The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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]
Experimental — accuracy not yet measuredIn the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
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
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
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
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
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.
Cited by
Sorted by citations
Items 101–200 of 782
Hannas, B. R., Lambright, C. S., Furr, J., Evans, N., Foster, P. M. D., Gray, L. E., & Wilson, V. S. (2011) · Toxicological Sciences · doi:10.1093/toxsci/kfr315 · Cited by 99
Hart, R. J., Doherty, D. A., Frederiksen, H. W., Keelan, J. A., Hickey, M., Sloboda, D. M., Pennell, C. E., Newnham, J. P., Skakkebæk, N. E., & Main, K. M. (2013) · Reproduction · doi:10.1530/rep-13-0331 · Cited by 99
Drake, A. J., van den Driesche, S., Scott, H. M., Hutchison, G. R., Seckl, J. R., & Sharpe, R. M. (2009) · Endocrinology · doi:10.1210/en.2009-0700 · Cited by 97
“AGD was measured before opening of the abdomen, using digital calipers (Faithfull Tools, Kent, UK) as was the length of the penis after being dissected out (11).”
InfluentialHuman Fetal Testis Xenografts Are Resistant to Phthalate-Induced Endocrine Disruption
Heger, N. E., Hall, S. J., Sandrof, M. A., McDonnell, E. V., Hensley, J. B., McDowell, E. N., Martin, K. A., Gaido, K. W., Johnson, K. J., & Boekelheide, K. (2012) · Environmental Health Perspectives · doi:10.1289/ehp.1104711 · Cited by 96
Critical androgen-sensitive periods of rat penis and clitoris development
Welsh, M., MacLeod, D. J., Walker, M., Smith, L., & Sharpe, R. (2010) · International Journal of Andrology · doi:10.1111/j.1365-2605.2009.00978.x · Cited by 107
Self-citationSun, X., Li, D., Liang, H., Miao, M., Song, X., Wang, Z., Zhou, Z., & Yuan, W. (2018) · Environment International · doi:10.1016/j.envint.2018.08.055 · Cited by 94
Dean, A., Smith, L. B., Macpherson, S., & Sharpe, R. M. (2012) · International Journal of Andrology · doi:10.1111/j.1365-2605.2011.01236.x · Cited by 94
Håkonsen, L. B., Ernst, A., & Ramlau‐Hansen, C. H. (2014) · Asian Journal of Andrology · doi:10.4103/1008-682x.122351 · Cited by 91
Jain, V. G., & Singal, A. K. (2013) · Human Reproduction · doi:10.1093/humrep/det286 · Cited by 95
“Fetal testosterone levels are reported to be highest during early gestation (12–16 weeks) (Welsh et al., 2008; Thorup et al., 2010).”
InfluentialLind, D. V., Main, K. M., Kyhl, H. B., Kristensen, D. M., Toppari, J., Andersen, H. R., Andersen, M., Skakkebæk, N. E., & Jensen, T. K. (2016) · Human Reproduction · doi:10.1093/humrep/dew285 · Cited by 91
Søeborg, T., Frederiksen, H. W., & Andersson, A. (2012) · International Journal of Andrology · doi:10.1111/j.1365-2605.2011.01240.x · Cited by 90
van den Driesche, S., Walker, M., McKinnell, C., Scott, H. M., Eddie, S. L., Mitchell, R. T., Seckl, J. R., Drake, A. J., Smith, L. B., Anderson, R. A., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037064 · Cited by 90
Lassen, T. H., Frederiksen, H. W., Kyhl, H. B., Swan, S. H., Main, K. M., Andersson, A., Lind, D. V., Husby, S., Wohlfahrt‐Veje, C., Skakkebæk, N. E., et al. (2016) · Environmental Health Perspectives · doi:10.1289/ehp.1409637 · Cited by 89
“Thus, a reduced AGD in males may be indicative of insufficient testosterone during the early stages of development of male reproductive organs, whereas an increased AGD in females suggests excessive androgen exposure during the early stages of development of female reproductive organs (Welsh et al. 2008).”
InfluentialZhang, L., Dong, L., Ding, S., Qiao, P., Wang, C., Zhang, M., Zhang, L., Du, Q., Li, Y., Tang, N., et al. (2014) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2014.01.016 · Cited by 89
The differential role of androgens in early human sex development
Hiort, O. (2013) · BMC Medicine · doi:10.1186/1741-7015-11-152 · Cited by 87
“5 [6,7].”
Buaas, F. W., Gardiner, J. R., Clayton, S. A., Val, P., & Swain, A. (2012) · Development · doi:10.1242/dev.087247 · Cited by 86
Jensen, M. S., Wilcox, A. J., Olsen, J., Bonde, J. P., Thulstrup, A. M., Ramlau‐Hansen, C. H., & Henriksen, T. B. (2012) · American Journal of Epidemiology · doi:10.1093/aje/kwr421 · Cited by 85
“Normal androgen action seems crucial during this time (13), and disruption leads to both cryptorchidism and hypospadias in rats (12).”
The effects of perfluorooctanoic acid (PFOA) on fetal and adult rat testis
Eggert, A., Cisneros-Montalvo, S., Anandan, S., Musilli, S., Stukenborg, J., Adamsson, A., Nurmio, M., & Toppari, J. (2019) · Reproductive Toxicology · doi:10.1016/j.reprotox.2019.08.005 · Cited by 84
Draskau, M. K., Boberg, J., Taxvig, C., Pedersen, M., Frandsen, H. L., Christiansen, S., & Svingen, T. (2019) · Environmental Pollution · doi:10.1016/j.envpol.2019.113309 · Cited by 82
Stress and Androgen Activity During Fetal Development
Barrett, E. S., & Swan, S. H. (2015) · Endocrinology · doi:10.1210/en.2015-1335 · