Six billion pounds of bisphenol A (BPA) is produced throughout the world each year and is continually leaching into our food, drinks and environment. Consequently, 93% of Americans carry biologically significant levels of this compound. We are now learning that acute exposures likely compromise adult reproductive health and success. As evidence, men with occupational exposure to BPA suffer with reduced sperm counts and exposure to women is associated with repeated miscarriage. We do not currently understand the biological connections between BPA exposure and reproductive biology. However, given the latest exposure statistics and apparent acute impact of BPA on reproductive health, it is imperative that we determine these mechanisms. The overall objective of this proposal is to investigate the acute biological impact of BPA exposure on adult reproductive neuroendocrine function. Specifically, we aim to study how BPA influences the release of gonadotropin releasing hormone (GnRH), a central mediator of reproductive biology. Specialized hypothalamic neurons release GnRH in nearly metronomic pulses to control pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretions. Typical release patterns govern gamete maturation, ovulation, steroid hormone secretion and maintenance of luteal function. Consequently, disruption of GnRH release has tremendous consequences on reproductive physiology. Pulsatile GnRH release is influenced by inter-related signaling mechanisms, which include steroid hormones (e.g. estradiol), neurotransmitters (e.g. GABA and glutamate) and neuropeptides (e.g. kisspeptin). The known biological activities of BPA, such as steroid receptor binding and modulation of neurotransmitter (glutamate) activity, support the hypothesis that BPA exerts acute effects on reproductive function by altering GnRH pulsatility. In fact, our preliminary work indicates that BPA directly influences GnRH release and neuronal activity. However, to better support this hypothesis, using an in vivo microdialysis approach, we propose to address the following aims: 1) determine the dynamics of GnRH release during BPA exposure, 2) examine the hypothesis that BPA exposure alters signaling mechanisms that control GnRH release and 3) examine the hypothesis that baseline physiologic differences (i.e. steroid hormone profile) influence the effects of BPA on GnRH release.
Through environmental exposures, 93% of Americans carry detectable levels of Bisphenol A (BPA). Recent evidence shows BPA interferes with adult reproductive health (e.g. men with occupational exposure to BPA suffer with reduced sperm counts, exposure to women is associated with repeated miscarriage, and female laboratory animals exposed to this compound are less successful in conceiving). However, we do not know with certainty how BPA exerts these effects. We aim to understand how exposures of BPA to the hypothalamus influence release of gonadotropin releasing hormone (GnRH), a central mediator of reproductive biology. As GnRH agonists and antagonists have become standard clinical treatments for precocious and delayed puberty in children, and infertility in adult human patients, this work may have direct clinical application for management of BPA exposure.
|Kurian, Joseph R; Louis, Somaja; Keen, Kim L et al. (2016) The Methylcytosine Dioxygenase Ten-Eleven Translocase-2 (tet2) Enables Elevated GnRH Gene Expression and Maintenance of Male Reproductive Function. Endocrinology 157:3588-603|
|Kurian, Joseph R; Keen, Kim L; Kenealy, Brian P et al. (2015) Acute Influences of Bisphenol A Exposure on Hypothalamic Release of Gonadotropin-Releasing Hormone and Kisspeptin in Female Rhesus Monkeys. Endocrinology 156:2563-70|