Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window

Sander van den Driesche; Karen R Kilcoyne; Ida Wagner; Diane Rebourcet; Ashley Boyle; Rod Mitchell; Chris McKinnell; Sheila Macpherson; Roland Donat; Chitranjan J Shukla; Anne Jorgensen; Ewa Rajpert-De Meyts; Niels E Skakkebaek; Richard M Sharpe

doi:10.1172/jci.insight.91204

Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window

Sander van den Driesche, Karen R Kilcoyne, Ida Wagner, Diane Rebourcet, Ashley Boyle, Rod Mitchell, Chris McKinnell, Sheila Macpherson, Roland Donat, Chitranjan J Shukla, Anne Jorgensen, Ewa Rajpert-De Meyts, Niels E Skakkebaek, Richard M Sharpe

Department of Clinical Medicine

47 Citations (Scopus)

Abstract

The testicular dysgenesis syndrome (TDS) hypothesis, which proposes that common reproductive disorders of newborn and adult human males may have a common fetal origin, is largely untested. We tested this hypothesis using a rat model involving gestational exposure to dibutyl phthalate (DBP), which suppresses testosterone production by the fetal testis. We evaluated if induction of TDS via testosterone suppression is restricted to the "masculinization programming window" (MPW), as indicated by reduction in anogenital distance (AGD). We show that DBP suppresses fetal testosterone equally during and after the MPW, but only DBP exposure in the MPW causes reduced AGD, focal testicular dysgenesis, and TDS disorders (cryptorchidism, hypospadias, reduced adult testis size, and compensated adult Leydig cell failure). Focal testicular dysgenesis, reduced size of adult male reproductive organs, and TDS disorders and their severity were all strongly associated with reduced AGD. We related our findings to human TDS cases by demonstrating similar focal dysgenetic changes in testes of men with preinvasive germ cell neoplasia (GCNIS) and in testes of DBP-MPW animals. If our results are translatable to humans, they suggest that identification of potential causes of human TDS disorders should focus on exposures during a human MPW equivalent, especially if negatively associated with offspring AGD.

Original language	English
Article number	e91204
Journal	JCI insight
Volume	2
Issue number	6
Number of pages	20
ISSN	2379-3708
DOIs	https://doi.org/10.1172/jci.insight.91204
Publication status	Published - 23 Mar 2017

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Journal Article

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van den Driesche, S., Kilcoyne, K. R., Wagner, I., Rebourcet, D., Boyle, A., Mitchell, R., McKinnell, C., Macpherson, S., Donat, R., Shukla, C. J., Jorgensen, A., Meyts, E. R-D., Skakkebaek, N. E., & Sharpe, R. M. (2017). Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window. JCI insight, 2(6), [e91204]. https://doi.org/10.1172/jci.insight.91204

van den Driesche, S, Kilcoyne, KR, Wagner, I, Rebourcet, D, Boyle, A, Mitchell, R, McKinnell, C, Macpherson, S, Donat, R, Shukla, CJ, Jorgensen, A, Meyts, ER-D, Skakkebaek, NE & Sharpe, RM 2017, 'Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window', JCI insight, vol. 2, no. 6, e91204. https://doi.org/10.1172/jci.insight.91204

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AU - Boyle, Ashley

AU - Mitchell, Rod

AU - McKinnell, Chris

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AU - Donat, Roland

AU - Shukla, Chitranjan J

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AU - Sharpe, Richard M

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AB - The testicular dysgenesis syndrome (TDS) hypothesis, which proposes that common reproductive disorders of newborn and adult human males may have a common fetal origin, is largely untested. We tested this hypothesis using a rat model involving gestational exposure to dibutyl phthalate (DBP), which suppresses testosterone production by the fetal testis. We evaluated if induction of TDS via testosterone suppression is restricted to the "masculinization programming window" (MPW), as indicated by reduction in anogenital distance (AGD). We show that DBP suppresses fetal testosterone equally during and after the MPW, but only DBP exposure in the MPW causes reduced AGD, focal testicular dysgenesis, and TDS disorders (cryptorchidism, hypospadias, reduced adult testis size, and compensated adult Leydig cell failure). Focal testicular dysgenesis, reduced size of adult male reproductive organs, and TDS disorders and their severity were all strongly associated with reduced AGD. We related our findings to human TDS cases by demonstrating similar focal dysgenetic changes in testes of men with preinvasive germ cell neoplasia (GCNIS) and in testes of DBP-MPW animals. If our results are translatable to humans, they suggest that identification of potential causes of human TDS disorders should focus on exposures during a human MPW equivalent, especially if negatively associated with offspring AGD.

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Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window

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