Early effects of ovotoxicity induced by 4-vinylcyclohexene diepoxide in rats and mice.

The industrial chemical 4-vinylcyclohexene diepoxide (VCD) causes specific destruction of oocyte-containing small preantral follicles (primordial and primary) in ovaries of rats and mice. The mouse seems more susceptible to ovotoxic effects of VCD than the rat. The purpose of this study was to better understand these species differences in susceptibility to VCD by comparing the initial rates of VCD-induced follicle damage and loss in response to dosing in both species. Female Fischer 344 rats and B6C3F1 mice (age, Day 28) were dosed daily (vehicle or 80 mg/kg, i.p.) for 6, 8, 10, or 12 d. Ovaries collected after the final dose were prepared for histologic evaluation. Primordial and primary follicles in ovarian slices were counted and classified as healthy or atretic. A VCD-dependent increase (P < 0.05) in percent atretic primordial follicles was first observed 4 h after the final dose in mice on Day 8 (VCD-treated, 44.4 +/- 3.1% vs. control, 26.9 +/- 5.4%). Conversely, in rats, this significant increase was not seen until Day 10 (VCD-treated, 44.3 +/- 1.3% vs. control, 23.1 +/- 4.0%). A VCD-dependent increase in percent atretic primary follicles was not observed in either species before Day 12. There was no significant effect on growing or preantral follicles on any day in either species. Significant loss of primordial and primary follicles (P < 0.05) was first measured on day 12 in both rats and mice. However, when compared with controls, follicle loss on that day was greater (P < 0.05) in mice (64.2 +/- 4.5%) than in rats (34.7 +/- 4.9%). Once VCD-dependent follicle loss was observed, the rate of follicle damage was similar in rats and mice, and was fairly constant in response to each dose. VCD-induced follicle damage in mice, as with rats, also displayed morphologic characteristics of atresia (apoptosis). In summary, follicle destruction seems to be similar in rats and mice; however, follicle damage is initiated earlier and to a greater extent in mice than in rats. Additionally, ovotoxic effects of VCD seem to initially directly target primordial follicles. These results provide temporal evidence that mice are more susceptible to VCD-induced ovotoxicity than rats.