Polycyclic aromatic hydrocarbons (PAH), derived from the incomplete combustion of fossil fuels and tobacco smoke, elicit their toxic actions on tissues primarily through activation of the aryl hydrocarbon receptor (AHR). The AHR is a member of the Per/ARNT/Sim family of transcription factors that regulates 'target' gene expression in response to physiological or pathological (e.g., environmental toxicants) cues. Virtually nothing is known about the expression or function of this protein in the uterus during pregnancy. Expression of AHR at the maternal-fetal interface, coupled with the fact that AHR-deficient female mice have reduced litter sizes, suggests that this transcription factors serves a biological function during pregnancy. AHR-activating ligands, such as PAH, have been implicated from both epidemiological and animal studies to have deleterious effects on reproductive function. From our own in vivo dosing scheme, we know that PAH profoundly effect pregnancy when administered early in gestation. Gene profiling experiments using uterine decidual tissue of early pregnancy demonstrate that wholesale repression of several cell cycle genes occurs in response to PAH treatment in vivo. A corresponding decrease in decidual stromal cell mitosis was observed. Computer-based sequence analysis identified consensus AHR response elements in the promoters of many of these cell cycle genes, suggesting possible involvement of AHR as part of the gene repression mechanism. Interestingly, AHR protein expression through early gestation mirrors that of two type I histone deacetylases (HDAC) and AHR was shown by immunoprecipitation to form a physical interact with the HDAC2 in vivo. It is hypothesized that selective repression of several cell cycle regulatory genes in the uterus by PAH occurs through epigenetic measures involving an interaction between the AHR and histone deacetylases. If found to be the case, this would suggest that hazardous chemicals found essentially everywhere in our environment can epigenetically alter the expression of genes on a global scale through histone modifications. Furthermore, we believe that AHR functions as an environmental sentinel to signal cell cycle arrest when cells are exposed to environmental toxicants such as PAH.
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