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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Microglia originate from the embryonic yolk sac, migrate and colonize the brain during early development, around E9.5 in mice.
“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]
The Introduction discusses fetal reproductive-tract masculinization, and the Figure 6 passage discusses androgen action in rats; neither addresses microglia. Searches for microglia, yolk-sac origin, brain colonization, and E9.5 in mice found no relevant passage in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredMicroglial colonization precedes a hormonal surge in the brain, with androgens and estrogens peaking at around E17.5-18.
“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]
The Introduction (page unavailable) discusses fetal testosterone production and mentions brain masculinization in primates, but does not describe a hormonal surge in the rat brain. Figure 3 (page unavailable) reports testicular testosterone concentrations from E15.5 to E21.5, not brain androgen or estrogen peaks. Searches for a prenatal brain hormone peak, estrogens, and microglia found no passage establishing the claimed sequence or E17.5–18 peak. (LLM, conf=0.74)
Experimental — accuracy not yet measuredNormal masculinization of the fetus is dependent upon androgen secretion by the testis, and androgens act initially during a critical masculinization programming window.
“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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Shorter Anogenital Distance Predicts Poorer Semen Quality in Young Men in Rochester, New York
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“As animal studies (Welsh et al. 2008) have clearly shown, AGD is determined within a discrete masculinization programming window that is determined by androgen action.”
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Synergistic Disruption of External Male Sex Organ Development by a Mixture of Four Antiandrogens
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Prenatal phthalate exposure and reduced masculine play in boys
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“…animals, when exposure occurs during the period of foetal sexual differentiation, some phthalates, notably di(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP), inhibit the synthesis of testosterone by Leydig cells, thereby reducing foetal testosterone concentration (Welsh et al., 2008).”
InfluentialHunt, P. A., Sathyanarayana, S., Fowler, P., & Trasande, L. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-2873 · Cited by 199 · see citing works
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“For humans, it is hypothesized that androgen activity around weeks 8–14 of gestation programs later transinguinal descent during weeks 26–35, which would move the susceptible time window to a much earlier gestational age than previously assumed.(4) In humans, late transinguinal testicular descent is androgendependent…”
Analgesic use — prevalence, biomonitoring and endocrine and reproductive effects
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The Regulation of Testicular Descent and the Effects of Cryptorchidism
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“( Wartenberg 1989 ). Sertoli cells then differentiate in the gonadal ridge and surround the germ”
Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells
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“5 in rats when intratesticular testosterone levels are high/increasing (33, 40).”
Testicular dysgenesis syndrome: foetal origin of adult reproductive problems
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“In reviewing the toxicological data on phthalate exposure and fertility outcomes, the panel identified extensive and strong evidence that developmental exposure to several antiandrogenic phthalates affected male reproductive development, leading to a long list of adverse effects including reduced AGD, increased preval…”
Alternative (backdoor) androgen production and masculinization in the human fetus
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Factors controlling testis descent
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Hormone Regulation in Testicular Development and Function
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Hypogonadism and Cryptorchidism
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“5 in rats (equivalent to GW 7–15 in humans) is related to the occurrence of cryptorchidism (9, 18, 146, 147).”
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“ing the MPW can lead to maldevelopment of the male sexual organs, leading to shortened AGD, hypospadias, cryptorchidism, and altered penile length (Bowman et al., 2003; Hsieh, 2008; Welsh et al., 2008).”
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Of Mice and Men (and Rats): Phthalate-Induced Fetal Testis Endocrine Disruption Is Species-Dependent
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“These types of studies are difficult to perform because of the need to examine phthalate exposure during the critical window of male reproductive tract masculinization (presumed to be gestational weeks 8–14; Welsh et al., 2008), the relatively low level of human phthalate exposure in pregnant women, and the lack of ac…”
InfluentialGonadal Maldevelopment as Risk Factor for Germ Cell Cancer: Towards a Clinical Decision Model
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“This observation provides a mechanism by which endocrine disrupters could exert a direct or indirect effect on the gonad during embryonic development [33], especially during a definedwindowof sensitivity.”
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“intratesticular testosterone (ITT) can result in a subsequent male reproductive disorder (2, 3).”
InfluentialThankamony, A., Lek, N., Carroll, D., Williams, M. P. L., Dunger, D. B., Acerini, C. L., Ong, K. K., & Hughes, I. A. (2013) · Environmental Health Perspectives · doi:10.1289/ehp.1307178 · Cited by 143 · see citing works
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“…al., 2012a); these effects were found to depend on the compound considered, its dose, the rat strain used and the male genital tract development window at which the fetuses are exposed (Ema et al., 2000; Gray et al., 2000; Wilson et al., 2004, 2007; Carruthers and Foster, 2005; Welsh et al., 2008).”
InfluentialRegulation of testicular descent
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Human infertility: are endocrine disruptors to blame?
