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Candidate genes and their response to environmental agents in the etiology of hypospadias

Nature Clinical Practice Urology volume 4, pages 270–279 (2007)Cite this article

Abstract

The molecular events that lead to isolated hypospadias remain largely unknown, and the etiology of this common congenital anomaly seems to be multifactorial. We have explored the response of several candidate genes to environmental agents that cause hypospadias in a mouse model. Here, we provide an overview of current findings in relation to candidate genes and their response to environmental agents, including the results of genomic analyses of both mouse and human tissues. In addition to steroid-hormone receptors, one gene of specific interest is activating transcription factor 3 (ATF3). We hypothesize a potential mechanism of action for ATF3 and other identified genes, including TGF-B.

Key Points

  • Hypospadias probably has multifactorial origins that involve the actions of environmental factors and endocrine-active compounds against a genetic backdrop, although few molecular and mechanistic studies have been done

  • Mesenchymal–epithelial signaling and transitions are hypothesized to form a large part of the appropriate development of the male urethra

  • Microarray studies that compared gene expression in genital tubercle epithelium and mesenchyme throughout development suggest the involvement of the transforming growth factor β signaling pathway, among others, in urethral development

  • Microarray studies have identified the upregulation of a handful of genes that are also estrogen-responsive, which potentially supports the proposed involvement of estrogenic or antiandrogenic environmental compounds in the etiology of hypospadias

  • Characterization of the activating transcription factor 3 gene has shown that it is estrogen-responsive in vivo and in vitro, and that its expression is associated with human hypospadiac tissue

  • Activating transcription factor 3 is also involved in transforming growth factor β signaling, along with SMAD3 or SMAD4, estrogen receptor 1, and the inhibitor of DNA binding 1; this mechanistic pathway seems to be a candidate for further exploration

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Figure 1: A suggested mechanism for the cause of hypospadias
Figure 2: Different severities of hypospadias
Figure 3: A mouse model of hypospadias

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Acknowledgements

This work was supported by NIH grant R01 DK058105.

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Authors and Affiliations

  1. Department of Urology, E Willingham is a former Postdoctoral Fellow and LS Baskin is Chief of Pediatric Urology at UCSF Institute for the Study and Treatment of Hypospadias, University of California, San Francisco, CA, USA.,

    Emily Willingham & Laurence S Baskin

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  1. Emily Willingham
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  2. Laurence S Baskin
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Correspondence to Emily Willingham.

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The authors declare no competing financial interests.

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Willingham, E., Baskin, L. Candidate genes and their response to environmental agents in the etiology of hypospadias. Nat Rev Urol 4, 270–279 (2007). https://doi.org/10.1038/ncpuro0783

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