Association of sperm measures with reproductive outcome: National Toxicology Program studies in mice

In reproductive assessment by continuous breeding (RACB) studies, a crossover mating trial was conducted if an adverse effect on fertility was detectable over an 18-week cohabitation period during which Swiss (CD-1) mice were continuously treated. Results of 25 RACB crossover mating studies conducted to determine the affected sex were compared with results of sperm morphology and vaginal cytology examinations (SMVCE) performed at the conclusion of each mating trial. SMVCE endpoints included epididymal sperm concentration, motility, and morphology, vaginal cytology, and male reproductive organ weights. In most studies, multiple SMVCE endpoints were adversely affected. With this group of chemicals, epididymis weight was sensitive and specific to male reproductive toxicants and nontoxicants, respectively. Sperm motility and testis weight were also highly sensitive to male reproductive toxicants. The above endpoints demonstrated the greatest statistical significance relative to other SMVCE parameters, and were highly associated with fertility measurements from breeding experiments. These characteristics suggest that some SMVCE endpoints are more useful for screening chemicals for potential male reproductive toxicity than others. Caution must be exercised, however, because the compounds used in these studies are not representative of all classes of chemicals, and chemicals not tested here may produce adverse reproductive effects by different mechanisms of action. The dose-response effects of two glycol ethers evaluated in RACB, ethylene glycol monomethyl ether and ethylene glycol monoethyl ether, on reproductive outcome and SMVCE endpoints were examined in detail. Both caused adverse effects on testis weight and sperm head morphology, and these changes were associated with adverse effects on reproductive outcome. Until we have more experience with SMVCE and other screens, multiple endpoints should continue to be used for screening for reproductive toxicants.