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Fetal programming of sexual development and reproductive function
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Obstetrical outcomes and biomarkers to assess exposure to phthalates: A review
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Hormones as epigenetic signals in developmental programming
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InfluentialChauvigné, F., Menuet, A., Lesné, L., Chagnon, M., Chevrier, C., Regnier, J.-F., Angerer, J., & Jégou, B. (2008) · Environmental Health Perspectives · doi:10.1289/ehp.11870 · Cited by 123 · see citing works
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“…the androgen/estrogen balance in the developing male fetus and impact external genital differentiation in animals (Vos et al., 2000; Guillette and Gunderson, 2001; Gulledge et al., 2001; Welsh et al., 2008, 2010) and humans (Sultan et al., 2001a,b; Vidaeff and Sever, 2005; Martin et al., 2008).”
InfluentialMetformin exposure affects human and mouse fetal testicular cells
Tartarin, P., Moison, D., Guibert, E., Dupont, J., Habert, R., Rouiller, V., Frydman, N., Pozzi, S., Frydman, R., Lécureuil, C., et al. (2012) · Human Reproduction · doi:10.1093/humrep/des264 · Cited by 115 · see citing works
“Based on the timing in rats, the programming window in humans is likely to be between 8 and 14 weeks after fertilization (Welsh et al., 2008).”
Androgens and the masculinization programming window: human–rodent differences
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Cryptorchidism and endocrine disrupting chemicals
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Prenatal phthalate exposure and reproductive function in young men
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Low-dose effects of bisphenol A on early sexual development in male and female rats
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The Impact of Environmental and Occupational Exposures on Reproductive Health
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Amniotic Fluid Phthalate Levels and Male Fetal Gonad Function
Lindhard, M. S., Anand‐Ivell, R., Nørgaard‐Pedersen, B., Jönsson, B., Bonde, J. P., HOUGAARD, D. M., Cohen, A. S., Lindh, C. H., Ivell, R., & Toft, G. V. (2014) · Epidemiology · doi:10.1097/ede.0000000000000198 · Cited by 107 · see citing works
Comparative Aspects of Pre‐ and Postnatal Development of the Male Reproductive System
Picut, C., Ziejewski, M. K., & Stanislaus, D. (2018) · Birth Defects Research · doi:10.1002/bdr2.1133 · Cited by 82 · see citing works
“The AGD is the simplest and least invasive measure of reduced androgen exposure during the MPW (Welsh et al., 2008, 2010; Scott et al., 2009).”
Influentialvan den Driesche, S., Scott, H. M., MacLeod, D. J., Fisken, M., Walker, M., & Sharpe, R. M. (2011) · International Journal of Andrology · doi:10.1111/j.1365-2605.2011.01175.x · Cited by 107 · see citing works
“, 2009), consistent with occurrence of an MPW in humans (Welsh et al., 2008).”
InfluentialO’Hara, L., Welsh, M., Saunders, P. T. K., & Smith, L. B. (2010) · Endocrinology · doi:10.1210/en.2010-0928 · Cited by 107 · see citing works
Self-citationBisphenol A: developmental toxicity from early prenatal exposurea
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“In rodents, AGD is a marker for other abnormalities of genital differentiation (Welsh et al., 2008).”
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“normal phenotypic masculinization [11,12].”
Prenatal paracetamol exposure is associated with shorter anogenital distance in male infants
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“…function, which in animal models reflects androgen action during the masculinisation programming window (MPW), the developmental period during which sufficient androgen exposure must occur to ensure subsequent normal differentiation and growth of male reproductive organs (Welsh et al., 2008).”
InfluentialThe Masculinization Programming Window
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Self-citationEndocrinology of the mammalian fetal testis
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“…are essential for masculinization of the fetus (Geissler et al. 1994, Kremer et al. 1995, Caron et al. 1997) during a critical ‘masculinization programming window’, which extends from 15.5 to 17.5 dpc in the rat and from about 8 to 12 GW in the human (Welsh et al. 2008, Scott et al. 2009).”
InfluentialEndocrine Disrupting Chemicals and Reproductive Health in Boys and Men
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Presence of parabens, phenols and phthalates in paired maternal serum, urine and amniotic fluid
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“, 2013) and reproductive disorders in offspring (Skakkebaek et al., 2016; Welsh et al., 2008).”
Cadmium Increases Human Fetal Germ Cell Apoptosis
Angenard, G., Muczynski, V., Coffigny, H., Pairault, C., Duquenne, C., Frydman, R., Habert, R., Rouiller, V., & Livera, G. (2009) · Environmental Health Perspectives · doi:10.1289/ehp.0900975 · Cited by 101 · see citing works
“Elsewhere, Cd was also found to lead to the disruption of the blood–testis barrier (Chung and Cheng 2001; Wong et al. 2004).”
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- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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