therefore, we propose RASAA as a feasible index for improvement of lipid metabolism by amino acids. Although it is not clear how SAAs influence gene expression and lipid metabolism at a molecular level, SAAs change the metabolic pathway through transcriptional stimulation and posttranslational modification of regulatory proteins.
PMID: 16702337
44. Sparing of methionine requirements: evaluation of human data takes sulfur amino acids beyond protein
Fukagawa NK.
J Nutr. 2006 Jun;136(6 Suppl):1676S-1681S.
http://jn.nutrition.org/cgi/content/full/136/6/1676S
The intimate relation between amino acids and protein and nitrogen requirements is well recognized. Nutrition research has focused on the capacity of food to meet the need for nitrogen and indispensable amino acids (IAA) and led to the conclusion that the quality, not just the quantity, of protein is critical. This is especially relevant in regard to the sulfur amino acids (SAA) methionine and cysteine because of the increased understanding of their relation to chronic diseases (e.g., cardiovascular disease, dementia, cirrhosis), immunomodulation, DNA transcription, and RNA translation. Considerable effort has been expended to determine whether and to what extent cysteine can spare the requirement for the IAA methionine. In vivo studies in humans generally concur that the dietary requirement of the SAA ranges between 13 and 16 mg.kg(-1).d(-1), but how much can be met by cysteine relative to methionine remains controversial. This review examines the current status of in vivo estimates of methionine and cysteine requirements in human adults and considers needs beyond what is necessary for protein synthesis. Factors influencing the utilization of methionine and cysteine, especially those conditions that lead to toxicity on the one hand or beneficial effects on the other, are discussed. Data on alternative dietary sources of methyl groups (e.g., betaine, choline, phosphatidylcholine, S-adenosylmethionine, S-methylmethionine) or sulfur (e.g., N-acetylcysteine or L-2-oxothiazolidine-4-carboxylic acid) support a role for the SAA "beyond protein." Other pathways may influence the specific requirement for methionine and/or cysteine, especially when the person is challenged by disease, inadequate availability of food, or environmental stress.
PMID: 16702339
45. The effects of sulfur amino acid intake on immune function in humans
Grimble RF.
J Nutr. 2006 Jun;136(6 Suppl):1660S-1665S.
http://jn.nutrition.org/cgi/content/full/136/6/1660S
No direct data exist on the influence of supranormal intakes of sulfur amino acids on immune function in humans. However 3 major products of sulfur amino acids, glutathione (GSH), homocysteine (Hcy), and taurine (Tau), influence, mainly, inflammatory aspects of the immune response in vitro and in vivo. Methionine intakes above approximately 1 g/d transiently raise plasma Tau, Hcy, and GSH. Tau and GSH ameliorate inflammation. Hcy has the opposite effect. A biphasic relation, between cellular GSH and CD4+ and CD8+ numbers occurs in healthy men. How changes in sulfur amino acid intake influence this phenomenon is unknown. In animals, high Tau intakes are antiinflammatory. How immune function in humans is affected is unknown. A positive relation between plasma neopterin (a marker of a Th-1-type immune response) and Hcy indicates that Hcy may play a part in inflammatory aspects of Parkinson's disease and aging. In vitro, Hcy, at concentrations seen following consumption of approximately 6 g L-methionine/d in adults, increases the interactions among T lymphocytes, monocytes, and endothelium. Whether a similar phenomenon occurs in vivo is unknown. Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with raised plasma Hcy in young but not old subjects. The relation of this observation to immune function is unknown. The relationships among Hcy, inflammatory aspects of disease, and in vitro alterations in immune cell behavior create a cautionary note about supplementation of diets with l-methionine to raise intake above approximately 1 g/d. Studies directly linking methionine intake, genetics, plasma Hcy, Tau, and GSH and immune function are needed.
PMID: 16702336
46. Mammalian cysteine metabolism: new insights into regulation of cysteine metabolism
Stipanuk MH, Dominy JE Jr, Lee JI, Coloso RM.
J Nutr. 2006 Jun;136(6 Suppl):1652S-1659S.
http://jn.nutrition.org/cgi/content/full/136/6/1652S
The mammalian liver tightly regulates its free cysteine pool, and intracellular cysteine in rat liver is maintained between 20 and 100 nmol/g even when sulfur amino acid intakes are deficient or excessive. By keeping cysteine levels within a narrow range and by regulating the synthesis of glutathione, which serves as a reservoir of cysteine, the liver addresses both the need to have adequate cysteine to support normal metabolism and the need to keep cysteine levels below the threshold of toxicity. Cysteine catabolism is tightly regulated via regulation of cysteine dioxygenase (CDO) levels in the liver, with the turnover of CDO protein being dramatically decreased when intracellular cysteine levels increase. This occurs in response to changes in the intracellular cysteine concentration via changes in the rate of CDO ubiquitination and degradation. Glutathione synthesis also increases when intracellular cysteine levels increase as a result of increased saturation of glutamate-cysteine ligase (GCL) with cysteine, and this contributes to removal of excess cysteine. When cysteine levels drop, GCL activity increases, and the increased capacity for glutathione synthesis facilitates conservation of cysteine in the form of glutathione (although the absolute rate of glutathione synthesis still decreases because of the lack of substrate). This increase in GCL activity is dependent on up-regulation of expression of both the catalytic and modifier subunits of GCL, resulting in an increase in total catalytic subunit plus an increase in the catalytic efficiency of the enzyme. An important role of cysteine utilization for coenzyme A synthesis in maintaining cellular cysteine levels in some tissues, and a possible connection between the necessity of controlling cellular cysteine levels to regulate the rate of hydrogen sulfide production, have been suggested by recent literature and are areas that deserve further study.
