The Relationships among Reproductive Endpoints in Swiss Mice, Using the Reproductive Assessment by Continuous Breeding Database

Abstract

The database of Continuous Breeding mouse studies was evaluated to determine the relationships between the functional indicators of reproduction (pup measures) and the various necropsy endpoints collected for males and females. Of 72 chemicals studied, both males and females were affected in 33 studies, while females and/or conceptuses were affected in 7. Two compounds affected only males, 17 studies were negative, and in 13 studies with effects it was not possible to clearly determine the affected gender(s). Greater F₀dam weight was correlated with increased pup mass per litter; this relationship was strongest for the first litter, and weakest for the fifth litter. For both generations of treated females (F₀and F₁), longer estrous cycles correlated with reduced numbers of pups; the relationship was stronger in F₀than in F₁females and was not seen in controls. Sperm parameters had different distributions in treated mice than in control mice. Fertility (total live pups/number of pairs cohabited) was reduced if there were > ∼15% sperm abnormalities or if sperm motility (moving/not moving) was < ≈37%. Both of these relationships appeared to have thresholds. Epididymal sperm count in treated animals, however, was linearly related to fertility, even within the control range, suggesting strongly that other factors are important. Using both treated and control data together, combining sperm count with motility could explain much (r= 0.77) of the variation in fertility; adding morphology did not significantly improve the correlation. The model was almost as strong using count and morphology, in which case adding motility did not strengthen the model. This analysis of these studies shows that while some endpoints (e.g., random-estrous-cycle-point ovary weight) correlate poorly with fertility, other necropsy endpoints (epididymal sperm count and motility, estrous cycle length, and testis and epididymal weights) can be useful (though not complete) surrogates of overall reproductive function. Indeed, over many studies, epididymal sperm count in treated animals correlates with fertility so well that even small reductions (≈20%) in count result in reduced fertility, suggesting that mice may be better models of human fertility than was previously believed.