Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism
Michelle Welsh, … , Lee B. Smith, Richard M. Sharpe
Michelle Welsh, … , Lee B. Smith, Richard M. Sharpe
Published March 13, 2008
Citation Information: J Clin Invest. 2008;118(4):1479-1490. https://doi.org/10.1172/JCI34241.
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Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism

Abstract

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.

Authors

Michelle Welsh, Philippa T.K. Saunders, Mark Fisken, Hayley M. Scott, Gary R. Hutchison, Lee B. Smith, Richard M. Sharpe

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Figure 3

Androgen concentrations and AR expression in a representative target tissue during the programming and differentiation windows.

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Androgen concentrations and AR expression in a representative target tis...
(A) Fetal testicular testosterone concentration (ng per testis) increases in line with mean fetal body weight (dotted line) between E15.5 and E21.5; red dotted line represents mean ovarian testosterone concentrations from E17.5 females. Note that there was no significant increase in testicular testosterone concentrations at any age compared with values for the previous day. Values are mean ± SEM (n = 4–17). (B) AR (red) expression in urogenital tubercles in males and females at E17.5 and E21.5, showing that the AR expression pattern is comparable in males and females at both ages. The urogenital tubercle has already begun to differentiate into a penis in the E21.5 male, as evidenced by the presence of the os bone (OS) and the corpus cavernosum (CC). Note also that the urethral folds have begun to fuse in the male to form the urethral seam (US; cytokeratin-stained, green), unlike in the female. U, urethra; TA, tunica albuginea; MB, membranous bone. Scale bar: 200 μm.