Review
Hypospadias: Interactions between environment and genetics

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Abstract

Hypospadias is one of the most common congenital malformations. It is considered to be a mild form of the 46,XY disorders of sex development (DSD), but its precise etiology remains to be elucidated. Compromised androgen synthesis or effects can cause this frequent malformation, although the mutational analyses of the genes involved in androgen actions have identified abnormalities in only a very small portion of patients. The overwhelming majority of cases remain unexplained and hypospadias may be a highly heterogeneous condition subject to multiple genetic and environmental factors. We here review the recent advances in this field and discuss the potential interactions between the environment and genetics.

Section snippets

Genetic background

Before evaluating the role of the environment, it should be acknowledged that several arguments are in favor of a predominant role for the genetic background. Familial clustering is seen in about 10% of the cases (Chen and Woolley, 1971, Czeizel et al., 1979, Kallen et al., 1986, Fredell et al., 2002), and the recurrence risk in the male siblings of an affected patient is about 15% (Bauer et al., 1979, Stoll et al., 1990, Asklund et al., 2007). Seven percent of the fathers of children with

Arguments for an environmental contribution

Several findings in both animal and human studies raise suspicion of an environmental contribution to this malformation. Hypospadias, whether associated with micropenis or not, has been reported in numerous wildlife species when the habitat is contaminated by pesticides (Hayes et al., 2002). The effects of prenatal xenoestrogens on animal male reproductive tract development have been studied by several groups. Male rat pups exposed to DES during gestation (at concentrations similar to those

Types of action of environmental pollutants

Environmental pollutants exhibit several genomic and non-genomic actions. They bind to the nuclear receptors such as estrogen receptors α and β (ERα/ERβ), inducing transcription activation (or repression) of specific gene expression (Miyagawa et al., 2010, Couse and Korach, 2004). Non-genomic actions are mediated by a plasma membrane estrogen or androgen receptor. Xenoestrogens have both estrogenic and antiandrogenic actions and compete with natural androgens for the ligand-binding domain (LBD)

Limitations and questions

Although numerous studies point toward a major role for the environment in hypospadias, two limitations should be considered before attempting to draw definitive conclusions. First, caution should be exercised when extrapolating from murine experiments to humans. In these experiments, xenoestrogens induced hypospadias in male offspring exposed in utero, but the doses given to animals may not be comparable to environmental exposure. Second, several epidemiological studies have reported

Conclusion

The study of hypospadias is of interest for several reasons. It is an easily diagnosed malformation and, although minor, it recapitulates the pathophysiology of the disorders of sex development; the investigation of hypospadias thus offers insight into the mechanisms of sex determination and differentiation. Moreover, because hypospadias is at the crossroads of genetics and environment, it is a model for exploring genetic and environmental interactions (Fig. 1). The environmental data to date,

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