PMID: 16702335
47. The sulfur-containing amino acids: an overview
Brosnan JT, Brosnan ME.
J Nutr. 2006 Jun;136(6 Suppl):1636S-1640S.
http://jn.nutrition.org/cgi/content/full/136/6/1636S
Methionine, cysteine, homocysteine, and taurine are the 4 common sulfur-containing amino acids, but only the first 2 are incorporated into proteins. Sulfur belongs to the same group in the periodic table as oxygen but is much less electronegative. This difference accounts for some of the distinctive properties of the sulfur-containing amino acids. Methionine is the initiating amino acid in the synthesis of virtually all eukaryotic proteins; N-formylmethionine serves the same function in prokaryotes. Within proteins, many of the methionine residues are buried in the hydrophobic core, but some, which are exposed, are susceptible to oxidative damage. Cysteine, by virtue of its ability to form disulfide bonds, plays a crucial role in protein structure and in protein-folding pathways. Methionine metabolism begins with its activation to S-adenosylmethionine. This is a cofactor of extraordinary versatility, playing roles in methyl group transfer, 5'-deoxyadenosyl group transfer, polyamine synthesis, ethylene synthesis in plants, and many others. In animals, the great bulk of S-adenosylmethionine is used in methylation reactions. S-Adenosylhomocysteine, which is a product of these methyltransferases, gives rise to homocysteine. Homocysteine may be remethylated to methionine or converted to cysteine by the transsulfuration pathway. Methionine may also be metabolized by a transamination pathway. This pathway, which is significant only at high methionine concentrations, produces a number of toxic endproducts. Cysteine may be converted to such important products as glutathione and taurine. Taurine is present in many tissues at higher concentrations than any of the other amino acids. It is an essential nutrient for cats.
PMID: 16702333
48. Comparative nutrition and metabolism: explication of open questions with emphasis on protein and amino acids
Baker DH.
Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):17897-902. Epub 2005 Dec 2.
http://www.pnas.org/cgi/content/full/102/50/17897
The 20th century saw numerous important discoveries in the nutritional sciences. Nonetheless, many unresolved questions still remain. Fifteen questions dealing with amino acid nutrition and metabolism are posed in this review. The first six deal with the functionality of sulfur amino acids (methionine and cysteine) and related compounds. Other unresolved problems that are discussed include priorities of use for amino acids having multiple functions; interactions among lysine, niacin and tryptophan; amino acid contributions to requirements from gut biosynthesis; the potential for gluconeogenesis to divert amino acids away from protein synthesis; the unique nutritional and metabolic idiosyncrasies of feline species, with emphasis on arginine; controversies surrounding human amino acid requirements; and the potential for maternal diet to influence sex ratio of offspring.
PMID: 16326801
49. Vitamins and respiratory disease: antioxidant micronutrients in pulmonary health and disease
Kelly FJ.
Proc Nutr Soc. 2005 Nov;64(4):510-26.
http://tinyurl.com/5n9vp3
The lungs are continually exposed to relatively-high O(2) tensions, and as such, in comparison with other organs, they represent a unique tissue for the damaging effects of oxidant attack. At particular times during a lifetime this every day challenge may increase exponentially. The first oxidative insult occurs at birth, when cells are exposed to a sudden 5-fold increase in O(2) concentration. Thereafter, the human lung, from infancy through to old age, can be subjected to deleterious oxidative events as a consequence of inhaling environmental pollutants or irritants, succumbing to several pulmonary diseases (including infant and adult respiratory distress syndromes, asthma, chronic obstructive pulmonary disease, cystic fibrosis and cancer) and receiving treatment for these diseases. The present paper will review the concept that consumption of a healthy diet and the consequent ability to establish and then maintain adequate micronutrient antioxidant concentrations in the lung throughout life, and following various oxidative insults, could prevent or reduce the incidence of oxidant-mediated respiratory diseases. Furthermore, the rationale, practicalities and complexities of boosting the antioxidant pool of the respiratory-tract lining fluid in diseases in which oxidative stress is actively involved, by direct application to the lung v. dietary modification, in order to achieve a therapeutic effect will be discussed.
