The aryl hydrocarbon receptor (AHR), AHR nuclear translocator (ARNT) and hypoxia-inducing factor-la (HIF-l a) are members of the Per/Arnt/Sim (PAS) family of proteins that regulate transcription of target' genes in response to physiological (e.g., endogenous signals) and pathological (e.g., environmental toxicants) cues. Interestingly, PAS family members, including the AHR and ARNT, are constitutively expressed in many tissues, including those of the female reproductive system. Of relevance to this application, expression of the AHR and ARNT at uterine implantation sites (fetal and maternal interfaces), coupled with the fact that Ahr-deficient female mice have reduced litter sizes, suggest that the members of the PAS family have a biological function during pregnancy. Moreover, chemical Iigands of the AHR, such as polycyclic aromatic hydrocarbons (PAH) derived from the incomplete combustion of fossil fuels and tobacco smoke, have been implicated from both epidemiological and animal studies to have deleterious effects on pregnancy. Computer-based sequence analysis of a number of genes previously shown to be functionally required for the establishment of pregnancy and decidualization, in addition to novel genes regulated by the embryo (presented herein), has revealed that the promoters of many of these genes harbor AHR response elements. Such findings are in keeping with results from Dr. Tilly's lab using PAH-exposed ovaries in gene profiling experiments (microarrays), Which identified many of these same genes as being putative targets for the AHR. Based on these observations, it is hypothesized that PAS family members serve as key regulatory switches to coordinate the expression of specific genes in the uterus during pregnancy, both in response to the decidualization process and in response to an embryonic-derived factor(s). Of particular interest for consideration of PAS transactivation are the genes cylooxygenase-2, prostaglandin '2 synthase, peroxisome proliferator-activated receptor-? and retinoic acid X receptor a (general decidualization process), and acid sphingomyelinase and interferon stimulated gene 15 (induced by the embryo). Furthermore, the candidate also hypothesizes that environmental toxicants, such as PAH, alter the expression of these genes in a manner incompatible with the establishment or maintenance of pregnancy. As such, results from the proposed experiments will not only shed new light on the role of PAS family members and their target genes in embryo implantation and pregnancy, but also how the magnitude and temporal aspects of this expression must be precisely coordinated for pregnancy to occur.
| Takai, Yasushi; Canning, Jacqueline; Perez, Gloria I et al. (2003) Bax, caspase-2, and caspase-3 are required for ovarian follicle loss caused by 4-vinylcyclohexene diepoxide exposure of female mice in vivo. Endocrinology 144:69-74 |
