US EPA

171480 

Journal Article 

Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism 

Welsh, M; Saunders, PTK; Fisken, M; Scott, HM; Hutchison, GR; Smith, LB; Sharpe, RM 

2008 

Yes 

Journal of Clinical Investigation
ISSN: 0021-9738
EISSN: 1558-8238 

118 

4 

1479-1490 

English 

18340380 

10.1172/jci34241 

WOS:000254588600041 

Becoming a phenotypic male is ultimately determined by androgen-induced masculinization. Disorders of fetal masculinization, resulting in hypospadias or cryptorchidism, are common, but their cause remains unclear. Together with the adult-onset disorders low sperm count and testicular cancer, they can constitute a testicular dysgenesis syndrome (TDS). Although masculinization is well studied, no unifying concept explains normal male reproductive development and its abnormalities, including TDS. We exposed rat fetuses to either anti-androgens or androgens and showed that masculinization of all reproductive tract tissues was programmed by androgen action during a common fetal programming window. This preceded morphological differentiation, when androgen action was, surprisingly, unnecessary. Only within the programming window did blocking androgen action induce hypospadias and cryptorchidism and altered penile length in male rats, all of which correlated with anogenital distance (AGD). Androgen-driven masculinization of females was also confined to the same programming window. This work has identified in rats a common programming window in which androgen action is essential for normal reproductive tract masculinization and has highlighted that measuring AGD in neonatal humans could provide a noninvasive method to predict neonatal and adult reproductive disorders. Based on the timings in rats, we believe the programming window in humans is likely to be 8-14 weeks of gestation. [ABSTRACT FROM AUTHOR]; Copyright of Journal of Clinical Investigation is the property of American Society for Clinical Investigation and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) 

TESTIS -- Cancer; RATS as laboratory animals; HYPOSPADIAS; CRYPTORCHISM; ANDROGENS