PMID: 16313695
50. Polyphenols and glutathione synthesis regulation
Moskaug JØ, Carlsen H, Myhrstad MC, Blomhoff R.
Am J Clin Nutr. 2005 Jan;81(1 Suppl):277S-283S.
http://www.ajcn.org/cgi/content/full/81/1/277S
Polyphenols in food plants are a versatile group of phytochemicals with many potentially beneficial activities in terms of disease prevention. In vitro cell culture experiments have shown that polyphenols possess antioxidant properties, and it is thought that these activities account for disease-preventing effects of diets high in polyphenols. However, polyphenols may be regarded as xenobiotics by animal cells and are to some extent treated as such, ie, they interact with phase I and phase II enzyme systems. We recently showed that dietary plant polyphenols, namely, the flavonoids, modulate expression of an important enzyme in both cellular antioxidant defenses and detoxification of xenobiotics, ie, gamma-glutamylcysteine synthetase. This enzyme is rate limiting in the synthesis of the most important endogenous antioxidant in cells, glutathione. We showed in vitro that flavonoids increase expression of gamma-glutamylcysteine synthetase and, by using a unique transgenic reporter mouse strain, we showed increased expression in vivo, with a concomitant increase in the intracellular glutathione concentrations in muscles. Because glutathione is important in redox regulation of transcription factors and enzymes for signal transduction, our results suggest that polyphenol-mediated regulation of glutathione alters cellular processes. Evidently, glutathione is important in many diseases, and regulation of intracellular glutathione concentrations may be one mechanism by which diet influences disease development. The aim of this review is to discuss some of the mechanisms involved in the glutathione-mediated, endogenous, cellular antioxidant defense system, how its possible modulation by dietary polyphenols such as flavonoids may influence disease development, and how it can be studied with in vivo imaging.
PMID: 15640491
51. Total equivalent of reactive chemicals in 142 human food items is highly variable within and between major food groups
He M, Openo K, McCullough M, Jones DP.
J Nutr. 2004 May;134(5):1114-9.
http://jn.nutrition.org/cgi/content/full/134/5/1114
Many reactive electrophilic chemicals (e.g., acrylamide and hydrazine) occur in foods, and these could individually or cumulatively contribute to human cancer or other diseases. Glutathione (GSH) reacts with and detoxifies electrophilic compounds and is used physiologically to protect against a broad range of toxic and mutagenic compounds. To elucidate the distribution of reactive chemicals in foods, we added a known amount of GSH to 142 commonly consumed food items and assayed the relative amounts of reactive chemicals in terms of the amount of GSH lost during homogenization and extraction, defined quantitatively in terms of glutathione-reactive units (GRUs). Thirty-four items contained GRUs but no detectable GSH; 53 items contained both GSH and GRUs; 18 items contained no GSH or GRUs; and 37 items contained GSH but no detectable GRUs. Among the food groups, cereals, bread, milk, and milk products had relatively high GRU concentrations and low GSH concentrations; several common beverages also had high GRU concentrations and low GSH concentrations; meats and main course dishes were generally low in GRUs and high in GSH. Fruits and vegetables varied in GRU concentration, but most fresh fruits and vegetables had considerably more GSH than GRUs; exceptions were canned vegetables, which had no GSH or GRUs; fruit drinks, which had moderate levels of GRUs and no GSH; and 3 fruits (blueberries, cherries, and prunes), which had high GRU levels. The results provide a database that can be used with food frequency analyses to evaluate the possible association of health risks with the consumption of foods high in GSH-reactive chemicals.
PMID: 15113955
52. The effects of diet on DNA bulky adduct levels are strongly modified by GSTM1 genotype: a study on 634 subjects
Palli D, Masala G, Peluso M et al.
Carcinogenesis. 2004 Apr;25(4):577-84. Epub 2003 Dec 4.
