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Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism
Open accessAbstract
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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“Originating from the embryonic yolk sac, microglia migrate and colonize the brain during early development, around embryonic day (E)9.5 in mice.”
From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [31]
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“This precedes a hormonal surge in the brain, with androgens and estrogens peaking at around E17.5–18 [29–34].”
From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [31]
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“Normal masculinization of the fetus is dependent upon androgen secretion by the testis, and androgens act initially during a critical masculinization programming window to ensure normal male reproductive development [3–5].”
From Alternative (backdoor) androgen production and masculinization in the human fetus (2019) · cites this paper as [5]
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Developmental and Reproductive Outcomes in Male Rats Exposed to Triclosan: Two-Generation Study
Montagnini, B. G., Forcato, S., Pernoncini, K. V., Monteiro, M. C., Pereira, M. R. F., Costa, N. O., Moreira, E. G., Anselmo-Franci, J. A., & Gerardin, D. C. C. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.738980 · Cited by 18
“Regarding sexual development, exposure to TCS during intrauterine development, lactation, and, subsequently, throughout development did not alter the AGD of F1 and F2 males, which is a marker of fetal androgen action (74), and also did not affect the day of preputial separation (an indicator of puberty onset) of F1 ma…”
Malm, H. T., & Borisch, C. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-408078-2.00002-0 · Cited by 18
Copulatory efficiency and fertility in male rats exposed perinatally to flutamide
Leonelli, C., Garcia, P. C., & Pereira, O. C. M. (2010) · Reproductive Toxicology · doi:10.1016/j.reprotox.2010.08.003 · Cited by 17
Anogenital Distance: A Marker of Steroidal Endocrine Disruption
Swan, S. H., & Kristensen, D. M. (2018) · Encyclopedia of Reproduction · doi:10.1016/b978-0-12-801238-3.64379-9 · Cited by 17
Bobotis, B. C., Khakpour, M., Braniff, O., de Andrade, E. G., Gargus, M., Allen, M., Carrier, M., Baillargeon, J., Rangachari, M., & Tremblay, M.-È. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03341-6 · Cited by 17
Human sex chromosome aneuploidies: The hypothalamic–pituitary–gonadal axis
Rogol, A. D. (2020) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.31782 · Cited by 16
“This critical time epoch does not coincide with the differentiation of the male reproductive tract, but rather, the appropriate development of the male reproductive tissues depends on earlier in gestation androgen exposure and action (Siiteri & Wilson, 1974; Welsh et al., 2008).”
Sun, X., Liu, C., Wang, Z., Yang, F., Liang, H., Miao, M., Yuan, W., & Kan, H. (2020) · Environmental Pollution · doi:10.1016/j.envpol.2020.114684 · Cited by 17
Evans, S. F., Raymond, S., Sethuram, S., Barrett, E. S., Bush, N. R., Nguyen, R. H. N., Sathyanarayana, S., & Swan, S. H. (2020) · Environmental Research · doi:10.1016/j.envres.2020.110264 · Cited by 18
Paracetamol Use During Pregnancy—A Call for Precautionary Action
Bauer, A. Z., Swan, S. H., Kriebel, D., Liew, Z., Taylor, H. S., Bornehag, C., Martino‐Andrade, A. J., Olsen, J., Jensen, R., Mitchell, R. T., et al. (2022) · Obstetrical & Gynecological Survey · doi:10.1097/ogx.0000000000001019 · Cited by 17
A not so circular healthcare economy: A review of challenges with plastic associated chemicals
Ramos, T. M., Christensen, T. B., Bour, A., Almroth, B. C., Kristensen, D. M., Selck, H., & Syberg, K. (2023) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2023.117191 · Cited by 19
Barthold, J. S., Wang, Y., Robbins, A. K., Pike, J. W., McDowell, E. N., Johnson, K. J., & McCahan, S. M. (2013) · Biology of Reproduction · doi:10.1095/biolreprod.113.112953 · Cited by 17
“1); 2) AR protein is expressed primarily in mesenchymal cell nuclei at E16 to E19 [3, 6–8], coincident with the window of susceptibility to antiandrogen-induced cryptorchidism [34, 38–40]; and 3) targeted disruption of Ar in the developing fetal gubernaculum impairs its development [7].”
Llorca, M., Pérez, F., Farré, M., Agramunt, S., Kogevinas, M., & Barceló, . (2012) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2012.05.080 · Cited by 17
Olsson, A. C., Togawa, K., Schüz, J., Cornet, C. L., Fervers, B., Dalton, S. O., Pukkala, ., Feychting, M., Skakkebæk, N. E., & Hansen, J. (2018) · Scandinavian Journal of Work Environment & Health · doi:10.5271/sjweh.3732 · Cited by 19
“Experimental studies have suggested that prenatal exposure to EDC adversely affects the development of reproductive organs in offspring (10, 11) and supported a potential effect of solvent exposure, notably toluene, on the testes (37, 38).”
Christensen, J. V. R., Bangash, K. K., Weihe, P., Grandjean, P., Nielsen, F., Jensen, T. K., & Petersen, M. S. (2021) · Reproductive Toxicology · doi:10.1016/j.reprotox.2021.06.016 · Cited by 16
Dioxin-induced changes in epididymal sperm count and spermatogenesis
Foster, W. G., Maharaj-Briceño, S., & Cyr, D. G. (2011) · Ciência & Saúde Coletiva · doi:10.1590/s1413-81232011000600027 · Cited by 17
“Fetal androgen development in humans occurs during weeks 8–37 of gestation (Siiteri and Wilson 1974), so the early programming window of development in rats corresponds to weeks 8–14 of development in humans (Welsh et al. 2008).”
