Hypospadias, a congenital malformation in which the urethral opening is on the ventral side of the penis, is one of the most common congenital malformations. The main mechanisms believed to underlie hypospadias are environmental and genetic factors that impair maternal, fetal, or placental androgen and estrogen metabolism. However, the contribution of such factors to hypospadias risk has either not been evaluated or has largely been investigated with epidemiologic studies that have numerous limitations. We propose to address these shortcomings with a population-based nested case-control study of pesticides and candidate genes. This study will test the hypothesis that pesticides and candidate genes which interfere with maternal, fetal, or placental sex steroid metabolism affect hypospadias risk through the following specific aims:
Aim 1 - Pesticides and hypospadias. We will determine whether maternal residential proximity to applications of agricultural pesticides around the time of urethral development is associated with increased hypospadias risk. We will examine individual pesticides as well as groupings of pesticides that have common physicochemical or functional properties.
Aim 2 - Candidate genes and hypospadias. We will decipher the association between hypospadias risk and variants in 47 genes from the following mechanistic pathways important to urethral development: fetal and placental biosynthesis and biotransformation of sex steroid hormones, regulation of sex steroid hormone biosynthesis and action, and regulation of genital tubercle outgrowth and differentiation.
These aims will be achieved by linking several sources of existing information: 1) detailed phenotypic data collected as part of a population-based, actively ascertained birth defects registry;2) data from California pesticide-use reports;3) newborn bloodspots collected as part of routine newborn screening;and 4) maternal and newborn descriptive characteristics from vital statistics. Thus, a critical strength of this proposal is that it will utilize epidemiologic data that were collected using rigorous case ascertainment and classification criteria and highly detailed data on exposures and covariates. The proposed research represents the first large-scale epidemiologic study to explore genetic and environmental exposures and hypospadias risk. This work will fill an important gap in our knowledge regarding the highly discussed but minimally studied association of endocrine-related exposures with hypospadias risk. Ultimately this research will provide valuable information about the causes of hypospadias and give avenues for preventive measures against this common congenital malformation.

Public Health Relevance

The proposed research will improve our understanding of the causes of hypospadias. Its findings will contribute to the development of effective interventions or prevention messages, so that hypospadias can be prevented. While this malformation can be treated with surgery, it has a significant impact both on an individual's-and the overall public's-health, with long-term consequences such as impaired sexual function and psychosocial difficulties related to sexuality and sexual activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES017060-06
Application #
8279352
Study Section
Special Emphasis Panel (ZRG1-RUS-F (03))
Program Officer
Mcallister, Kimberly A
Project Start
2008-09-25
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
6
Fiscal Year
2012
Total Cost
$428,856
Indirect Cost
$128,228
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Carmichael, S L; Witte, J S; Ma, C et al. (2014) Hypospadias and variants in genes related to sex hormone biosynthesis and metabolism. Andrology 2:130-7
Carmichael, Suzan L (2014) Birth defects epidemiology. Eur J Med Genet 57:355-8
Woud, Sander Groen In 't; van Rooij, Iris A L M; van Gelder, Marleen M H J et al. (2014) Differences in risk factors for second and third degree hypospadias in the national birth defects prevention study. Birth Defects Res A Clin Mol Teratol 100:703-11
Lind, Jennifer N; Tinker, Sarah C; Broussard, Cheryl S et al. (2013) Maternal medication and herbal use and risk for hypospadias: data from the National Birth Defects Prevention Study, 1997-2007. Pharmacoepidemiol Drug Saf 22:783-93
Carmichael, Suzan L; Cogswell, Mary E; Ma, Chen et al. (2013) Hypospadias and maternal intake of phytoestrogens. Am J Epidemiol 178:434-40
Carmichael, Suzan L; Ma, Chen; Choudhry, Shweta et al. (2013) Hypospadias and genes related to genital tubercle and early urethral development. J Urol 190:1884-92
Carmichael, Suzan L; Mohammed, Nebil; Ma, Chen et al. (2013) Diacylglycerol kinase K variants impact hypospadias in a California study population. J Urol 189:305-11
Carmichael, Suzan L; Yang, Wei; Roberts, Eric M et al. (2013) Hypospadias and residential proximity to pesticide applications. Pediatrics 132:e1216-26