http://carcin.oxfordjournals.org/cgi/content/full/25/4/577
Frequent consumption of fresh fruit and vegetables, and polymorphisms in the detoxifying enzyme glutathione S-transferase M1 (GSTM1) and other metabolic genes have been shown to modulate cancer risk at some sites. We have shown recently that DNA adducts, a reliable indicator of genotoxic damage and, possibly, of cancer risk, are modulated by plasma levels of selected micronutrients. Here we further investigate the association between DNA adduct levels and consumption of major food groups and foods, and the estimated dietary intake of nutrients, taking into account the possible modifying effect of metabolic polymorphisms, in a larger sample of 634 healthy adults enrolled in a prospective study in Italy. DNA adducts and five polymorphic metabolic genotypes (GSTM1, GSTT1, NAT2, CYP1A1 and MTHFR) were determined in peripheral leukocytes by using 32P-postlabeling technique and PCR methods. DNA bulky adducts (mean: 7.82 +/- 0.40/10(9) nt) were detected in 482/634 samples (76.0%). Overall, DNA adduct levels were significantly and inversely associated with the intake of raw leafy vegetables (P = 0.02), non-citrus fruits (P = 0.04), potassium (P = 0.01) and beta-carotene (P = 0.05). No association was evident with the five genotypes. Stratification by GSTM1 genotype showed strong inverse associations of DNA adduct levels with increasing consumption of all vegetables combined (P = 0.04), leafy vegetables (P = 0.004), raw leafy vegetables (P = 0.002) and fish (P = 0.03) among 307 GSTM1-null subjects; strong inverse associations also emerged with estimated dietary intakes of beta-carotene (P = 0.004), vitamin E (P = 0.004), niacin (P = 0.02) and potassium (P = 0.01). In contrast, no association emerged among 295 subjects with a GSTM1-wild genotype. Overall, statistically significant interactions in predicting DNA adduct levels were observed between the GSTM1-null genotype and consumption of leafy vegetables (P = 0.01), white meat (P = 0.04), and intake of vitamin C (P = 0.04), vitamin E (P = 0.05) and beta-carotene (P = 0.02). Our results suggest that the role of a diet rich in antioxidants in preventing or reducing DNA adduct formation is restricted to subjects lacking the detoxifying activity of GSTM1 isoenzyme (approximately 50% of the general population).
PMID: 14656945
53. The influence of nutrition on methyl mercury intoxication
Chapman L, Chan HM.
Environ Health Perspect. 2000 Mar;108 Suppl 1:29-56.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1637774&blobtype=pdf
This article reviews progress in the research of methyl mercury (MeHg) and nutrient interactions during the past two decades. Special emphasis is placed on the following three major areas: a) effects on kinetics, b) effects on toxicity, and c) possible mechanisms. Dietary information is not usually collected in most epidemiologic studies examining of the effects of MeHg exposure. However, inconsistency of the MeHg toxicity observed in different populations is commonly attributed to possible effects of dietary modulation. Even though the mechanisms of interaction have not been totally elucidated, research in nutritional toxicology has provided insights into the understanding of the effects of nutrients on MeHg toxicity. Some of this information can be readily incorporated into the risk assessment of MeHg in the diets of fish-eating populations. It is also clear that there is a need for more studies designed specifically to address the role of nutrition in the metabolism and detoxification of MeHg. It is also important to collect more detailed dietary information in future epidemiologic studies of MeHg exposure.
PMID: 10698722
54. Sulfur in human nutrition and applications in medicine
Parcell S.
Altern Med Rev. 2002 Feb;7(1):22-44.
http://www.thorne.com/media/sulfur.pdf
Because the role of elemental sulfur in human nutrition has not been studied extensively, it is the purpose of this article to emphasize the importance of this element in humans and discuss the therapeutic applications of sulfur compounds in medicine. Sulfur is the sixth most abundant macromineral in breast milk and the third most abundant mineral based on percentage of total body weight. The sulfur-containing amino acids (SAAs) are methionine, cysteine, cystine, homocysteine, homocystine, and taurine. Dietary SAA analysis and protein supplementation may be indicated for vegan athletes, children, or patients with HIV, because of an increased risk for SAA deficiency in these groups. Methylsulfonylmethane (MSM), a volatile component in the sulfur cycle, is another source of sulfur found in the human diet. Increases in serum sulfate may explain some of the therapeutic effects of MSM, DMSO, and glucosamine sulfate. Organic sulfur, as SAAs, can be used to increase synthesis of S-adenosylmethionine (SAMe), glutathione (GSH), taurine, and N-acetylcysteine (NAC). MSM may be effective for the treatment of allergy, pain syndromes, athletic injuries, and bladder disorders. Other sulfur compounds such as SAMe, dimethylsulfoxide (DMSO), taurine, glucosamine or chondroitin sulfate, and reduced glutathione may also have clinical applications in the treatment of a number of conditions such as depression, fibromyalgia, arthritis, interstitial cystitis, athletic injuries, congestive heart failure, diabetes, cancer, and AIDS. Dosages, mechanisms of action, and rationales for use are discussed. The low toxicological profiles of these sulfur compounds, combined with promising therapeutic effects, warrant continued human clinical trails.
PMID: 11896744
55. Cysteine metabolism and metal toxicity
Quig D.
