Negative Effects of Bisphenol A on the Monkey CNS

Summary

Principal Investigator: C Leranth
Abstract: [unreadable] DESCRIPTION (provided by applicant): Bisphenol A (BPA) is an estrogenic chemical that is widely used in the manufacture of policarbonate plastics and epoxy resins. Because BPA leaches out of plastic food and drink containers, including baby bottles, as well as the BPA-containing dental prostheses and sealants, considerable potential exists for human exposure to this compound. We have demonstrated for the first time that treatment of ovariectomized female rats with BPA dose- dependently inhibits both the hippocampal synaptoplastic and the positive cognitive effects of estrogen administration. These effects of BPA can already be observed at a dose of 40 [unreadable]g/kg that is below the current U.S. Environmental Protection Agency reference daily limit for human exposure. Moreover, several publications have also raised the same worrysome issue that low- dose BPA might compromise normal sexual development and function of the brain. However, the majority of these studies, including our own, investigating BPA effects on the brain have been performed in rats. Hence, the implications of these alarming results to human health are intensively debated. Therefore, we propose to reveal the effect of BPA on estrogen-induced spine synapse formation in the brain of nonhuman primates, which will provide more relevance to human health. There is ample evidence that remodeling of synaptic contacts might mediate the beneficial effects of estrogen on both hippocampus- and prefrontal cortex-dependent executive functioning, particularly working memory. Thus, we hypothesize that BPA exposure may interfere with estrogen-induced synaptogenesis in the hippocampal CA1 and CA3 areas and dentate gyrus, as well as in the prefrontal cortex of nonhuman primates. This hypothesis will be tested using ovariectomized, adult young vervet monkeys that will be treated with vehicle- (controls), estrogen-, BPA- and estrogen+BPA. Furthermore, regarding the receptor target(s) of BPA, we will test whether BPA interferes with the positive effects of estrogen on the hypothalamic expression of oxytocin (O) and the progestin receptor (PR). Neurons producing PR and O contain different estrogen receptors, ERa and ER[unreadable], respectively. Light and electron microscopic unbiased stereological calculations will be used to determine the total number of spine synapses in the hippocampus and prefrontal cortex, and the number of hypothalamic PR- containing and O-producing neurons. Bisphenol A (BPA) is an estrogenic chemical that is widely used in the manufacture of policarbonate plastics and epoxy resins. Because BPA leaches out of plastic food and drink containers, including baby bottles, as well as the BPA-containing dental prostheses and sealants, considerable potential exists for human exposure to this compound. We have demonstrated for the first time that treatment of ovariectomized female rats with 40 [unreadable]g/kg BPA, which is below the the current U.S. Environmental Protection Agency reference daily limit for human exposure, inhibits both the hippocampal synaptoplastic and the positive cognitive effects of estrogen administration. This study, has been performed in rats. Thus, the implications of these alarming results to human health are intensively debated by the chemical industry. Therefore, we propose to reveal the effect of BPA on estrogen-induced spine synapse formation in the brain of non-human primates, which will provide more relevance to human health. [unreadable] [unreadable] [unreadable]
Funding Period: 2007-07-01 - 2010-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Calretinin expression in hilar mossy cells of the hippocampal dentate gyrus of nonhuman primates and humans
    László Seress
    Central Electron Microscopic Laboratory, Faculty of Medicine, University of Pecs, Pecs, Hungary
    Hippocampus 18:425-34. 2008
  2. pmc Bisphenol A prevents the synaptogenic response to estradiol in hippocampus and prefrontal cortex of ovariectomized nonhuman primates
    Csaba Leranth
    Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA
    Proc Natl Acad Sci U S A 105:14187-91. 2008
  3. pmc Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression
    Tibor Hajszan
    Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Biol Psychiatry 65:392-400. 2009
  4. pmc Effects of estradiol on learned helplessness and associated remodeling of hippocampal spine synapses in female rats
    Tibor Hajszan
    Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Biol Psychiatry 67:168-74. 2010
  5. pmc Bisphenol A interferes with synaptic remodeling
    Tibor Hajszan
    Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA
    Front Neuroendocrinol 31:519-30. 2010

Detail Information

Publications5

  1. ncbi Calretinin expression in hilar mossy cells of the hippocampal dentate gyrus of nonhuman primates and humans
    László Seress
    Central Electron Microscopic Laboratory, Faculty of Medicine, University of Pecs, Pecs, Hungary
    Hippocampus 18:425-34. 2008
    ..Taken together, mossy cells of nonhuman primates and humans exhibit different expression pattern for calretinin whereas they show similarities in neurochemical content, such as the cocaine and amphetamine-related transcript peptide...
  2. pmc Bisphenol A prevents the synaptogenic response to estradiol in hippocampus and prefrontal cortex of ovariectomized nonhuman primates
    Csaba Leranth
    Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA
    Proc Natl Acad Sci U S A 105:14187-91. 2008
    ..This study is the first to demonstrate an adverse effect of BPA on the brain in a nonhuman primate model and further amplifies concerns about the widespread use of BPA in medical equipment, and in food preparation and storage...
  3. pmc Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression
    Tibor Hajszan
    Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Biol Psychiatry 65:392-400. 2009
    ....
  4. pmc Effects of estradiol on learned helplessness and associated remodeling of hippocampal spine synapses in female rats
    Tibor Hajszan
    Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Biol Psychiatry 67:168-74. 2010
    ....
  5. pmc Bisphenol A interferes with synaptic remodeling
    Tibor Hajszan
    Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA
    Front Neuroendocrinol 31:519-30. 2010
    ..Finally, we discuss why children may particularly be vulnerable to BPA, which represents future direction of research in our laboratory...