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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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Research Article Development Article has an altmetric score of 135

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

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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 4

The early programming window determines experimental masculinization of the reproductive tract in female rats.

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The early programming window determines experimental masculinization of ...
Reproductive tracts from female rats exposed in utero to testosterone in EW (E15.5–E17.5), MW (E17.5–E19.5), LW (E19.5–E21.5), or FW (E15.5–E21.5) were examined at P17. Exposure to testosterone during the EW or MW resulted in formation of a ventral prostate (A), while exposure to testosterone during the EW induced seminal vesicle formation (B) and increased AGD in females to a male length (C). Exposure to testosterone during any time window increased phallus length compared with that in control females, but not to a male length (D). Values are mean ± SEM (n = 8–21 rats from 2–5 litters per treatment group). ***P < 0.001 compared with control male values; †P < 0.001 compared with control female values. Blue dotted line highlights mean control male level; red dotted line highlights mean control female level.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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