Altern Med Rev. 1998 Aug;3(4):262-70.
http://www.thorne.com/media/cysteineandheavymetals.pdf
Chronic, low level exposure to toxic metals is an increasing global problem. The symptoms associated with the slow accumulation of toxic metals are multiple and rather nondescript, and overt expression of toxic effects may not appear until later in life. The sulfhydryl-reactive metals (mercury, cadmium, lead, arsenic) are particularly insidious and can affect a vast array of biochemical and nutritional processes. The primary mechanisms by which the sulfhydryl-reactive metals elicit their toxic effects are summarized. The pro-oxidative effects of the metals are compounded by the fact that the metals also inhibit antioxidative enzymes and deplete intracellular glutathione. The metals also have the potential to disrupt the metabolism and biological activities of many proteins due to their high affinity for free sulfhydryl groups. Cysteine has a pivotal role in inducible, endogenous detoxication mechanisms in the body, and metal exposure taxes cysteine status. The protective effects of glutathione and the metallothioneins are discussed in detail. Basic research pertaining to the transport of toxic metals into the brain is summarized, and a case is made for the use of hydrolyzed whey protein to support metal detoxification and neurological function. Metal exposure also affects essential element status, which can further decrease antioxidation and detoxification processes. Early detection and treatment of metal burden is important for successful detoxification, and optimization of nutritional status is paramount to the prevention and treatment of metal toxicity.
PMID: 9727078
56. Clinical applications of N-acetylcysteine
Kelly GS.
Altern Med Rev. 1998 Apr;3(2):114-27.
http://www.thorne.com/media/n_acetylcysteine.pdf
N-acetylcysteine (NAC), the acetylated variant of the amino acid L-cysteine, is an excellent source of sulfhydryl (SH) groups, and is converted in the body into metabolites capable of stimulating glutathione (GSH) synthesis, promoting detoxification, and acting directly as free radical scavengers. Administration of NAC has historically been as a mucolytic agent in a variety of respiratory illnesses; however, it appears to also have beneficial effects in conditions characterized by decreased GSH or oxidative stress, such as HIV infection, cancer, heart disease, and cigarette smoking. An 18-dose oral course of NAC is currently the mainstay of treatment for acetaminophen-induced hepatotoxicity. N-acetylcysteine also appears to have some clinical usefulness as a chelating agent in the treatment of acute heavy metal poisoning, both as an agent capable of protecting the liver and kidney from damage and as an intervention to enhance elimination of the metals.
PMID: 9577247
57. Attention deficit/hyperactivity disorder (ADHD) in children: rationale for its integrative management
Kidd PM.
Altern Med Rev. 2000 Oct;5(5):402-28.
http://www.thorne.com/media/attention_deficit.pdf
Attention Deficit/Hyperactivity Disorder (ADHD) is the most common behavioral disorder in children. ADHD is characterized by attention deficit, impulsivity, and sometimes overactivity ("hyperactivity"). The diagnosis is empirical, with no objective confirmation available to date from laboratory measures. ADHD begins in childhood and often persists into adulthood. The exact etiology is unknown; genetics plays a role, but major etiologic contributors also include adverse responses to food additives, intolerances to foods, sensitivities to environmental chemicals, molds, and fungi, and exposures to neurodevelopmental toxins such as heavy metals and organohalide pollutants. Thyroid hypofunction may be a common denominator linking toxic insults with ADHD symptomatologies. Abnormalities in the frontostriatal brain circuitry and possible hypofunctioning of dopaminergic pathways are apparent in ADHD, and are consistent with the benefits obtained in some instances by the use of methylphenidate (Ritalin) and other potent psychostimulants. Mounting controversy over the widespread use of methylphenidate and possible life-threatening effects from its long-term use make it imperative that alternative modalities be implemented for ADHD management. Nutrient deficiencies are common in ADHD; supplementation with minerals, the B vitamins (added in singly), omega-3 and omega-6 essential fatty acids, flavonoids, and the essential phospholipid phosphatidylserine (PS) can ameliorate ADHD symptoms. When individually managed with supplementation, dietary modification, detoxification, correction of intestinal dysbiosis, and other features of a wholistic/integrative program of management, the ADHD subject can lead a normal and productive life.
PMID: 11056411
58. Autism, an extreme challenge to integrative medicine. Part: 1: The knowledge base
Kidd PM.
Altern Med Rev. 2002 Aug;7(4):292-316.
http://www.thorne.com/media/autism.pdf
Autism, archetype of the autistic spectrum disorders (ASD), is a neurodevelopmental disorder characterized by socially aloof behavior and impairment of language and social interaction. Its prevalence has surged in recent years. Advanced functional brain imaging has confirmed pervasive neurologic involvement. Parent involvement in autism management has accelerated understanding and treatment. Often accompanied by epilepsy, cognitive deficits, or other neurologic impairment, autism manifests in the first three years of life and persists into adulthood. Its etiopathology is poorly defined but likely multifactorial with heritability playing a major role. Prenatal toxic exposures (teratogens) are consistent with autism spectrum symptomatology. Frequent vaccinations with live virus and toxic mercurial content (thimerosal) are a plausible etiologic factor. Autistic children frequently have abnormalities of sulfoxidation and sulfation that compromise liver detoxification, which may contribute to the high body burden of xenobiotics frequently found. Frequent copper-zinc imbalance implies metallothionein impairment that could compound the negative impact of sulfur metabolism impairments on detoxification and on intestinal lining integrity. Intestinal hyperpermeability manifests in autistic children as dysbiosis, food intolerances, and exorphin (opioid) intoxication, most frequently from casein and gluten. Immune system abnormalities encompass derangement of antibody production, skewing of T cell subsets, aberrant cytokine profiles, and other impairments consistent with chronic inflammation and autoimmunity. Coagulation abnormalities have been reported. Part 2 of this review will attempt to consolidate progress in integrative management of autism, aimed at improving independence and lifespan for people with the disorder.
