Introduction: A greater than 50-year decline in human sperm counts, rising incidences of testicular germ cell cancer and malformations at birth have been linked to exposure to environmental chemicals (ECs). In the female, EC exposures have been linked to ovarian failure, polycystic ovarian syndrome, ovarian cancer and precocious puberty. Since human studies are largely epidemiological/associative and exposures are to chemical mixtures, determining cause and effect has proved difficult. We have used sentinel and experimental animal models to explore mixture effects relevant to the human, periods of EC sensitivity and mechanisms underlying reported effects.
Methods: Animal models included: (1) dogs as sentinels of human exposure to EC mixtures, (2) pregnant ewes exposed to chemical mixtures in biosolids (sewage sludge) fertiliser: a real-life model and (3) neonatal mouse gonads exposed in vitro to selected chemicals to determine early developmental effects. In combination with ethically approved human studies, exposure effects were investigated across the life cycle.
Results: (Household Dog): A 30% decline in semen quality over more than 26 years parallels that reported in humans. Pups (same population) exhibit an increased incidence of cryptorchidism and contaminants detected in testes exhibited region specific profiles. (Sheep) Maternal exposure effects on the fetus (male, female), neonate and F1 adult include altered gonadal morphology, endocrine function and transcriptomic changes in reproductive tissues. Multigenerational consequences of maternal exposures are under study. (Mouse) EC sensitive periods of early gonadal development have been identified. (Human) short term sperm exposures altered indices of health. The relative merits of each paradigm alongside alternative animal and human studies will be addressed.
Conclusion: Companion animal ‘canary in the coalmine’ sentinels and sheep exposed to biosolids provide relevant translational models of human exposure. Since critical mechanistic information is provided through alternative in vivo and in vitro approaches, a combination of models is essential in characterising EC mixture effects on fertility and reproductive health.