Perfluorooctanoic acid induces gene promoter hypermethylation of glutathione-S-transferase Pi in human liver L02 cells.
ABSTRACT Perfluorooctanoic acid (PFOA) is one of the most commonly used perfluorinated compounds. Being a persistent environmental pollutant, it can accumulate in human tissues via various exposure routes. PFOA may interfere in a toxic fashion on the immune system, liver, development, and endocrine systems. In utero human exposure had been associated with cord serum global DNA hypomethylation. In light of this, we investigated possible PFOA-induced DNA methylation alterations in L02 cells in order to shed light into its epigenetic-mediated mechanisms of toxicity in human liver. L02 cells were exposed to 5, 10, 25, 50 or 100 mg/L PFOA for 72h. Global DNA methylation levels were determined by LC/ESI-MS, glutathione-S-transferase Pi (GSTP) gene promoter DNA methylation was investigated by methylation-specific polymerase chain reaction (PCR) with bisulfite sequencing, and consequent mRNA expression levels were measured with quantitative real-time reverse transcriptase PCR. A dose-related increase of GSTP promoter methylation at the transcription factor specificity protein 1 (SP1) binding site was observed. However, PFOA did not significantly influence global DNA methylation; nor did it markedly alter the promoter gene methylation of p16 (cyclin-dependent kinase inhibitor 2A), ERα (estrogen receptor α) or PRB (progesterone receptor B). In addition, PFOA significantly elevated mRNA transcript levels of DNMT3A (which mediates de novo DNA methylation), Acox (lipid metabolism) and p16 (cell apoptosis). Considering the role of GSTP in detoxification, aberrant methylation may be pivotal in PFOA-mediated toxicity response via the inhibition of SP1 binding to GSTP promoter.
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ABSTRACT: The advent of modern medicine has allowed for significant advances within the fields of emergency care, surgery, and infectious disease control. Health threats that were historically responsible for immeasurable tolls on human life are now all but eradicated within certain populations, specifically those that enjoy higher degrees of socio-economic status and access to healthcare. However, modernization and its resulting lifestyle trends have ushered in a new era of chronic illness; one in which an unprecedented number of people are estimated to contract cancer and other inflammatory diseases. Here, we explore the idea that homeostasis has been redefined within just a few generations, and that diseases such as colorectal cancer are the result of fluctuating physiological and molecular imbalances. Phytochemical-deprived, pro-inflammatory diets combined with low-dose exposures to environmental toxins, including bisphenol-A (BPA) and other endocrine disruptors, are now linked to increasing incidences of cancer in westernized societies and developing countries. There is recent evidence that disease determinants are likely set in utero and further perpetuated into adulthood dependent upon the innate and environmentally acquired phenotype unique to each individual. In order to address a disease as multi-factorial, case-specific, and remarkably adaptive as cancer, research must focus on its root causes in order to elucidate the molecular mechanisms by which they can be prevented or counteracted via plant-derived compounds such as epigallocatechin-3-gallate (EGCG) and resveratrol. The significant role of epigenetics in the regulation of these complex processes is emphasized here to form a comprehensive view of the dynamic interactions that influence modern-day carcinogenesis, and how sensibly restoring homeostatic balance may be the key to the cancer riddle.Frontiers in Oncology 01/2012; 2:57.
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ABSTRACT: Epidemiological studies have consistently supported the notion that environmental and/or dietary factors play a central role in the aetiology of cancers of the breast and prostate. However, for more than five decades investigators have failed to identify a single cause-and-effect factor, which could be implicated; identification of a causative entity would allow the implementation of an intervention strategy in at-risk populations. This suggests a more complex pathoaetiology for these cancer sites, compared to others. When one examines the increases or decreases in incidence of specific cancers amongst migrant populations, it is notable that disease arising in colon or stomach requires one or at most two generations to exhibit a change in incidence to match that of high-incidence regions, whereas for breast or prostate cancer, at least three generations are required. This generational threshold could suggest a requirement for nonmutation-driven epigenetic alterations in the F0/F1 generations (parental/offspring adopting a more westernized lifestyle), which then predisposes the inherited genome of subsequent generations to mutagenic/genotoxic alterations leading to the development of sporadic cancer in these target sites. As such, individual susceptibility to carcinogen insult would not be based per se on polymorphisms in activating/detoxifying/repair enzymes, but on elevated accessibility of crucial target genes (e.g., oncogenes, tumour suppressor genes) or hotspots therein to mutation events. This could be termed a genomic susceptibility organizational structure (SOS). Several exposures including alcohol and heavy metals are epigens (i.e., modifiers of the epigenome), whereas others are mutagenic/genotoxic, for example, heterocyclic aromatic amines; humans are continuously and variously exposed to mixtures of these agents. Within such a transgenerational multistage model of cancer development, determining the interaction between epigenetic modification to generate a genomic SOS and genotoxic insult will facilitate a new level of understanding in the aetiology of cancer.ISRN oncology. 01/2013; 2013:624794.