PMID: 12197782
59. Autism, an extreme challenge to integrative medicine. Part 2: medical management
Kidd PM.
Altern Med Rev. 2002 Dec;7(6):472-99.
http://www.thorne.com/media/autism7-6.pdf
Autism and allied autistic spectrum disorders (ASD) present myriad behavioral, clinical, and biochemical abnormalities. Parental participation, advanced testing protocols, and eclectic treatment strategies have driven progress toward cure. Behavioral modification and structured education are beneficial but insufficient. Dietary restrictions, including removal of milk and other casein dairy products, wheat and other gluten sources, sugar, chocolate, preservatives, and food coloring are beneficial and prerequisite to benefit from other interventions. Individualized IgG or IgE testing can identify other troublesome foods but not non-immune mediated food sensitivities. Gastrointestinal improvement rests on controlling Candida and other parasites, and using probiotic bacteria and nutrients to correct dysbiosis and decrease gut permeability. Detoxification of mercury and other heavy metals by DMSA/DMPS chelation can have marked benefit. Documented sulfoxidation-sulfation inadequacies call for sulfur-sulfhydryl repletion and other liver p450 support. Many nutrient supplements are beneficial and well tolerated, including dimethylglycine (DMG) and a combination of pyridoxine (vitamin B6) and magnesium, both of which benefit roughly half of ASD cases. Vitamins A, B3, C, and folic acid; the minerals calcium and zinc; cod liver oil; and digestive enzymes, all offer benefit. Secretin, a triggering factor for digestion, is presently under investigation. Immune therapies (pentoxifyllin, intravenous immunoglobulin, transfer factor, and colostrum) benefit selected cases. Long-chain omega-3 fatty acids offer great promise. Current pharmaceuticals fail to benefit the primary symptoms and can have marked adverse effects. Individualized, in-depth clinical and laboratory assessments and integrative parent-physician-scientist cooperation are the keys to successful ASD management.
PMID: 12495373
60. Mercury toxicity and antioxidants: Part 1: role of glutathione and alpha-lipoic acid in the treatment of mercury toxicity
Patrick L.
Altern Med Rev. 2002 Dec;7(6):456-71.
http://www.thorne.com/media/mercury_toxicity7-6_2.pdf
Mercury exposure is the second-most common cause of toxic metal poisoning. Public health concern over mercury exposure, due to contamination of fish with methylmercury and the elemental mercury content of dental amalgams, has long been a topic of political and medical debate. Although the toxicology of mercury is complex, there is evidence for antioxidant protection in the prevention of neurological and renal damage caused by mercury toxicity. Alpha-lipoic acid, a coenzyme of pyruvate and alpha-ketoglutarate dehydrogenase, has been used in Germany as an antioxidant and approved treatment for diabetic polyneuropathy for 40 years. Research has attempted to identify the role of antioxidants, glutathione and alpha-lipoic acid specifically, in both mitigation of heavy metal toxicity and direct chelation of heavy metals. This review of the literature will assess the role of glutathione and alpha-lipoic acid in the treatment of mercury toxicity.
PMID: 12495372
61. Lead toxicity part II: the role of free radical damage and the use of antioxidants in the pathology and treatment of lead toxicity
Patrick L.
Altern Med Rev. 2006 Jun;11(2):114-27.
http://www.thorne.com/media/lead.pdf
Lead is an environmentally persistent toxin that causes neurological, hematological, gastrointestinal, reproductive, circulatory, and immunological pathologies. The propensity for lead to catalyze oxidative reactions and generate reactive oxygen species has been demonstrated in multiple studies. These reactive oxygen species (ROS) inhibit the production of sulfhydryl antioxidants, inhibit enzyme reactions impairing heme production, cause inflammation in vascular endothelial cells, damage nucleic acids and inhibit DNA repair, and initiate lipid peroxidation in cellular membranes. These wide-ranging effects of ROS generation have been postulated to be major contributors to lead-exposure related disease. Antioxidants - vitamins B6, C and E, zinc, taurine, N-acetylcysteine, and alpha-lipoic acid, either alone or in conjunction with standard pharmaceutical chelating agents - have been studied in lead-exposed animals. The evidence for their use in lead exposure, alone and in conjunction with chelating agents, is reviewed in this article.
PMID: 16813461
62. Toxic metals and antioxidants: Part II. The role of antioxidants in arsenic and cadmium toxicity
Patrick L.
