Bisphenol-A and Reproductive Dysfunction

Summary

Principal Investigator: Vasantha Padmanabhan
Abstract: 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. PUBLIC HEALTH RELEVANCE: 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.
Funding Period: 2009-02-11 - 2014-11-30
more information: NIH RePORT

Top Publications

  1. pmc Developmental reprogramming of reproductive and metabolic dysfunction in sheep: native steroids vs. environmental steroid receptor modulators
    V Padmanabhan
    Department of Pediatrics and the Reproductive Sciences Program, The University of Michigan, Ann Arbor, MI48109, USA
    Int J Androl 33:394-404. 2010
  2. pmc Urinary, circulating, and tissue biomonitoring studies indicate widespread exposure to bisphenol A
    Laura N Vandenberg
    Tufts Center for Regenerative and Developmental Biology, Tufts University, Medford, Massachusetts, USA
    Environ Health Perspect 118:1055-70. 2010
  3. pmc Developmental programming: impact of fetal exposure to endocrine-disrupting chemicals on gonadotropin-releasing hormone and estrogen receptor mRNA in sheep hypothalamus
    Megan M Mahoney
    Veterinary Biosciences and Neuroscience Program, University of Illinois, 2001 S Lincoln Ave, Urbana, IL 61802, USA
    Toxicol Appl Pharmacol 247:98-104. 2010
  4. pmc Developmental programming: impact of prenatal exposure to bisphenol-A and methoxychlor on steroid feedbacks in sheep
    Bachir Abi Salloum
    Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA
    Toxicol Appl Pharmacol 268:300-8. 2013
  5. pmc Developmental programming: gestational bisphenol-A treatment alters trajectory of fetal ovarian gene expression
    Almudena Veiga-Lopez
    Department of Pediatrics and Reproductive Sciences Program, University of Michigan, 300 North Ingalls Building, Room 1138, Ann Arbor, Michigan 48109 5404, USA
    Endocrinology 154:1873-84. 2013
  6. pmc Evolutionary conservation and modulation of a juvenile growth-regulating genetic program
    Angela Delaney
    Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development Microarray Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, MSC 1103 Building 10, Room 1 3330, Bethesda, Maryland 20892, USA Department of Pediatrics and the Reproductive Sciences Program, The University of Michigan, Ann Arbor, Michigan, USA
    J Mol Endocrinol 52:269-77. 2014

Research Grants

  1. Prenatal Programming of Reproductive Health and Disease
    Vasantha Padmanabhan; Fiscal Year: 2013

Detail Information

Publications6

  1. pmc Developmental reprogramming of reproductive and metabolic dysfunction in sheep: native steroids vs. environmental steroid receptor modulators
    V Padmanabhan
    Department of Pediatrics and the Reproductive Sciences Program, The University of Michigan, Ann Arbor, MI48109, USA
    Int J Androl 33:394-404. 2010
    ..These findings provide evidence in support of developmental origin of adult reproductive and metabolic diseases and highlight the risk posed by exposure to environmental endocrine disrupting chemicals...
  2. pmc Urinary, circulating, and tissue biomonitoring studies indicate widespread exposure to bisphenol A
    Laura N Vandenberg
    Tufts Center for Regenerative and Developmental Biology, Tufts University, Medford, Massachusetts, USA
    Environ Health Perspect 118:1055-70. 2010
    ..Thus, there are concerns that the amount of BPA to which humans are exposed may cause adverse health effects. Importantly, results from a large number of biomonitoring studies are at odds with the results from two toxicokinetic studies...
  3. pmc Developmental programming: impact of fetal exposure to endocrine-disrupting chemicals on gonadotropin-releasing hormone and estrogen receptor mRNA in sheep hypothalamus
    Megan M Mahoney
    Veterinary Biosciences and Neuroscience Program, University of Illinois, 2001 S Lincoln Ave, Urbana, IL 61802, USA
    Toxicol Appl Pharmacol 247:98-104. 2010
    ..These findings provide support that prenatal exposure to EDCs alters the neural developmental trajectory leading to long-term reproductive consequences in the adult female...
  4. pmc Developmental programming: impact of prenatal exposure to bisphenol-A and methoxychlor on steroid feedbacks in sheep
    Bachir Abi Salloum
    Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA
    Toxicol Appl Pharmacol 268:300-8. 2013
    ..These findings suggest that the postpubertal reproductive defects seen in these animals may have stemmed from ovarian defects and the steroidal signals emanating from them...
  5. pmc Developmental programming: gestational bisphenol-A treatment alters trajectory of fetal ovarian gene expression
    Almudena Veiga-Lopez
    Department of Pediatrics and Reproductive Sciences Program, University of Michigan, 300 North Ingalls Building, Room 1138, Ann Arbor, Michigan 48109 5404, USA
    Endocrinology 154:1873-84. 2013
    ....
  6. pmc Evolutionary conservation and modulation of a juvenile growth-regulating genetic program
    Angela Delaney
    Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development Microarray Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, MSC 1103 Building 10, Room 1 3330, Bethesda, Maryland 20892, USA Department of Pediatrics and the Reproductive Sciences Program, The University of Michigan, Ann Arbor, Michigan, USA
    J Mol Endocrinol 52:269-77. 2014
    ..These findings support the hypothesis that a growth-regulating genetic program is conserved among mammalian species but that its pace is modulated to allow more prolonged growth and therefore greater adult body size in larger mammals. ..

Research Grants30

  1. Prenatal Programming of Reproductive Health and Disease
    Vasantha Padmanabhan; Fiscal Year: 2013
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