Mechanisms linking chronic exposure to synthetic chemicals and disease

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Searching for a unifying mechanism

Searching for a unifying mechanism linking diet and chronic exposure to environmental chemicals with epigenetic changes due to DNA hypomethylation is now the basis of some exciting interdisplinary conversations in the scientific literature of the 21st century.[1] Epigenetics is the study of meiotically and mitotically induced heritable changes in gene expression through DNA methylation, histone modifications, or microRNA change without actual modification in the genomic DNA sequence.[2][3] various common environmental chemical agents, including some endocrine disruptors, can affect normal developmental epigenetic processes and hence contribute to increase the risk of chronic disease in adults.[4] Unfortunately, epigenetic changes due to these two important types of environmental factors - nutrition and chemicals - have tended to be studied separately by researchers in different fields.

Many chemical agents contaminate food chains, however, these nutrition and chemicals can no longer be separated from each other in the real world. Furthermore, these two factors can synergistically cause epigenetic changes through a common pathway.[1] Environmental epidemiology observes freely living animal and human populations and tries to both disentangle and integrate complex etiopathogenic processes that involve very diverse risk factors. It is critical to better understand how nutrition and synthetic chemicals interact.

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.[1][4]

One of the best-studied areas of gene regulation is epigenetics, especially DNA methylation. Examples of environmentally induced changes in DNA methylation are presented in the context of early fetal and neonatal 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.[4]

Glutathione depletion affects xenobiotic detoxification

It is suggested that exposure to chemicals substantially increases the need for the tripeptide glutathione n mammals to maintain its detoxification pathways.[5] At least twenty five years ago, it was known that glutathione and its transferases had evolved as a major biochemical protection mechanism deployed against reactive xenobiotics and reactive compounds produced during the metabolism of endogenous and exogenous compounds.[6] The glutathione transferases have broad and overlapping substrate specificities, which allow them to participate in the detoxification of a chemically diverse group of compounds. The most common reactions involve nucleophilic attack by glutathione on electrophiles, usually the epoxides of aromatic and aliphatic organic compounds.[7] These substrates have in common a degree of hydrophobicity and possess electrophilic centers.[7]

If the exposure to toxic chemicals is transient and succesful detoxification & excretion , chronic GSH depletion is averted.[1] However, when there is prolonged exposure to chemicals, it can eventually progress to the depletion of intracellular glutathione through consumption by conjugation.[8] Field studies on aquatic organisms living in polluted areas have reported decreased glutathione content compared with those of unpolluted areas.[9][10] Monitoring the glutathione status of marine organisms, in respect of the duration of exposure and/or the number of xenobiotic exposures, offers a example of useful ecotoxicological biomarker relevant to human communities with background exposures to mixed xenobiotic substances.[1] Experimentally at least, depleting glutathoione GSH the level of s-adenosylmethionine in cells and leads to genome-wide DNA hypomethylation.[11] In human populations living in chemical-contaminated areas, a more common mechanism for glutathione depletion may be through its consumption by way of conjugation with xenobiotics or their metabolites.[1] Depletion of intracellular glutathione can trigger adverse cellular events resulting from the loss of antioxidant defense in the cell and production of reactive oxygen/nitrogen species.[12]

DNA hypomethylation and genomic instability

Hypomethylation of the genome largely affects the intergenic and intronic [non-encoding ‘intrusive’ sequence] regions of the DNA, particularly repeat sequences and transposable elements; this is believed to result in chromosomal instability, increased mutation events and aneuploidy.[13] Regardless of tissue type, human cancers have in common both global genomic hypomethylation and focal CpG island hypo- and hyper-methylation.[8] (CpG island regions within the genome are regions of cytosine-guanine doublets in upstream sites of genes, especially house-keeping genes. Normally these CpG islands are protected from methylation and are instrumental in transcription of almost half of mammalian genes.[14])

