Human chorionic gonadotropin partially mediates phthalate association with male and female anogenital distance

Context: Prenatal exposure to phthalates disrupts male sex development in rodents. In humans, the placental glycoproteinhormonehumanchorionic gonadotropin (hCG) is required formaledevelopment, and may be a target of phthalate exposure. Objective: This study aimed to test the hypothesis that phthalates disrupt placental hCG differentially in males and females with consequences for sexually dimorphic genital development. Design: The Infant Development and Environment Study (TIDES) is a prospective birth cohort. Pregnant women were enrolled from 2010-2012 at four university hospitals. Participants: Participants were TIDES subjects (n = 541) for whom genital and phthalate measurements were available and who underwent prenatal serum screening in the first or second trimester. MainOutcomeMeasures:OutcomesincludedhCGlevels in maternal serum in the firstandsecond trimestersand anogenital distance (AGD), which is the distance from the anus to the genitals in male and female neonates. Results: Higher first-trimester urinary mono-n-butyl phthalate (MnBP; P = .01), monobenzyl phthalate (MBzP; P = .03), and mono-carboxy-isooctyl phthalate (P < .01) were associated with higher first-trimester hCG in women carrying female fetuses, and lower hCG in women carrying males. First-trimester hCG was positively correlated with the AGD z score in female neonates, and inversely correlated in males (P=0.01).Wemeasured significant associations of MnBP(P<.01),MBzP(P=.02),andmono-2-ethylhexyl phthalate (MEHP; P<.01) with AGD, after adjusting for sex differences. Approximately 52% (MnBP) and 25%(MEHP) of this association in males, and78%in females (MBzP), could be attributed to the phthalate association with hCG. Conclusions:First-trimesterhCGlevels,normalizedbyfetalsex,mayreflectsexuallydimorphicactionofphthalates on placental function and on genital development.