The potential effects of man-made substances on the reproductive health of humans and other animal species is an area of increasing concern, however, efforts to clearly delineate the reproductive effects of specific substances have been hampered by the lack of a suitable assay system. The inadvertent exposure of mice in our colony to bisphenol A (BPA) during the course of meiotic studies provided evidence that this """"""""estrogen mimic"""""""" disrupts mammalian female meiosis, increasing the risk of meiotic nondisjuntion. Subsequent investigations in our laboratory suggest that the meiotic process in both male female mice is exquisitely sensitive to BPA, as doses that are 1000-fold lower than the currently accepted NOEL induce detectable meiotic abnormalities. These findings raise serious concerns about the potential reproductive effects of BPA on humans. However, effective studies in humans can best be designed if we first accurately define the effects of BPA exposure in an animal model. The proposed studies are designed to explore these preliminary findings in depth, allowing us to determine how, when, and at what level of exposure BPA acts to disrupt mammalian meiosis during both oogenesis and spermatogensis. Importantly, we will determine whether other estrogenic compounds (e.g., estradiol, diethylstilbesterol) elicit similar effects and thereby begin to elucidate the cellular/molecular mechanisms of BPA action. Further, we will use estrogen receptor knockout mice to test the hypothesis that apparent BPA-specific meiotic effects are mediated through non-traditional mechanisms (i.e., act independently of the known estrogen receptors). Lastly, we will use a newly devised screening tool involving the budding yeast, Saccharomyces cerevisiae, to determine the mechanism(s) by which BPA exerts its effects. The combined data from these studies will not only provide important insight concerning the potential effects of BPA exposure in humans, but will test the efficacy of meiotic studies in assessing the reproductive effects of chemical exposures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES013527-05
Application #
7574487
Study Section
Special Emphasis Panel (ZRG1-EMNR-C (02))
Program Officer
Heindel, Jerrold
Project Start
2005-06-06
Project End
2010-08-31
Budget Start
2009-03-01
Budget End
2010-08-31
Support Year
5
Fiscal Year
2009
Total Cost
$393,879
Indirect Cost
Name
Washington State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Horan, Tegan S; Pulcastro, Hannah; Lawson, Crystal et al. (2018) Replacement Bisphenols Adversely Affect Mouse Gametogenesis with Consequences for Subsequent Generations. Curr Biol 28:2948-2954.e3
Gerona, Roy R; Schwartz, Jackie M; Pan, Janet et al. (2018) Suspect screening of maternal serum to identify new environmental chemical biomonitoring targets using liquid chromatography-quadrupole time-of-flight mass spectrometry. J Expo Sci Environ Epidemiol 28:101-108
Wang, Shunxin; Hassold, Terry; Hunt, Patricia et al. (2017) Inefficient Crossover Maturation Underlies Elevated Aneuploidy in Human Female Meiosis. Cell 168:977-989.e17
Vandenberg, Laura N; Gerona, Roy R; Kannan, Kurunthachalam et al. (2016) Erratum to: A round robin approach to the analysis of bisphenol a (BPA) in human blood samples. Environ Health 15:43
Gruhn, Jennifer R; Al-Asmar, Nasser; Fasnacht, Rachael et al. (2016) Correlations between Synaptic Initiation and Meiotic Recombination: A Study of Humans and Mice. Am J Hum Genet 98:102-15
Gerona, Roy R; Pan, Janet; Zota, Ami R et al. (2016) Direct measurement of Bisphenol A (BPA), BPA glucuronide and BPA sulfate in a diverse and low-income population of pregnant women reveals high exposure, with potential implications for previous exposure estimates: a cross-sectional study. Environ Health 15:50
Yang, Qi-En; Nagaoka, So I; Gwost, Ivy et al. (2015) Inactivation of Retinoblastoma Protein (Rb1) in the Oocyte: Evidence That Dysregulated Follicle Growth Drives Ovarian Teratoma Formation in Mice. PLoS Genet 11:e1005355
Vrooman, Lisa A; Oatley, Jon M; Griswold, Jodi E et al. (2015) Estrogenic exposure alters the spermatogonial stem cells in the developing testis, permanently reducing crossover levels in the adult. PLoS Genet 11:e1004949
Rowsey, Ross; Gruhn, Jennifer; Broman, Karl W et al. (2014) Examining variation in recombination levels in the human female: a test of the production-line hypothesis. Am J Hum Genet 95:108-12
Vandenberg, Laura N; Gerona, Roy R; Kannan, Kurunthachalam et al. (2014) A round robin approach to the analysis of bisphenol A (BPA) in human blood samples. Environ Health 13:25

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