Abstract

Abnormal penile foreskin development in hypospadias is the most frequent genital malformation in male children, which has increased dramatically in recent decades. A number of environmental factors 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 (distal), moderate (mid shaft), and severe (proximal) hypospadias. Penile foreskin samples were collected from hypospadias and non-hypospadias individuals to identify alterations in DNA methylation associated with 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 a component of the disease etiology. A genome-wide (> 95%) epigenetic analysis was used and the genomic features of the DMRs identified. The DMR associated genes identified a number of novel hypospadias associated genes and pathways, as well as genes and networks known to be involved in hypospadias etiology. Observations demonstrate altered DNA methylation sites in penile foreskin is a component of hypospadias etiology. In addition, a potential role of environmental epigenetics and epigenetic inheritance in hypospadias disease etiology is suggested.

Details

Title
Role of epigenetics in the etiology of hypospadias through penile foreskin DNA methylation alterations
Author
Kaefer, Martin 1 ; Rink, Richard 1 ; Misseri, Rosalia 1 ; Winchester, Paul 2 ; Proctor, Cathy 2 ; Ben Maamar, Millissia 3 ; Beck, Daniel 3 ; Nilsson, Eric 3 ; Skinner, Michael K. 3 

 Indiana University, Department of Pediatric Urology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919) 
 Indiana University, Department of Pediatrics, St. Franciscan Hospital, School of Medicine, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919) 
 Washington State University, Center for Reproductive Biology, School of Biological Sciences, Pullman, USA (GRID:grid.30064.31) (ISNI:0000 0001 2157 6568) 
Pages
555
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2764039348
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.