DIFFERENTIAL FOLLICLE COUNTS AS A SCREEN FOR CHEMICALLY-INDUCED OVARIAN TOXICITY IN MICE - RESULTS FROM CONTINUOUS BREEDING BIOASSAYS

Ovaries from National Toxicology Program Reproductive Assessment by Co ntinuous Breeding (RACB) bioassays were used to directly compare diffe rential ovarian follicle counts and reproductive performance for 15 ch emicals, Ovaries of 10 animals per group from 16 studies in CD-1 mice and 1 study each in C3H and C57BL/6 mice were sectioned serially at 6 mu m. Counts of small, growing, and antral follicles were obtained in every 10th section, For all follicle types, younger mice had more foll icles than older mice, and CD-1 mice had more follicles than age-match ed animals from either inbred strain. The in-life portion of the RACB protocols demonstrated that 9 of 15 chemicals altered reproductive out come in one or both sexes of mice, with six agents affecting females ( R. E. Morrissey et al., 1989, Fundam. Appl. Toxicol. 13, 747-777), Thr ee of six female toxicants [2,2-bis(boromoethyl)-1,3-propanediol, BPD; ethylene glycol monomethyl ether, EGME; methoxyacetic acid, MAA] sign ificantly decreased counts of small and/or growing follicles by 33 to 92% in CD-1 mice; EGME also reduced follicle counts in the other strai ns. Follicle counts were decreased in progeny of animals treated with EGME or its active metabolite, MAA. For BPD, reductions in follicle nu mbers were proportional to dose. In CD-1 mice, female toxicants di-N-h exyl phthalate, propantheline bromide, and tricresyl phosphate reduced reproductive performance but not follicle numbers. Counts were not af fected by toxicants for which the susceptible sex could not be determi ned (bisphenol A, ethylene glycol, oxalic acid). Altered follicle coun ts without apparent reproductive impairment occurred in CD-1 mice at l ower doses of BPD but were not observed for nontoxic chemicals. These data suggest that differential follicle counts (1) are a quantifiable endpoint of ovarian injury in conventional bioassays, and (2) in some instances, may provide a more sensitive indicator of female reproducti ve toxicity than fertility. (C) 1997 Society of Toxicology.