S-adenosylmethionine is a critical methyl donor for most methyltransferases that modify DNA, RNA, histones, and other proteins.[15] The methylation cycle is very well known and frequently cited to explain relations between diet and epigenetic changes. However, even without nutritional deficiency of methyl groups, impaired synthesis of s-adenosylmethionine and perturbed DNA methylation can happen when the need for the synthesis of tripeptide molecule - glutathione - increases. Under the current situation of chronic exposure to chemical compounds, mammals need more glutathione for healthy homeostasis.[5]

[to be continued]

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Lee D.-H., D.R. Jacobs Jr and M. Porta M. Hypothesis: a Unifying Mechanism for Nutrition and Chemicals 
as Lifelong Modulators of DNA Hypomethylation. Environmental Health Perspectives 2009, Volume 117, pages 1799-1802. doi:10.1289/ehp.0900741
  2. ↑ Feinberg A.P. Phenotypic plasticity and the epigenetics of human disease. Nature 2007, Volume 447(7143), pages 433–440
  3. ↑ Ozanne S.E. and M. Constancia M Mechanisms of disease: the developmental origins of disease and the role of the epigenotype. 2007 Nat Clin Pract Endocrinol Metab 2007, Volume 3, pages 539–546
  4. ↑ 4.0 4.1 4.2 Edwards T.M. and J.P. Myers Environmental exposures and gene regulation in disease etiology. Environmental Health Perspectives 2007, Volume 115, pages 1264–1270
  5. ↑ 5.0 5.1 Jones, D.P., L.A. Brown and P. Sternberg Variability in glutathione-dependent detoxication in vivo and its relevance to detoxication of chemical mixtures. Toxicology 1995, Volume 105, pages 267–274
  6. ↑ Ketterer, B., B. Coles and D.J. Meyer The role of glutathione in detoxication. Environmental Health Perspectives 1983, Volume 49, pages 59–69
  7. ↑ 7.0 7.1 Coles, B. and B. Ketterer The role of glutathione and glutathione transferases in chemical carcinogenesis. Crit Rev Biochem Mol Biol 1990, Volume 25, pages 47–70
  8. ↑ 8.0 8.1 Franco, R., O.J. Schoneveld, A. Pappa and m.I. Panayiotidis The central role of glutathione in the pathophysiology of human diseases. Arch Physiol Biochem 2007, Volume 113, pages 234–258
  9. ↑ Cossu, C., A. Doyotte, M.C. Jacquin, M. Babut, A. Exinger and P. Vasseur Glutathione reductase, selenium-dependent glutathione peroxidase, glutathione levels, and lipid peroxidation in freshwater bivalves, Unio tumidus, as biomarkers of aquatic contamination in field studies. Ecotoxicol Environ Saf 1997, Volume 38, pages 122–131
  10. ↑ Otto, D.M. and T.W. Moon TW Phase I and II enzymes and antioxidant responses in different tissues of brown bullheads from relatively polluted and non-polluted systems. Arch Environ Contam Toxicol 1996, Volume 31, pages 141–147
  11. ↑ Lertratanangkoon, K., C.J. Wu, N. Savaraj and M.L. Thomas Alterations of DNA methylation by glutathione depletion Cancer Letters 1997, Volume 120, pages 149–156
  12. ↑ Higuchi, Y. Glutathione depletion-induced chromosomal DNA fragmentation associated with apoptosis and necrosis. J Cell Mol Med 2004, Volume 8, pages 455–464
  13. ↑ Wilson, A.S., B.E. Power and P.L. Molloy DNA hypomethylation and human diseases. Biochem Biophys Acta 2007, 1775(1), pages 138–162
  14. ↑ Redei, G.P. Encylopedic Dictionary of Genetics, Genomics and Proteomics. Second Edition 2004 Publishers:Wiley-Liss/John Wiley & Sons, Inc
  15. ↑ Loenen, W.A. S-Adenosylmethionine: jack of all trades and master of everything?. Biochem Soc Trans 2006, Volume 34, pages 330–333
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