Altern Med Rev. 2003 May;8(2):106-28.
http://www.thorne.com/media/toxic_metal_antioxidant8-2.pdf
Exposure to toxic metals has become an increasingly recognized source of illness worldwide. Both cadmium and arsenic are ubiquitous in the environment, and exposure through food and water as well as occupational sources can contribute to a well-defined spectrum of disease. The symptom picture of arsenic toxicity is characterized by dermal lesions, anemia, and an increased risk for cardiovascular disease, diabetes, and liver damage. Cadmium has a significant effect on renal function, and as a result alters bone metabolism, leading to osteoporosis and osteomalacia. Cadmium-induced genotoxicity also increases risk for several cancers. The mechanisms of arsenic- and cadmium-induced damage include the production of free radicals that alter mitochondrial activity and genetic information. The metabolism and excretion of these heavy metals depend on the presence of antioxidants and thiols that aid arsenic methylation and both arsenic and cadmium metallothionein-binding. S-adenosylmethionine, lipoic acid, glutathione, selenium, zinc, N-acetylcysteine (NAC), methionine, cysteine, alpha-tocopherol, and ascorbic acid have specific roles in the mitigation of heavy metal toxicity. Several antioxidants including NAC, zinc, methionine, and cysteine, when used in conjunction with standard chelating agents, can improve the mobilization and excretion of arsenic and cadmium.
PMID: 12777158
63. The role of chronic inflammation in cardiovascular disease and its regulation by nutrients
Osiecki H.
Altern Med Rev. 2004 Mar;9(1):32-53.
http://www.thorne.com/media/cardiovascular9-1.pdf
Multiple risk markers for atherosclerosis and cardiovascular disease act in a synergistic way through inflammatory pathways. This article discusses some of the key inflammatory biochemical risk markers for cardiovascular disease; in particular, the role of three basic cell types affected by these risk markers (endothelial cells, smooth muscle cells, and immune cells), the crucial role of inflammatory mediators, nitric oxide balance in cardiovascular pathology, and the use of nutrients to circumvent several of these inflammatory pathways. Most risk markers for cardiovascular disease have a pro-inflammatory component, which stimulates the release of a number of active molecules such as inflammatory mediators, reactive oxygen species, nitric oxide, and peroxynitrite from endothelial, vascular smooth muscle, and immune cells in response to injury. Nitric oxide plays a pivotal role in preventing the progression of atherosclerosis through its ability to induce vasodilation, suppress vascular smooth muscle proliferation, and reduce vascular lesion formation. Nutrients such as arginine, antioxidants (vitamins C and E, lipoic acid, glutathione), and enzyme cofactors (vitamins B2 and B3, folate, and tetrahydrobiopterin) help to elevate nitric oxide levels and may play an important role in the management of cardiovascular disease. Other dietary components such as DHA/EPA from fish oil, tocotrienols, vitamins B6 and B12, and quercetin contribute further to mitigating the inflammatory process.
PMID: 15005643
64. Glutathione, reduced (GSH). Monograph
[No authors listed]
Altern Med Rev. 2001 Dec;6(6):601-7.
http://www.thorne.com/media/glutathione_monograph.pdf
PMID: 11804544
65. Environmental medicine, part 4: pesticides - biologically persistent and ubiquitous toxins
Crinnion WJ.
Altern Med Rev. 2000 Oct;5(5):432-47.
http://www.thorne.com/media/environmental_4_pesticide.pdf
Although the use of pesticides has doubled every ten years since 1945, pest damage to crops is more prevalent now than it was then. Many pests are now pesticide resistant due to the ubiquitous presence of pesticides in our environment. Chlorinated pesticide residues are present in the air, soil, and water, with a concomitant presence in humans. Organophosphate and carbamate pesticides - the compounds comprising the bulk of current pesticide use - are carried around the globe on air currents. Municipalities, schools, churches, business offices, apartment buildings, grocery stores, and homeowners use pesticides on a regular basis. Pesticides are neurotoxins that can cause acute symptoms as well as chronic effects from repeated low-dose exposure. These compounds can also adversely affect the immune system, causing cell-mediated immune deficiency, allergy, and autoimmune states. Certain cancers are also associated with pesticide exposure. Multiple endocrine effects, which can alter reproduction and stress-handling capacity, can also be found. Limited testing is available to assess the toxic overload of these compounds, including serum pesticide levels and immune system parameters. Treatment for acute or chronic effects of these toxins includes avoidance, supplementation, and possibly cleansing.
PMID: 11056413
66. The etiologies, pathophysiology, and alternative/complementary treatment of asthma
Miller AL.
