Gestational Benzo[a]pyrene Exposure Destroys F1 Ovarian Germ Cells Through Mitochondrial Apoptosis Pathway and Diminishes Surviving Oocyte Quality

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Abstract
Polycyclic aromatic hydrocarbons, including benzo[a]pyrene (BaP), are products of incomplete combustion. In female mouse embryos primordial germ cells proliferate before and after arriving at the gonadal ridge around embryonic (E) 10 and begin entering meiosis at E13.5. Now oocytes, they arrest in the first meiotic prophase beginning at E17.5. We previously reported dose-dependent depletion of ovarian follicles in female mice exposed to 2 or 10 mg/kg-day BaP E6.5–15.5. We hypothesized that embryonic ovaries are more sensitive to gestational BaP exposure during the mitotic developmental window, and that this exposure results in persistent oxidative stress in ovaries and oocytes of exposed F1 female offspring. We orally dosed timed-pregnant female mice with 0 or 2 mg/kg-day BaP in oil from E6.5–11.5 (mitotic window) or E12.5–17.5 (meiotic window). Cultured E13.5 ovaries were utilized to investigate the mechanism of BaP-induced germ cell death. We observed statistically significant follicle depletion and increased ovarian lipid peroxidation in F1 pubertal ovaries following BaP exposure during either prenatal window. Culture of E13.5 ovaries with BaP induced germ cell DNA damage and release of cytochrome c from the mitochondria in oocytes, confirming that BaP exposure induced apoptosis via the mitochondrial pathway. Mitochondrial membrane potential, oocyte lipid droplet (LD) volume, and mitochondrial-LD colocalization were decreased and mitochondrial superoxide levels were increased in the MII oocytes of F1 females exposed gestationally to BaP. Results demonstrate similar sensitivity to germ cell depletion and persistent oxidative stress in F1 ovaries and oocytes following gestational BaP exposure during mitotic or meiotic windows.
Funding Information
  • National Institutes of Health (R01ES020454, R21HD097541)
  • Tobacco Related Diseases Research Program Predoctoral Fellowship (T30DT0816)
  • UC Irvine Summer Undergraduate Research Program fellowship
  • NIH Initiative for Minority Success (GM055246)
  • UC Irvine Chao Family Comprehensive Cancer Center Optical Biology Shared Resource
  • National Cancer Institute of the NIH (P30CA062203)
  • NIH

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