Role of Epigenetics in the Etiology of Hypospadias through Foreskin DNA Methylation Alterations

Abnormal foreskin and penile development in hypospadias is the most frequent genital malformation in male children, which has increased dramatically in recent decades. Environmental factors (i.e., endocrine disruptors) have been shown to be associated with hypospadias development. The current study investigated the role of epigenetics in the etiology of hypospadias and compared mild, moderate, and severe hypospadias. Dramatic numbers of differential DNA methylation regions (DMRs) were observed in the mild hypospadias, with reduced numbers in moderate and low numbers in severe hypospadias. Atresia (cell loss) of the principal foreskin fibroblast is suspected to be the cause. This study was designed to collect foreskin fibroblasts from mild, moderate, and severe hypospadias male patients and compare with foreskin from non-disease control population patients. The DNA methylation in the foreskin cell populations was assessed using MeDIP-seq and compared to identify differential DNA methylation regions (DMRs) associated with hypospadias disease etiology.