Altern Med Rev. 2001 Feb;6(1):20-47.
http://www.thorne.com/media/asthma.pdf
A chronic inflammatory disorder of the respiratory airways, asthma is characterized by bronchial airway inflammation resulting in increased mucus production and airway hyper-responsiveness. The resultant symptomatology includes episodes of wheezing, coughing, and shortness of breath. Asthma is a multifactorial disease process with genetic, allergic, environmental, infectious, emotional, and nutritional components. The underlying pathophysiology of asthma is airway inflammation. The underlying process driving and maintaining the asthmatic inflammatory process appears to be an abnormal or inadequately regulated CD4+ T-cell immune response. The T-helper 2 (Th2) subset produces cytokines including interleukin-4 (IL-4), IL-5, IL-6, IL-9, IL-10, and IL-13, which stimulate the growth, differentiation, and recruitment of mast cells, basophils, eosinophils, and B-cells, all of which are involved in humoral immunity, inflammation, and the allergic response. In asthma, this arm of the immune response is overactive, while Th1 activity, generally corresponding more to cell-mediated immunity, is dampened. It is not yet known why asthmatics have this out-of-balance immune activity, but genetics, viruses, fungi, heavy metals, nutrition, and pollution all can be contributors. A plant lipid preparation containing sterols and sterolins has been shown to dampen Th2 activity. Antioxidant nutrients, especially vitamins C and E, selenium, and zinc appear to be necessary in asthma treatment. Vitamins B6 and B12 also may be helpful. Omega-3 fatty acids from fish, the flavonoid quercetin, and botanicals Tylophora asthmatica, Boswellia serrata and Petasites hybridus address the inflammatory component. Physical modalities, including yoga, massage, biofeedback, acupuncture, and chiropractic can also be of help.
PMID: 11207455
67. Environmental medicine, part three: long-term effects of chronic low-dose mercury exposure
Crinnion WJ.
Altern Med Rev. 2000 Jun;5(3):209-23.
http://www.thorne.com/media/environmental_3_mercury.pdf
Mercury is ubiquitous in the environment, and in our mouths in the form of "silver" amalgams. Once introduced to the body through food or vapor, mercury is rapidly absorbed and accumulates in several tissues, leading to increased oxidative damage, mitochondrial dysfunction, and cell death. Mercury primarily affects neurological tissue, resulting in numerous neurological symptoms, and also affects the kidneys and the immune system. It causes increased production of free radicals and decreases the availability of antioxidants. It also has devastating effects on the glutathione content of the body, giving rise to the possibility of increased retention of other environmental toxins. Fortunately, effective tests are available to help distinguish those individuals who are excessively burdened with mercury, and to monitor them during treatment. Therapies for assisting the reduction of a mercury load include the use of 2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercato-1-propanesulfonic acid (DMPS). Additional supplementation to assist in the removal of mercury and to reduce its adverse effects is discussed.
PMID: 10869102
68. Environmental medicine, part 2 - health effects of and protection from ubiquitous airborne solvent exposure
Crinnion WJ.
Altern Med Rev. 2000 Apr;5(2):133-43.
http://www.thorne.com/media/environmental_2_solvents.pdf
Chemicals known as solvents are part of a broad class of chemicals called volatile organic compounds. These compounds are used in a variety of settings, are ubiquitous, and off-gas readily into the atmosphere. Asa result of their overuse, they can be found in detectable level virtually all samples of both indoor and outdoor air. Certain of these compounds are detectable in adipose samples of all U.S. residents Once in the body they can lead to a variety of neurological, immunological, endocrinological, genitourinary, and hematopoietic problems. Some individuals also have metabolic defects that diminish the liver's clearing capacity for these compounds. Supplementation may be of benefit to help clear these compounds from the body and to prevent adverse health effects.
PMID: 10798871
69. Insulin resistance: lifestyle and nutritional interventions
Kelly GS.
Altern Med Rev. 2000 Apr;5(2):109-32.
http://thorne.dyrectmedia.com/media/insulin_resistance.pdf
Insulin resistance appears to be a common feature and a possible contributing factor to several frequent health problems, including type 2 diabetes mellitus, polycystic ovary disease, dyslipidemia, hypertension, cardiovascular disease, sleep apnea, certain hormone-sensitive cancers, and obesity. Modifiable factors thought to contribute to insulin resistance include diet, exercise, smoking, and stress. Lifestyle intervention to address these factors appears to be a critical component of any therapeutic approach. The role of nutritional and botanical substances in the management of insulin resistance requires further elaboration; however, available information suggests some substances are capable of positively influencing insulin resistance. Minerals such as magnesium, calcium, potassium, zinc, chromium, and vanadium appear to have associations with insulin resistance or its management. Amino acids, including L-carnitine, taurine, and L-arginine, might also play a role in the reversal of insulin resistance. Other nutrients, including glutathione, coenzyme Q10, and lipoic acid, also appear to have therapeutic potential. Research on herbal medicines for the treatment of insulin resistance is limited; however, silymarin produced positive results in diabetic patients with alcoholic cirrhosis, and Inula racemosa potentiated insulin sensitivity in an animal model.
PMID: 10767668
see also: Nutrients and Immunity
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