Tumor and Stem Cell Biology Glutathione-Deficient Mice have Increased Sensitivity to Transplacental Benzo[a]pyrene-Induced Premature Ovarian Failure and Ovarian Tumorigenesis

Polycyclic aromatic hydrocarbons (PAH) such as benzo[a]pyrene (BaP) are ubiquitous environmental pollutants found in tobacco smoke, air pollution, and grilled foods. Prenatal exposure to BaP causes premature reproductive senescence in mice, and other PAHs are transplacental ovarian carcinogens. Glutathione (GSH) is critical for detoxification of the reactive metabolites of PAHs. Therefore, we hypothesized that mice that are genetically deficient in GSH synthesis, due to deletion of themodifier subunit of glutamate cysteine ligase (Gclm), the rate-limiting enzyme in GSH synthesis, have increased destruction of oogonia, premature ovarian failure, and ovarian tumorigenesis after transplacental BaP exposure compared with Gclmþ/þ females. Gclmþ/ female and male mice were mated, and dams were treated with 0, 2, or 10 mg/kg/d BaP in sesame oil by gavage from gestational days 7 to 16. Compared with oil-treated F1 females of the same genotype, Gclm / prenatally BaPtreated females had significantly greater decrements in offspring production than Gclmþ/þ BaP-treated females. Similarly, we observed significant BaP dose Gclm genotype interactions on ovarian follicle counts and ovarian tumormultiplicity at 7.5 months of age, withGclm / females having greater decrements in follicle numbers and more ovarian tumors in response to prenatal BaP exposure than Gclmþ/þ females. The ovarian tumors were positive for the epithelial marker cytokeratin. Our results show that prenatal exposure of females to BaP causes premature ovarian failure and ovarian tumorigenesis and that embryonic GSH deficiency due to deletion ofGclm increases sensitivity to these transplacental ovarian effects of BaP. Cancer Res; 73(2); 1–10. 2012 AACR.