Environmental chemicals may contribute to increases in male reproductive disorders that have been noted in industrial nations. While much of this discussion has revolved around environmental estrogens, the most compelling links between impaired male reproductive function and environmental agents have been demonstrated for anti-androgens, and phthalates, in particular. In rodents, diethylhexyl phthalate (DEHP) and dibutyl phthalate (DBP) induce a spectrum of male genital tract disorders termed the """"""""phthalate syndrome"""""""". Anogenital distance (AGD), the distance from anus to genitals, is a defining marker of this syndrome, which also includes small testes size and incomplete testicular descent. We found higher concentrations of metabolites of DEHP and DBP in prenatal urine to be associated with shorter AGD in male infants. DEHP metabolites were also negatively correlated with penile width (PW) and incomplete testicular descent. Pregnancy cohort: A primary aim of The Infant Development and Environment Study (TIDES) is to examine genital landmarks in male infants in relation to prenatal DEHP and DBP exposure. To address this aim, we will recruit 1,000 women in the first trimester of pregnancy from four centers (Seattle, WA, Minneapolis, MN, San Francisco, CA and Rochester, NY) and store a urine sample in each trimester from all women. We will examine DEHP and DBP metabolite concentrations in first trimester urine samples in women who give birth to males, and store urine from female births for future study. We will measure metabolite concentration in urine samples from each trimester for 50 per cent of mothers of males to estimate metabolite variability across pregnancy. Birth cohort:
The second aim of TIDES is to obtain population-based norms for AGD, PW, testicular volume (TV) and testicular location (TL) in male newborns, specific for birthweight and gestational age. We will examine 1,000 newborn males (including 500 males born to members of the pregnancy cohort and an additional sample of 500 boys from the newborn nursery) using precise methods and measures standardized across clinical centers with strict quality control procedures. Follow-up cohort: To examine the stability of birth measurements, we will repeat the birth exam at 6 and 12 months in males born to women in the pregnancy cohort. We will also pilot novel methods for conducting morphometry of the anogenital region from standardized digital images obtained by camera and ultrasound. Consequences: This research will provide standard methods for easily measuring AGD, PW, and TL (and perhaps TV) and norms for these genital landmarks obtained in a diverse, population-based, sample of male infants, which may be suitable for use in pediatric practice. Associations between phthalate metabolites and the androgen-sensitive measures we are examining could play an important role in public health policy given the ubiquitous nature of these exposures and the clinical importance of appropriate androgen stimulation during fetal development.

Public Health Relevance

This research will provide standard methods measuring four androgen-sensitive measures in human populations;anogenital distance, penile width, testicular volume and testicular location. We will develop age and weight adjusted norms for these genital landmarks in a diverse population-based sample of male infants, which may then be suitable for use in pediatric practice. The study will also examine patterns of associations among metabolites of DEHP and DBP and these measures, which, if significant, could play an important role in public health policy given the ubiquitous nature of these exposures and the clinical importance of appropriate androgen stimulation during fetal development.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
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Gray, Kimberly A
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Icahn School of Medicine at Mount Sinai
Public Health & Prev Medicine
Schools of Medicine
New York
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Barrett, E S; Hoeger, K M; Sathyanarayana, S et al. (2018) Anogenital distance in newborn daughters of women with polycystic ovary syndrome indicates fetal testosterone exposure. J Dev Orig Health Dis 9:307-314
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Sathyanarayana, Sheela; Barrett, Emily; Nguyen, Ruby et al. (2016) First Trimester Phthalate Exposure and Infant Birth Weight in the Infant Development and Environment Study. Int J Environ Res Public Health 13:
Barrett, Emily S; Parlett, Lauren E; Sathyanarayana, Sheela et al. (2016) Prenatal Stress as a Modifier of Associations between Phthalate Exposure and Reproductive Development: results from a Multicentre Pregnancy Cohort Study. Paediatr Perinat Epidemiol 30:105-14
Adibi, Jennifer J; Lee, Myoung Keun; Naimi, Ashley I et al. (2015) Human Chorionic Gonadotropin Partially Mediates Phthalate Association With Male and Female Anogenital Distance. J Clin Endocrinol Metab 100:E1216-24
Swan, S H; Sathyanarayana, S; Barrett, E S et al. (2015) First trimester phthalate exposure and anogenital distance in newborns. Hum Reprod 30:963-72

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