In utero phthalate exposure alters the developing reproductive system in males: Lessons from Toxicology.
Shanna H Swan, Department of Preventive Medicine, Mt Sinai School of Medicine, New York, NY
The reproductive toxicity of phthalates has been known since the 1990’s. Two of the best studied of this class of chemicals, diethylhexyl phthalate (DEHP) and dibutyl phthalate (DBP), are anti-androgenic and cause permanent and profound alterations of the male reproductive system. A narrow critical window in utero has been identified; mechanisms of action are less clear. The pattern of changes caused by these phthalates has been called the “phthalate syndrome”.
NHANES and national sampling in other industrialized countries has demonstrated widespread, chronic human and environmental exposure to a large number of phthalates, including DEHP and DBP. In 2003 we took advantage of our existing pregnancy cohort, the Study for Future Families (SFF), and examined babies born to SFF mothers who had stored prenatal urine samples. To look for the human analogue of the phthalate syndrome, we designed an exam that captured multiple endpoints of that syndrome: anogenital distance, penile and scrotal size and condition and testicular descent. We found significant associations between male AGD and three metabolites of DEHP, as well as their sum. We also saw a direct relationship between DEHP metabolites and penile width and testicular descent. We saw no phthalate-related changes in girls. A few other studies have examined AGD in relation to these endpoints in boys and girls with mixed results. Recent work (Fowler et al 2011) suggests that in humans, as in rodents, these developmental changes take place early in pregnancy. What, if any, are the clinical correlates of shorter male AGD? Consistent with results predicted by toxicology studies, shorter male AGD is associated with hypospadias and, in adults, decreased semen quality, infertility, lower testosterone and smaller testicles.
We also examined play behavior at 4-7 years in these children, using a parentally completed questionnaire, the Preschool Activities Inventory (PSAI). In that small study we found no associations in girls, and significantly less masculine scores in boys with higher prenatal exposure to DEHP and DBP.
The ”phthalate syndrome” may not be unique to phthalates; other studies have reported changes in male AGD following in utero exposure to other EDCs. We are currently conducting the Infant Development and the Environment Study (TIDES), which will examine these and other endpoints in relation to exposure to phthalates (and later other EDCs). Because of the importance of these endpoints for later reproductive function, these findings warrant concern that low dose prenatal exposure anti-androgenic chemicals may affect human male reproductive health.