Exposure of the developing embryo to endocrine disrupting chemicals (EDCs) has been proposed to underlie a number of human health problems, including birth defects of genitourinary organs, obesity, decreased fertility and cancer. The most common anomaly of the genitourinary system is hypospadias, a malformation of the external genitalia that is characterized by failure of urethral tube closure and incomplete formation of the prepuce (foreskin) and ventral penis. Affected children can have oversized or multiple urethral openings, and children with severe hypospadias are born with ambiguous genitalia. In the industrialized world, the incidence of hypospadias has risen steadily over the past thirty years and now affects approximately 1 in 125 live male births. Genetic screens of patients with hypospadias have, thus far, failed to identify mutations in candidate genes that can account for this condition, and it has been hypothesized that the high incidence of hypospadias may be due to exposure of the embryo to EDCs in the environment. A number of environmental EDCs have been shown to induce hypospadias in rats (and related defects in wildlife) but little is known about how these factors influence the genetic pathways that operate during development of the external genitalia. Our preliminary studies in mice show that EDCs can induce transient down-regulation of genes that control urethral tube formation, suggesting a mutation-independent mechanism by which these factors can disrupt the genetic program that directs genital development. In this project we propose to integrate mouse developmental genetics and ecotoxicology in order to identify how the gene networks that function during penile development are affected by EDCs. The overarching aim of this proposal is to identify the molecular and cellular events that translate embryonic exposure to an EDC into a structural defect of the genitalia. Identifying the genetic targets of EDCs and determining their functions in the genital tubercle (the embryonic anlagen of the penis and clitoris) is critical if we are to (a) understand the mechanisms by which EDCs perturb normal development, (b) understand why developing genitalia are sensitive to EDCs at specific stages of pregnancy, (c) develop new model systems to test EDC effects on genitourinary cells and tissues, and (d) develop preventative treatments such as supplementation to augment EDC-sensitive pathways.

Public Health Relevance

Malformation of the external genitalia is the second most common birth defect in humans, and there is increasing evidence that fetal exposure to endocrine disrupting chemicals (EDCs) plays a role in the rising frequency of occurrence in the industrialized world. This project aims to identify how EDCs alter developmental gene networks and cell behavior to produce hypospadias. The results will identify the mechanisms by which EDCs perturb normal genital development, determine why genitalia are sensitive to EDCs at particular stages of pregnancy, produce new model systems to screen for EDC effects in genitalia, and provide a foundation for development of preventative treatments.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-DKUS-C (90))
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Schug, Thaddeus
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University of Florida
Schools of Medicine
United States
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Armfield, Brooke A; Seifert, Ashley W; Zheng, Zhengui et al. (2016) Molecular Characterization of the Genital Organizer: Gene Expression Profile of the Mouse Urethral Plate Epithelium. J Urol 196:1295-302
Larkins, Christine E; Enriquez, Ana B; Cohn, Martin J (2016) Spatiotemporal dynamics of androgen signaling underlie sexual differentiation and congenital malformations of the urethra and vagina. Proc Natl Acad Sci U S A 113:E7510-E7517
Gredler, Marissa L; Seifert, Ashley W; Cohn, Martin J (2015) Tissue-specific roles of Fgfr2 in development of the external genitalia. Development 142:2203-12
Herrera, Ana M; Brennan, Patricia L R; Cohn, Martin J (2015) Development of avian external genitalia: interspecific differences and sexual differentiation of the male and female phallus. Sex Dev 9:43-52
Zheng, Zhengui; Armfield, Brooke A; Cohn, Martin J (2015) Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies. Proc Natl Acad Sci U S A 112:E7194-203
Gredler, Marissa L; Sanger, Thomas J; Cohn, Martin J (2015) Development of the cloaca, hemipenes, and hemiclitores in the green anole, Anolis carolinensis. Sex Dev 9:21-33
Larkins, Christine E; Cohn, Martin J (2015) Phallus development in the turtle Trachemys scripta. Sex Dev 9:34-42
O'Shaughnessy, Katherine L; Dahn, Randall D; Cohn, Martin J (2015) Molecular development of chondrichthyan claspers and the evolution of copulatory organs. Nat Commun 6:6698
Leal, Francisca; Cohn, Martin J (2015) Development of hemipenes in the ball python snake Python regius. Sex Dev 9:6-20
Gredler, Marissa L; Seifert, Ashley W; Cohn, Martin J (2015) Morphogenesis and patterning of the phallus and cloaca in the American alligator, alligator mississippiensis. Sex Dev 9:53-67

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