Evaluation of a New Reproductive Toxicology Protocol Using Diethylstilbestrol (DES) as a Positive Control Compound

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Abstract
A new National Toxicology Program (NTP) reproductive toxicology assay designated Fertility Assessment by Continuous Breeding was evaluated using trans-diethylstilbestrol (DES) as a positive control compound. The testing scheme employs young adult CD-1 male and female mice and is comprised of 5 possible tasks: task 1, 14-day dose-finding (repeated or continuous dosing); task 2, continuous breeding; task 3, determination of affected sex; task 4, offspring assessment; task 5, hormone patterns. Only tasks 2 and 3 were performed in the present study. Task 2 employed dietary levels of 0, 1, 10, and 50 ppb DES (99% pure). Task 3 used the control and high dose parental mice from task 2 in a crossover mating trial (control x treated) to determine whether one or both sexes in the F0 generation were adversely affected. Continuous exposure of F0 mice to 50 ppb DES in the diet during task 2 significantly decreased (P < 0.01) the proportion of pairs that produced at least 1 litter as compared to pairs continuously exposed to dietary levels of 0, 1, and 10 ppb DES. In addition, continuous exposure to 50 ppb DES in the diet had a cumulative adverse effect on the production and viability of litters. Thus, the pairs fed 50 ppb DES produced significantly fewer litters (P < 0.01), had fewer live pups per litter (P < 0.01), and tended toward a lower proportion of pups born alive per litter than did pairs in the 0, 1, and 10 ppb DES groups. In the crossover mating trial (task 3) the proportion of F0 females that mated (number with copulatory plugs/number cohabited) and that were fecund (number delivering litters/number with copulatory plugs) did not differ significantly among the 3 different combinations of paired mice. It was noted, however, that the proportion of cohabited F0 females delivering litters (number delivering litters/number cohabited) was significantly reduced (P < 0.05) in the control male x 50 ppb DES female group vs. the control male x control female group. The proportion of cohabited F0 females delivering litters in the 50 ppb DES male x control female group did not differ significantly from either of the above groups. Further, the number of live pups per litter and the proportion of pups born alive were significantly lower (P < 0.01) in the F0 control male x 50 ppb DES female group than in the other 2 groups. The proportion of male pups born alive (males/total) and the live pup weights, however, did not differ significantly among the 3 combinations of paired mice. Collectively, these results indicated that DES interfered with ovulation, conception, pre- and postimplantational processes in female mice. Thus, this new assay readily discriminated DES as a reproductive toxicant in CD-1 mice.