Endocrine disrupting chemicals in the pathogenesis of hypospadias; developmental and toxicological perspectives

Abstract

Hypospadias is a defect in penile urethral closure that occurs in approximately 1/150 live male births in developed nations, making it one of the most common congenital abnormalities worldwide. Alarmingly, the frequency of hypospadias has increased rapidly over recent decades and is continuing to rise. Recent research reviewed herein suggests that the rise in hypospadias rates can be directly linked to our increasing exposure to endocrine disrupting chemicals (EDCs), especially those that affect estrogen and androgen signalling. Understanding the mechanistic links between endocrine disruptors and hypospadias requires toxicologists and developmental biologists to define exposures and biological impacts on penis development. In this review we examine recent insights from toxicological, developmental and epidemiological studies on the hormonal control of normal penis development and describe the rationale and evidence for EDC exposures that impact these pathways to cause hypospadias. Continued collaboration across these fields is imperative to understand the full impact of endocrine disrupting chemicals on the increasing rates of hypospadias.

Keywords: Androgen; BBP, benzyl butyl phthalate; BPA, bisphenol A; DBP, Σdibutyl phthalate; DDT, dichlorodiphenyltrichloroethane; DEHP, Σdi-2(ethylhexyl)-phthalate; DHT, dihydrotestosterone; EDC, endocrine disrupting chemicals; EMT, epithelial to mesenchymal transition; ER, estrogen receptor; Endocrine disruptors; Estrogen; GT, genital tubercle; Hypospadias; NOAEL, no observed adverse effect level; PBB, polybrominated biphenyl; PBDE, polybrominated diphenyl ether; PCB, polychlorinated biphenyl; PCE, tetrachloroethylene; Penis.