Ribeiro, C. M., Ferreira, L. G. A., Thimoteo, D. S., Smith, L. B., Hinton, B. T., & Avellar, M. C. W. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.12.016 · Cited by 17
“During very early development of the WD, androgens are essential for the stabilization of the duct in male embryos and later are also needed for the 45! subsequent differentiation of the WD into the epididymis (Welsh et al., 2007, 2008; Murashima et al., 2011).”
Bourguignon, N. S., Bonaventura, M. M., Rodríguez-Muñoz, D., Bizzozzero-Hiriart, M., Ventura, C., Núñez, M., Lux-Lantos, V. A., & Libertun, C. (2017) · Reproductive Toxicology · doi:10.1016/j.reprotox.2017.01.002 · Cited by 17
Teratogenic effects of in utero exposure to di-(2-ethylhexyl)-phthalate (DEHP) in B6:129S4 mice
Ungewitter, E. K., Rotgers, E., Bantukul, T., Kawakami, Y., Kissling, G. E., & Yao, H. H. (2017) · Toxicological Sciences · doi:10.1093/toxsci/kfx019 · Cited by 17
Phthalate Toxicity in Rats and Its Relation to Testicular Dysgenesis Syndrome in Humans
Willson, C. J. (2021) · Toxicologic Pathology · doi:10.1177/01926233211045331 · Cited by 16
Morimoto, S., Solís‐Lemus, E., Jiménez‐Vivanco, J., Castellanos‐Ruiz, D., Díaz‐Díaz, E., & Mendoza-Rodríguez, C. A. (2022) · Environmental Toxicology · doi:10.1002/tox.23585 · Cited by 15
Holmboe, S. A., Henriksen, L. S., Frederiksen, H. W., Andersson, A., Priskorn, L., Jørgensen, N., Juul, A., Toppari, J., Skakkebæk, N. E., & Main, K. M. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1071761 · Cited by 16
Gray, L. E. (2023) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2023.116454 · Cited by 16
Sex chromosome aneuploidies and fertility: 47,XXY, 47,XYY, 47,XXX and 45,X/47,XXX
Rogol, A. D. (2023) · Endocrine Connections · doi:10.1530/ec-22-0440 · Cited by 21
“The masculinization programming window (late first to early second trimester) [14] depends on earlier in gestation androgen action [15, 16].”
Stephen, M. A., Burke, C. R., Steele, N. M., Pryce, J. E., Meier, S., Amer, P. R., Phyn, C. V. C., & Garrick, D. J. (2023) · Journal of Dairy Science · doi:10.3168/jds.2023-23427 · Cited by 16
Dar, J. A., Masoodi, K. Z., Eisermann, K., Isharwal, S., Ai, J., Pascal, L. E., Nelson, J. B., & Wang, Z. (2014) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2014.03.004 · Cited by 16
“Androgens play a vital role in the development and homeostasis of male sex organs (1) as well as the development and progression of benign prostatic hyperplasia (BPH) and prostate”
Endocrine-disrupting Chemicals (EDCs) in Mammals
Pelch, K. E., Beeman, J. M., Niebruegge, B. A., Winkeler, S. R., & Nagel, S. C. (2011) · Elsevier eBooks · doi:10.1016/b978-0-12-374928-4.10014-8 · Cited by 16
Assessment of the analgesic dipyrone as a possible (anti)androgenic endocrine disruptor
Passoni, M. T., Kristensen, M. N., de Morais, R. N., Woitkowiak, C., Boareto, A. C., Amaral, B. A. D. S., Grechi, N., Dalsenter, P. R., Munkboel, C. H., Styrishave, B., et al. (2017) · Toxicology Letters · doi:10.1016/j.toxlet.2017.12.021 · Cited by 16
Isoflavone Intake in Early Pregnancy and Hypospadias in the Japan Environment and Children's Study
Michikawa, T., Yamazaki, S., Ono, M., Kuroda, T., Nakayama, S. F., Suda, E., Isobe, T., Iwai‐Shimada, M., Kobayashi, Y., Yonemoto, J., et al. (2018) · Urology · doi:10.1016/j.urology.2018.11.008 · Cited by 16
“0/) the 8th-14th week of gestation.(1) Although androgen is the main masculinisation-related sex hormone, it appears that oestrogen also contributes to the differentiation of male external genitalia,(2) and the importance of the balance between androgen and oestrogen has been noted.”
Najdi, N., Safi, F., Dizaji, S. H., Sahraian, G., & Jand, Y. (2019) · International Journal of Reproductive BioMedicine (IJRM) · doi:10.18502/ijrm.v17i1.3820 · Cited by 16
“In animal models, this distance represents fetal exposure to androgens during masculinization (16, 17).”
The relationship between anogenital distance and lifelong premature ejaculation
Toprak, T., Şahin, A., Akgül, K. T., Kutluhan, M. A., Ramazanoglu, M. A., Yılmaz, M., Şahan, A., & Verit, A. (2019) · Andrology · doi:10.1111/andr.12709 · Cited by 16
Metadata
- 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
- Venue
- Journal of Clinical Investigation
- Published
- 2008-04-01
- Volume
- 118
- Issue
- 4
- Pages
- 1479-1490
- ISSN
- 0021-9738 (ISSN-L)
- 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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