Novel Epigenetic Approach to Investigate Hypospadias

Submitted by UCSF Urology on January 9, 2013 at 3:27 pm
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Shweta Choudhry, PhD

Hypospadias is one of the most frequent genital malformations in the male newborn, and results from abnormal penile and urethral development. The prevalence of hypospadias in the United States is approximately 5 per 1,000 live male births, and has been increasing during the last few decades. The etiology of hypospadias remains largely unknown despite intensive investigations. Associate Professor of Urology, Shweta Choudhry, PhD with senior investigator Dr. Lawrence S. Baskin, MD and Drs. Deshpande, Qiao, Beckman, and Sen, used a new exciting approach to study hypospadias and published the results in the Journal of Urology. The study brought together a multi-disciplinary team of investigators including urologists, genetic epidemiologists, statistical geneticists and molecular biologists from University of California San Francisco and University of Minnesota.

The development of the male urogenital tract is regulated by steroid hormones and it has been postulated that changes in the concentrations of sex hormones during the critical period of penile and urethral development causes hypospadias. Maternal exposure during fetal development to endocrine disrupting chemicals which mimic steroid hormones has been shown to be linked to hypospadias in both human epidemiologic and mouse in vivo studies. Recent studies on environmental chemicals and toxins have shown that they can alter DNA methylation patterns which result in epigenetic alterations.

“Based on these observations,” explains Choudhry, “we hypothesized that DNA methylation changes mediated by environmental exposure may play a role in the etiology of hypospadias.”

The term epigenetics refers to the overall molecular phenomenon which is heritable from parents and that regulates gene expression without any alteration of the genomic DNA sequence. These heritable epigenetic changes include DNA methylation, post-translational modifications of histones tails and chromatin remodeling. Dr. Choudhry and her group performed a systematic appraisal of DNA methylation changes to identify etiologically relevant loci for hypospadias using state-of the art genome-wide methylation panels which enable the direct investigation of methylation status of more than 485,000 individual sites throughout the genome. The methylation level at each site was then compared between patients with hypospadias and healthy controls. The study revealed 14 methylation sites across the genome that were associated with hypospadias including in the genes SCARB1, SORBS1 and HOXD11 that have previously been shown to play a role in male genital development.

The study supports the utility of a genome-wide DNA methylation approach, and the potential prospects for larger and subsequent replication studies to identify novel epigenomic factors in the etiology of hypospadias.

“We are excited about the future of this research,” says Choudhry, “especially considering that most epigenetic alterations are reversible both in vitro and in vivo. It suggests that a new therapy targeting complexes that catalyze epigenetic modifications could be found in the future.”

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