Of Mice and Men (and Rats): Phthalate-induced Fetal Testis Endocrine Disruption is Species-dependent

For over 15 years, reproductive toxicologists have explored the physiological outcomes and mechanism of fetal phthalate exposure to determine the risk posed to human male reproductive health. This review examines the fetal male reproductive system response to phthalate exposure across species including rat, mouse, and human, with emphasis on the testis. In the rat, in utero phthalate exposure causes male reproductive tract malformations, in large part, by targeting the testis and inhibiting fetal Leydig cell hormone production. Despite mouse phthalate pharmacokinetics being similar to the rat, inhibition of fetal Leydig cell hormone synthesis is not observed in the mouse. The species-specific differences in testicular response following in utero phthalate exposure and the discordant reaction of the rodent fetal testis when exposed to phthalates ex vivo versus in vivo have made determining risk to humans difficult, yet critically important. The recent use of fetal testis xenotransplants to study phthalate toxicity suggests that the human fetal testis responds like the mouse fetal testis; it appears refractory to phthalate-induced inhibition of testosterone production. Although this result is unfulfilling from the perspective of identifying environmental contributions to human reproductive maldevelopment, it has important implications for phthalate risk assessment.