Hormone-responsive genes in the SHH and WNT/β-catenin signaling pathways influence urethral closure and phallus growth

Biology of Reproduction
Yu ChenMarilyn B Renfree

Abstract

Environmental endocrine disruptors (EEDs) that affect androgen or estrogen activity may disrupt gene regulation during phallus development to cause hypospadias or a masculinized clitoris. We treated developing male tammar wallabies with estrogen and females with androgen from day 20-40 postpartum (pp) during the androgen imprinting window of sensitivity. Estrogen inhibited phallus elongation but had no effect on urethral closure and did not significantly depress testicular androgen synthesis. Androgen treatment in females did not promote phallus elongation but initiated urethral closure. Phalluses were collected for transcriptome sequencing at day 50 pp when they first become sexually dimorphic to examine changes in two signaling pathways, sonic hedgehog (SHH) and wingless-type MMTV integration site family (WNT)/β-catenin. SHH mRNA and β-catenin were predominantly expressed in the urethral epithelium in the tammar phallus, as in eutherian mammals. Estrogen treatment and castration of males induced an upregulation of SHH, while androgen treatment downregulated SHH. These effects appear to be direct since we detected putative estrogen receptor α (ERα) and androgen receptor (AR) binding sites near SHH. WNT5A, like SHH, was downreg...Continue Reading

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Citations

Feb 16, 2020·International Journal of Molecular Sciences·Gerard A TarulliMarilyn B Renfree
Sep 3, 2019·Journal of Developmental Origins of Health and Disease·Luke C GoversMark P Green
Aug 5, 2021·Current Research in Toxicology·Deidre M Mattiske, Andrew J Pask

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