Prior studies report that penile size and male anogenital distance (AGD), sensitive markers of androgen action in utero, may be shortened by prenatal exposure to certain phthalates, including diethylhexyl phthalate (DEHP), but no human study has investigated the importance of exposure timing in these associations. The aim of this study was to examine the significance of exposure timing on the action of prenatal phthalates in particular DEHP, on male infant penile size and AGD. In The Infant Development and the Environment Study (TIDES) we measured penile width (PW) as well as anoscrotal distance (AGDAS) and anopenile distance (AGPAP) in newborn males. We modeled these endpoints in relation to phthalate metabolite concentrations in maternal urine samples collected in each trimester (T1, T2, and T3) in a subset of TIDES mothers (N = 168). PW was inversely associated with T2 oxidized DEHP metabolites, mono-2-ethyl-5-oxohexyl (MEOHP, β=−0.48; 95% confidence interval, −0.93, −0.02), MEHHP (−0.48; −0.92, −0.05), mono-2-ethyl-5-carboxypentyl (MECPP, −0.51; −1.01, −0.004), although no appreciable associations were seen between PW and T1 and T3 DEHP metabolite concentrations in this subset. Concentrations of DEHP metabolites in T1 urine samples were inversely related to male AGD. For example, in T1 samples in this subset of women mono-2-ethyl-5-hydroxyhexyl (MEHHP) was inversely associated with male AGDAP (β = −1.73; 95% confidence interval, −3.45, 0.0004). However, no appreciable associations were seen between AGD measures and any DEHP metabolite in T2 and T3 samples. These data suggest that DEHP exposure is inversely associated with AGD and PW, with PW primarily associated with T2 exposure and AGD associations seen only for T1 exposure, but no associations were found between T3 DEHP metabolites and any of these genital endpoints. These findings are consistent with data on critical windows in rodent studies, supporting the biological plausibility of these associations in humans.
Bibliographical noteFunding Information:
Funding for TIDES was provided by the following grants from the National Institute of Environmental Health Sciences: R01ES016863-04 and R01ES016863-02S4. Anderson J Martino-Andrade is a fellowship recipient from CNPq/Brazil. Hagai Levine is a fellowship recipient from the Environment and Health Fund, Israel. We wish to acknowledge the contributions of the TIDES Study Team: Coordinating Center: Erica Scher; UCSF: Sarah Janssen, Marina Stasenko, Erin Ayash, Melissa Schirmer, Jason Farrell, Mari-Paule Thiet, Laurence Baskin; UMN: Heather Gray, Chelsea Georgesen, Brooke Rody, Carrie Terrell, Kapilmeet Kaur; URMC: Erin Brantley, Heather Fiore, Lynda Kochman, Lauren Parlett, Jessica Marino, William Hulbert, Robert Mevorach, Eva Pressman; UW/SCH: Kristy Ivicek, Bobbie Salveson, Garry Alcedo, and the families who participated in the study. In addition, we thank the TIDES families for their participation and the residents at URMC and UCSF who assisted in birth exams and Antonia Calafat at the Centers for Disease Control and Prevention for phthalate analyses.
© 2016 American Society of Andrology and European Academy of Andrology
- fetal development