Analysis the ovotoxicity and ovarian cancer stem-like progenitors generation in benzo[a]pyrene-treated Mice

Benzo(a)pyrene (BaP), a member of the polycyclic aromatic hydrocarbon (PAH) family, is a potent carcinogen and causes cancer in multiple organs. The present research investigates the toxicity of BaP in the reproductive tract of female Swiss mice.

A standardised dose of BaP (50 mg/kg body weight twice a week for one month) was administered to induce systemic oxidative stress in murine models. After 4 months, BaP administration reduces the numbers of primordial and primary ovarian follicles and induces stromal cell hyperplasia and inflammation inside the ovary. The thickness of uterine layers decreases, while the diameter of the uterine lumen and number of uterine glands rise. Atrophied uterine linings, as well as endometrial hyperplasia (EH) with abnormal glandular development are apparent. Using flow cytometry, three different ovarian cancer stem-like progenitors (CSLP) were identified based on the expression of CD44 and CD133 receptors: CD44⁺CD133⁻, CD44⁺CD133⁺, and CD44^-CD133⁺. BaP treatment increases CD44⁺CD133^-(7.3-fold, p < 0.005) and CD44⁺CD133⁺ cells (2.53-fold, p < 0.0005), while decreasing CD44^-CD133⁺ cells (52% reduction, p < 0.0005). BaP administration also increases the CD44 (4-fold, P < 0.0005) and CD133 surface expression (47% increase, p < 0.005) as well as ROS production (2-fold increment, p < 0.005) in ovarian cells. The RT-qPCR data suggests a marked reduction in the relative expressions of antioxidant genes (SOD1, SOD2, catalase, GPX1, and FOXO3) in ovarian cells.

BaPadministration disrupts folliculogenesis, reduces ovarian follicle size, and causes epithelial hyperplasia, lymphocytic infiltration, increased vascularisation, atrophied uterine lining, and abnormal glandular growth in the uterus. It induces CSLPs and CD44 and CD133 expression in ovaries. The BaP administration also increases ROS and decreases antioxidant gene expression in the ovaries.