OR42-5 Placental Human Chorionic Gonadotropin Is Associated with Sex-Specific Development and the Response to Endocrine Disruptors

Program: Abstracts - Orals, Poster Previews, and Posters
Session: OR42-Pregnancy-Related Reproductive Endocrinology
Sunday, March 8, 2015: 9:30 AM-11:00 AM
Presentation Start Time: 10:30 AM
Room 11 (San Diego Convention Center)

Outstanding Abstract Award
Jennifer Joan Adibi, MPH, ScD1, Myoung Keun Lee, MS1, Naimi I. Ashley, PhD2, Emily Barrett, Ph.D3, Ruby Nguyen, PhD4, Sheela Sathyanarayana, MD5, Mari-Paule Thiet, MD6, Sarah J Janssen, MD, PhD, MPH7, Laurence Baskin, MD8, J. Bruce Redmon, MD9 and Shanna H Swan, PHD10
1University of Pittsburgh, Pittsburgh, PA, 2McGill University, Montreal, QC, Canada, 3University of Rochester, Rochester, NY, 4University of Minnesota, 5University of Washington, 6University of California, San Francisco, 7University of California, San Francisco, CA, 8University of California, San Francisco, San Francisco, CA, 9Univ of MN Med Sch, Minneapolis, MN, 10Mount Sinai School of Medicine, New York, NY
Background. Human chorionic gonadotropin (hCG) is a sexually dimorphic placental secreted hormone that is essential to normal differentiation of the fetal testes. Mothers of cryptorchid neonates had 20% lower circulating hCG in the first trimester versus controls. An endocrine disrupting compound, mono-n-butyl phthalate (MnBP), increases expression of the hCG alpha subunit in female placentas and decreases expression in male placentas. In male infants, prenatal phthalate exposure is associated with shorter anogenital distance (AGD) at birth-- a marker of hormonal action in utero and fetal sex differentiation. The primary aim was to evaluate associations of hCG with a) AGD in male and female neonates, and with b) urinary phthalates. The secondary aim was to test the hypothesis that phthalates disrupt male sexual differentiation through their action on hCG.

Methods. Subjects were enrolled in multicenter prospective pregnancy cohort. Phthalates and hCG were measured in urine and serum samples, respectively, collected in the first trimester (N=362).  Neonatal exams were performed by trained study staff.  Multivariate linear regression was used to estimate sex-specific associations of the placental hormones with AGD (males: AS: anus to scrotum, AP: anus to penis; females AF: anus to fourchette; AC: anus to clitoris), birthweight for gestational age z-score, and 5 urinary phthalate concentrations including MnBP, mono-isobutyl phthalate (MiBP), monobenzyl phthalate (MBzP), monoethylhexyl phthalate (MEHP), and monoethyl phthalate (MEP). To combine data across centers, we generated z-scores of the analyte values. We applied causal inference methods to estimate the total effect of phthalates and hCG on AGD, and compared it to the controlled direct effect (CDE) of the phthalates after removing the hCG effect.  

Results. Higher hCG was associated with lower AGD-AS in males (-0.64 mm per 1 unit increase in the hCG z-score, standard error (SE) 0.31) but not females (interaction of hCG by fetal sex p=0.03). Higher MnBP and MBzP were associated with higher hCG expression in female fetuses and lower expression in males (interaction p-value=0.01). AGD-AP and AGD-AC were not correlated with first trimester placental hormones. In Aim 2, for every log unit increase in urinary MEHP and MnBP, male AGD decreased by 1.2 mm.  If we administered a hypothetical substance that completely blocked the effect of hCG, then MEHP and MnBP would induce only a 0.87 mm and 0.99 mm decrease in AGD respectively.  

Conclusion. The early placenta is a site of endocrine disruption, and a contributor to the development of the fetal genitalia.  hCG may partially mediate the effects of phthalates on fetal genitalia.  By monitoring of first trimester hCG, normalized by fetal sex, we may have the opportunity to identify abnormal development, intervene and improve the health of the child.

Nothing to Disclose: JJA, MKL, NIA, EB, RN, SS, MPT, SJJ, LB, JBR, SHS

*Please take note of The Endocrine Society's News Embargo Policy at https://www.endocrine.org/news-room/endo-annual-meeting

Sources of Research Support: JJA had grant support from the National Institutes of Environmental Health Sciences (1K99 ES017780-01, 5 R00 ES 017780 – 06). The Infant Development and Environment Study (SHS) was funded by the National Institute of Environmental Health Sciences: R01ES016863-04 and R01 ES016863-02S4.