Timing of prenatal phthalate exposure in relation to genital endpoints in male newborns

A J Martino-Andrade; F Liu; S Sathyanarayana; E S Barrett; J B Redmon; R H N Nguyen; H Levine; S H Swan; TIDES Study Team

doi:10.1111/andr.12180

Timing of prenatal phthalate exposure in relation to genital endpoints in male newborns

Andrology. 2016 Jul;4(4):585-93. doi: 10.1111/andr.12180. Epub 2016 Apr 7.

Authors

A J Martino-Andrade^{1

2}, F Liu¹, S Sathyanarayana^{3

4}, E S Barrett⁵, J B Redmon⁶, R H N Nguyen⁷, H Levine^{1

8}, S H Swan¹; TIDES Study Team

Affiliations

¹ Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² Department of Physiology, Federal University of Parana, Curitiba, Brazil.
³ Department of Pediatrics, University of Washington, Seattle, WA, USA.
⁴ Seattle Children's Research Institute, Seattle, WA, USA.
⁵ Department of Obstetrics and Gynecology, University of Rochester, Rochester, NY, USA.
⁶ Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
⁷ Department of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN, USA.
⁸ Braun School of Public Health and Community Medicine, Hebrew University-Hadassah and the Hebrew University Center of Excellence in Agriculture and Environmental Health, Jerusalem, Israel.

PMID: 27062102
DOI: 10.1111/andr.12180

Abstract

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.

Keywords: fetal development; genital; phthalates; prenatal; timing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Anthropometry
Environmental Exposure*
Female
Genitalia, Male / abnormalities
Genitalia, Male / drug effects*
Humans
Infant, Newborn
Male
Maternal Exposure*
Phthalic Acids / toxicity*
Pregnancy
Prenatal Exposure Delayed Effects*
Time Factors

Substances

Phthalic Acids
phthalic acid

Grants and funding

R01 ES016863/ES/NIEHS NIH HHS/United States