Cited by 782Sexual Differentiation and DisordersUrological Disorders and TreatmentsEffects and risks of endocrine disrupting chemicals

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

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Welsh, Michelle, Saunders, Philippa T.K., Fisken, Mark, Scott, Hayley M., Hutchison, Gary R., Smith, Lee B., Sharpe, Richard M.·2008·Journal of Clinical Investigation

DOI 10.1172/jci34241PMC PMC2267017

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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.

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The Physiology of Reproduction
Legendre, M., & Jalabert, B. (1988) · Annals of Internal Medicine · doi:10.7326/0003-4819-109-2-176_1 · Cited by 7,876
Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects: Opinion
Skakkebæk, N. E., Meyts, E. R., & Main, K. M. (2001) · Human Reproduction · doi:10.1093/humrep/16.5.972 · Cited by 2,261
Male development of chromosomally female mice transgenic for Sry
Koopman, P. A., Gubbay, J., Vivian, N., Goodfellow, P. N., & Lovell-Badge, R. H. (1991) · Nature · doi:10.1038/351117a0 · Cited by 2,193
Decrease in anogenital distance among male infants with prenatal phthalate exposure
Swan, S. H., Main, K. M., Liu, F., Stewart, S. L., Kruse, R. L., Calafat, A. M., Mao, C. S., Redmon, J. B., Ternand, C. L., Sullivan, S., et al. (2005) · Environmental Health Perspectives · doi:10.1289/ehp.8100 · Cited by 1,586
Book review
Brodie, S. E. (1996) · Survey of Ophthalmology · doi:10.1016/s0039-6257(96)80075-0 · Cited by 770
Testosterone Formation and Metabolism During Male Sexual Differentiation in the Human Embryo
Siiteri, P. K., & Wilson, J. D. (1974) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-38-1-113 · Cited by 591
Studies on Sex Differentiation in Mammals
JOST, A., Vigier, B., Prépin, J., & PERCHELLET, J. P. (1973) · Elsevier eBooks · doi:10.1016/b978-0-12-571129-6.50004-x · Cited by 566
Human 'testicular dysgenesis syndrome': a possible model using in-utero exposure of the rat to dibutyl phthalate
Fisher, J. S. (2003) · Human Reproduction · doi:10.1093/humrep/deg273 · Cited by 550
Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries
Boisen, K. A., Kaleva, M. M., Main, K. M., Virtanen, H. E., Haavisto, A.-M., Schmidt, I., Chellakooty, M., Damgaard, I., Kai, C. M., Reunanen, M. S., et al. (2004) · The Lancet · doi:10.1016/s0140-6736(04)15998-9 · Cited by 510
Testicular dysgenesis syndrome: mechanistic insights and potential new downstream effects
Sharpe, R. M., & Skakkebæk, N. E. (2008) · Fertility and Sterility · doi:10.1016/j.fertnstert.2007.12.026 · Cited by 452

Flagged first, then by citations

Show all 61 references

Research works printed but not linked: 10

Jost, 1972, Johns Hopkins Med. J., 130, 38
Sharpe, 2008, Fertil. Steril.
Inomata, 1985, Jikken Dobutsu., 34, 439
Jirasek, 1977, Birth Defects Orig. Artic. Ser., 13, 13
Wyndham, 1943, J. Anat., 77, 179
10.1210/en.131.3.1149 · DOI
Jost, 1973, Recent Prog. Horm. Res., 29, 1
Stinnakre, 1975, Arch. Anat. Microsc. Morphol. Exp., 64, 45
Murakami, 1987, J. Anat., 153, 223
Hsieh, 2008, Curr. Urol. Rep.

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Smith, L. B., & Walker, W. H. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-397175-3.00016-8 · Cited by 46
Association between levels of persistent organic pollutants in adipose tissue and cryptorchidism in early childhood: a case–control study
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The prepubertal testis
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“Androgens drive internal and external genital virilization [2,3], while both testosterone and INSL3 are involved in testicular descent [4 & ,5 & ].”
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Toni, L. D., Nisio, A. D., Speltra, E., Rocca, M. S., Ghezzi, M., Zuccarello, D., Turiaco, N., Ferlin, A., & Foresta, C. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-3967 · Cited by 41
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In vitro effects of Uranium on human fetal germ cells
Angenard, G., Muczynski, V., Coffigny, H., Duquenne, C., Frydman, R., Habert, R., Livera, G., & Rouiller, V. (2011) · Reproductive Toxicology · doi:10.1016/j.reprotox.2010.12.058 · Cited by 33
The GC-IGF1 axis-mediated testicular dysplasia caused by prenatal caffeine exposure
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Interpretation of studies on the developmental reproductive toxicology of 2,3,7,8-tetrachlorodibenzo-p-dioxin in male offspring
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Effects of maternal exposure to di-isononylphthalate (DINP) and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p′-DDE) on steroidogenesis in the fetal rat testis and adrenal gland
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Association between altered placental human chorionic gonadotrophin (hCG) production and the occurrence of cryptorchidism: a retrospective study
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Influential

Authors: Welsh, M., Saunders, P. T. K., Fisken, M., Scott, H. M., Hutchison, G. R., Smith, L. B., & Sharpe, R. M.
Affiliations: The Queen's Medical Research Institute (GB)
Corresponding author: Welsh, Michelle
ORCID: Welsh, Michelle
Saunders, Philippa T.K.
Scott, Hayley M.
Smith, Lee B.
Sharpe, Richard M.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2008-04-01
Volume: 118
Issue: 4
Pages: 1479-1490
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci34241
PMC: PMC2267017
OpenAlex: W2003163696
Cited by: 781
References: 61
Citations by year: 2026: 23 · 2025: 39 · 2024: 27 · 2023: 54 · 2022: 58 · 2021: 43 · 2020: 54 · 2019: 47 · 2018: 49 · 2017: 38 · 2016: 45 · 2015: 48 · 2014: 45 · 2013: 42 · 2012: 39
FWCI: 17.53
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Edinburgh Napier Research Repository (Edinburgh Napier University) (submittedVersion, cc-by-nc)
ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
Funders: Medical Research Council
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Sexual Differentiation and Disorders
Health Sciences › Medicine › Urology › Urological Disorders and Treatments
Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
Keywords: fetal programming, hypospadias, cryptorchidism, testicular dysgenesis, androgen action, androgen receptor antagonists, androgens, anogenital distance, penile length, fetal development, pregnancy timing
MeSH terms: Androgens, Animals, Cryptorchidism, Embryo, Mammalian, Female, Gonads, Hypospadias, Male, Receptors, Androgen, Sex Characteristics, Sex Differentiation, Testosterone, Rats, Wistar, Rats

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

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