Ovotoxicity in female Fischer rats and B6 mice induced by low-dose exposure to three polycyclic aromatic hydrocarbons: Comparison through calculationof an ovotoxic index

Extensive destruction of primordial follicles by exposure to ovarian toxica nts can cause early menopause in women. Primordial follicle destruction is known to result from dosing of mice and rats with three polycyclic aromatic hydrocarbons (PAHs), contaminants commonly found in cigarette smoke. There fore, the purpose of this study was to compare relative ovotoxicity in mice and rats using the PAHs, 9,10-dimethylbenzanthracene (DMBA), 3-methylchola nthrene (3-MC), and benzo[a]pyrene (BaP). Female B6C3F(1) mice and Fischer 344 rats (age 28 days) were dosed daily tip) with vehicle control or a rang e of doses of the PAHs. Two groups were dosed with the occupational chemica ls 4-vinylcyclohexene (VCH; 500 mg/kg ip) or its diepoxide metabolite (VCD; 80 mg/kg ip), other known ovotoxicants. After 15 days, ovaries were collec ted, histologically prepared, and follicles were microscopically classified (primordial, primary, or secondary) and counted. The dose of each chemical that produced 50% loss of primordial follicles (p < 0.05) was determined ( ED50) and used to calculate an ovotoxic index (OI) in mice and rats (ED50 x 15 days). Thus, a chemical with a lower OI is more toxic. Primordial folli cles in mice displayed a lower OI than rats to all chemicals tested (mouse: DMBA, 0.0012; 3-MC, 0.003; BaP, 0.18; VCD, 6.8; VCH, 69; rat: DMBA, 0.45; 3-MC, >3.4; BaP, >3.6; VCD, 8.6; VCH, >69). In mice, DMBA targeted primordi al follicles at a 10-fold lower concentration than primary and secondary fo llicles, whereas 3-MC exposure targeted primordial and primary follicles to a similar degree. BaP exposure targeted primordial and primary follicles a t a 100-fold higher concentration than DMBA or 3-MC. Although BaP and 3-MC did not target secondary follicles in mice, secondary follicles in rats wer e most susceptible to 3-MC. Furthermore, all three PAHs were more ovotoxic (lower OI) with repeated low-dose exposure compared with OIs calculated fro m other studies using single high-dose exposures. The earliest day of impen ding primordial follicle loss (increase in percentage of unhealthy follicle s, p < 0.05) in mice was factored into the OI (ED50 x first day of damage, p < 0.05 x % healthy follicles remaining, relative to control). The revised OI became DMBA d15, 0.0006; 3-MC d12, 0.0008; BaP d15, 0.132; and VCD d8, 2.96. These results predict that DMBA is the most potent ovarian toxicant ( lower OI) in both species but VCD damages primordial follicles after shorte r exposures. Calculation of the OI in mice and rats represents a method for comparing the relative potential risk of a variety of chemicals that produ ce ovarian damage at low levels following repeated exposures. The results a lso demonstrate that low-dose repeated exposures are substantially more tox ic to the ovary than a single high-dose exposure. This finding is particula rly important in view of the implications for chronic low-dose exposures of women to environmental chemicals. a tow Academic Press.