The United States manufactures and uses high volumes of a vast array of industrial chemicals, over 90% of which are not monitored for their potential toxicities towards human health. We do not have reproductive toxicity data for many of the industrial chemicals detected in the maternal and umbilical cord sera. Exposures to these chemicals, such as pesticides and plasticizers, in utero may adversely impact future reproductive health, particularly in females for whom this period comprises the initial stages of gametogenesis, when the oocyte is forming. Current data show that female reproductive health problems, including infertility and birth defects, affect nearly 12% of women and often are associated with impaired germ cell function. An impediment to identifying and understanding contributing factors is the prolonged delay between toxicant exposure and the manifestation of reproductive perturbations, leading to a paucity of information on reproductive toxicity. In this proposal, we address these needs through a transdisciplinary collaboration to analyze the reproductive effects of industrial chemicals identified in maternal and umbilical cord sera using two different in vivo models of germ cell development. To assay effects on meiosis, we will utilize the yeast Saccharomyces cerevisiae, a unicellular organism in which meiosis is best understood (Dr. Fung lead investigator). We will also utilize Caenorhabditis elegans to further assess toxicity during germ cell development (Dr. Allard lead investigator). Both of these model systems are particularly amenable to integration into high-throughput systems for testing. We will test up to 80 chemicals identified via suspect screening in maternal and infant sera (based on our parent R01, Dr. Woodruff PI) in the two assays. We will compare the results of the two model systems to each other; and evaluate the utility and predictive value of the two model systems with mammalian reproductive endpoints. This project will establish a transdisciplinary dialogue between the three investigators as they share chemical exposure findings (from Dr. Woodruff) to use in the in vivo assays in Drs. Fung's and Allard's labs, and then among the three collaborators as they evaluate the results from the assays and compare them to the mammalian system results. Upon the completion of this project, we will be able to compare findings across two model systems (S. cerevisiae and C. elegans) and to inform the potential for reproductive health risks on the basis of measured prenatal and neonatal exposures. The development of such much-needed model systems will expand our understanding of reproductive toxicity and provide an exciting opportunity for more-rapid screening techniques to more quickly identify which exposures measured in susceptible populations are potential reproductive toxicants. Thus, we will generate critical new data that can more fully inform prevention efforts to reduce harmful chemical risks
Our transdisciplinary collaboration will advance our ability to more quickly assess reproductive effects of industrial chemicals identified in maternal serum and cord sera by using established in vivo models of meiosis that can be integrated into high-throughput systems for testing. By generating predictive models using the information gleaned from the combination of the two model systems, we will be able to better assess reproductive risk of potential toxicants.
