Endocrine disrupting compounds (EDC) are hormonally active, synthetic or natural chemicals that interfere with normal functioning of the endocrine system, most notably the reproductive endocrine axis. Concern about EDC has mainly been fueled by studies that point to likely effects of EDC exposure on humans including dramatic increases in estrogen sensitive cancers, decline in human sperm quality and quantity, a notable rise in endometriosis, and early puberty in women. Because of the universal and crucial role estradiol plays in reproduction and other biologic processes, estrogenic pollutants in the environment are of particular concern. Given that sex steroids play a crucial role in organ differentiation during development, it is reasonable to expect in utero exposure to exogenous steroid mimics may alter the developmental trajectory of the fetus culminating in adult reproductive dysfunction. Our preliminary studies using sheep as a model revealed that prenatal exposure to the plasticizer bisphenol A (BPA), an environmentally relevant EDC, at levels approaching that found in human maternal blood and amniotic fluids, resulted in low birth weight female offspring, early postnatal hypergonadotropism, and cycle defects manifested as severe dampening of the LH surge. In this proposal, we will test the hypothesis that prenatal exposure to BPA, an environmental estrogen mimic, at levels similar to what human fetuses are exposed to, will disrupt adult reproductive function by disrupting the mechanisms controlling postnatal neuroendocrine feedback controls of GnRH/LH secretion and ovarian sensitivity to gonadotropins. Further, prenatal exposure to BPA will exacerbate postnatal reproductive susceptibility to steroid exposure and culminate in reproductive failure.
Three Specific Aims will test these hypotheses.
In Specific Aim 1, we will determine if unconjugated BPA in the maternal circulation reaches the fetus and at levels seen by the human fetus disrupt adult reproductive function.
In Specific Aim 2, we will determine if prenatal BPA effect is mediated at the neuroendocrine or ovarian level and involves disruption of the mechanisms controlling postnatal neuroendocrine feedback controls of GnRH/LH secretion and/or ovarian sensitivity to gonadotropins.
In Specific Aim 3, we will determine if prenatal exposure to BPA exacerbates reproductive susceptibility to postnatal estradiol exposure culminating in reproductive failure. The proposal targets key elements of strategic plans that emanated from workshops convened by the NICHD in 2000-01 by focusing on three targeted areas: fetal antecedents of disease, reproductive health for the 21st century, and developmental biology. The findings will be relevant to research on fetal origin of infertility and the threat estrogenic environmental disruptors at current exposure levels pose to human health.
Endocrine disrupting compounds (EDC) are hormonally active, synthetic or natural chemicals that interfere with normal functioning of the endocrine system, most notably the reproductive endocrine axis. Because of the universal and crucial role estradiol plays in reproduction and other biologic processes, estrogenic EDCs in the environment are of particular concern. This proposal will determine the mechanisms by which fetal exposure to bisphenol-A, an environmental estrogenic EDC, at levels similar to what human fetuses are exposed to will disrupt reproductive function in the female and if such effects are exaggerated with continued exposure to estrogenic compounds. The findings will be of relevance to the threat estrogenic environmental disruptors pose at current exposure levels to reproductive health.
|Padmanabhan, V; Veiga-Lopez, A (2014) Reproduction Symposium: developmental programming of reproductive and metabolic health. J Anim Sci 92:3199-210|
|Delaney, Angela; Padmanabhan, Vasantha; Rezvani, Geoffrey et al. (2014) Evolutionary conservation and modulation of a juvenile growth-regulating genetic program. J Mol Endocrinol 52:269-77|
|Veiga-Lopez, A; Beckett, E M; Abi Salloum, B et al. (2014) Developmental programming: prenatal BPA treatment disrupts timing of LH surge and ovarian follicular wave dynamics in adult sheep. Toxicol Appl Pharmacol 279:119-28|
|Peretz, Jackye; Vrooman, Lisa; Ricke, William A et al. (2014) Bisphenol a and reproductive health: update of experimental and human evidence, 2007-2013. Environ Health Perspect 122:775-86|
|Veiga-Lopez, Almudena; Luense, Lacey J; Christenson, Lane K et al. (2013) Developmental programming: gestational bisphenol-A treatment alters trajectory of fetal ovarian gene expression. Endocrinology 154:1873-84|
|Abi Salloum, Bachir; Steckler, Teresa L; Herkimer, Carol et al. (2013) Developmental programming: impact of prenatal exposure to bisphenol-A and methoxychlor on steroid feedbacks in sheep. Toxicol Appl Pharmacol 268:300-8|
|Vandenberg, Laura N; Chahoud, Ibrahim; Heindel, Jerrold J et al. (2010) Urinary, circulating, and tissue biomonitoring studies indicate widespread exposure to bisphenol A. Environ Health Perspect 118:1055-70|
|Padmanabhan, V; Sarma, H N; Savabieasfahani, M et al. (2010) Developmental reprogramming of reproductive and metabolic dysfunction in sheep: native steroids vs. environmental steroid receptor modulators. Int J Androl 33:394-404|
|Mahoney, Megan M; Padmanabhan, Vasantha (2010) Developmental programming: impact of fetal exposure to endocrine-disrupting chemicals on gonadotropin-releasing hormone and estrogen receptor mRNA in sheep hypothalamus. Toxicol Appl Pharmacol 247:98-104|