The aryl hydrocarbon receptor signaling pathway and adverse reproductive outcomes
Reproductive senescence or menopause in women occurs when a female’s reproductive capability is terminated naturally by aging of the body or terminated abnormally because of factors such as exposure to environmental chemicals. For millions of women, the menopausal transition is accompanied by various debilitating symptoms including hot flashes and sleep disturbances. These symptoms may persist even years after they have started, leading to disrupted normal daily functioning. Previous studies have reported that race/ethnicity, body mass index, smoking status, and low estradiol levels may increase the risk of experiencing these debilitating menopausal symptoms. However, these risk factors do not fully explain why women have hot flashes and sleep disturbances and why these symptoms vary between and within women. Therefore, the first goal of my dissertation work was to better understand the role of the aryl hydrocarbon receptor (AHR) signaling pathway and the circadian locomotor output cycles kaput (CLOCK) gene in experiencing adverse reproductive outcomes during the transition into reproductive senescence. Specifically, I examined the associations between selected genetic polymorphisms in the AHR signaling pathway and menopausal hot flashes and I examined the associations between selected polymorphisms in the AHR signaling pathway, CLOCK, and sleep disturbances. To conduct this part of my doctoral work, I compared selected single nucleotide polymorphisms in the AHR signaling pathway and CLOCK, and sex steroid hormone levels in blood and serum samples from women (n=639) with and without hot flashes or sleep disturbances, enrolled in a midlife women’s health study. The results from my studies suggest that: 1) only CYP1B1 is associated with menopausal hot flashes via pathways that may involve changes in serum estradiol concentrations; and 2) AHRR and CLOCK may play roles in decreasing the risk of experiencing insomnia during the menopausal transition. Previous studies indicate that environmental chemicals can accelerate timing to reproductive senescence by directly targeting ovarian follicles. Thus, in my dissertation work, I tested the hypothesis that various doses of bisphenol A (BPA) inhibit growth and reduce estradiol biosynthesis in isolated mouse antral follicles. I also tested the hypothesis that the toxic effects of BPA are mediated via the AHR signaling pathway. To test these hypotheses, I cultured mouse antral follicles with various doses of BPA (0.001-100 μg/ml) for up to 96 hours, while examining their growth every 24 hours. Expression levels of selected genes in the AHR signaling pathway and estradiol levels were measured at the end of the cultures. To further examine if the AHR is involved in mediating BPA toxic effects, I compared the ability of BPA to inhibit follicle growth and estradiol synthesis in follicles isolated from wild-type and Ahr global knock-out mice. Collectively, my data indicate that BPA at 25 μg/ml or higher inhibits follicle growth. Deletion of the Ahr only partially restores follicular growth following treatment with BPA 25 μg/ml. Lastly, BPA exposure at doses equal or higher than 10 μg/ml decreases estradiol synthesis independent of the AHR signaling pathway. Overall, the findings from my doctoral work point toward a novel involvement of the AHR signaling pathway in various aspects of reproductive senescence and ovarian damage.
aryl hydrocarbon receptor (AHR), hot flashes, sleep disturbances, single nucleotide polymorphism (SNP), bisphenol (BPA), ovary, toxicology
University of Illinois - Urbana-Champaign
Networked Digital Library of Theses and Dissertations
University of Illinois at Urbana-Champaign