Mechanisms linking chronic exposure to synthetic chemicals and disease
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. 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. 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. 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. 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.
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.
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. 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. 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. These substrates have in common a degree of hydrophobicity and possess electrophilic centers.
If the exposure to toxic chemicals is transient and succesful detoxification & excretion , chronic GSH depletion is averted. However, when there is prolonged exposure to chemicals, it can eventually progress to the depletion of intracellular glutathione through consumption by conjugation. Field studies on aquatic organisms living in polluted areas have reported decreased glutathione content compared with those of unpolluted areas. 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. Experimentally at least, depleting glutathoione GSH the level of s-adenosylmethionine in cells and leads to genome-wide DNA hypomethylation. 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. 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.
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. Regardless of tissue type, human cancers have in common both global genomic hypomethylation and focal CpG island hypo- and hyper-methylation. (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.)
S-adenosylmethionine is a critical methyl donor for most methyltransferases that modify DNA, RNA, histones, and other proteins. 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.
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