AhR and reproductive aging

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DESCRIPTION (provided by applicant): The aryl hydrocarbon receptor (AhR) is an orphan nuclear receptor and a central mediator of the effects of an entire class of environmental toxicants. The AhR has an undefined role in normal and disrupted embryogenesis as well. Reproductive senescence is accelerated by 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD, dioxin), the specific and potent AhR ligand, at environmentally relevant exposures and one consequence is a decline in oocyte and subsequent embryo quality. As women increasingly delay attempts at pregnancy into their 30s and beyond, any acceleration of reproductive aging has dire consequences for the possibility of successful pregnancy and the risk of birth defects. Furthermore, early reproductive senescence in women is associated with decreased lifespan and quality of life. Although the effects of AhR ligands on oocyte numbers have been studied extensively, little is known about the AhR, oocyte quality and subsequent organization of the early embryo. In our preliminary work, we have identified early chromosomal and cytoskeletal defects that may be pathognomonic for exposure of oocytes and embryos to AhR ligands such as dioxins; this can explain the decreased fertility resulting from chronic exposure with age. The objective of this project is to identify checkpoints of oocyte development and early embryogenesis that are regulated by AhR ligands. Our central hypothesis is that environmental exposure to AhR ligands reinforces the decline in oocyte and embryo quality with age. This work, once completed, promises new insights to prevent the loss of fertility in polluted environments and slow the loss of fertility with age. The research team will achieve these experimental goals through the following specific aims: Specific Aim 1: Determine the effect of defined AhR activation on critical periods of oocyte maturation and early embryogenesis in vitro. This aim encompasses the most detailed investigation into the impact of AhR activation or antagonism on the loss of oocyte and embryo quality to date. Endpoints include embryonic morphology, cytoskeleton and chromatin and its epigenetic modulation in oocytes and embryo. Specific Aim 2: Determine the impact of chronic, environmentally relevant AhR activation and antagonism on oocyte and embryo quality during normal and accelerated reproductive senescence. Oocytes and embryos from young and middle aged rats will be assessed for morphological and cytoskeletal conformation and chromatin remodeling and epigenetic modification and imprinting from oogenesis to early embryogenesis. This will provide insight into decreased oocyte and embryo quality and fertility with age and the importance of the AhR pathway in the aging ovary and oocyte. This work is novel through use of realistic exposures to AhR agonists and a focus on subtle measures oocyte and embryo quality and epigenetics. These studies explore a novel diagnostic indicator of compromised oocyte and embryo quality due to exposure to toxic AhR ligands. This project will provide crucial knowledge for the identification and prevention of infertility and birth defects due to the AhR pathway in older mothers. Hundreds of manmade compounds including dioxins, polychlorinated biphenyls and carcinogens in cigarette smoke act on cells through the aryl hydrocarbon receptor (AhR) pathway. We have recently reported detrimental effects of AhR activation on aging of the ovary and a number of defects in eggs and embryos from females exposed to AhR ligands. This project will provide crucial knowledge for the identification and prevention of infertility and birth defects due to the AhR pathway in older mothers.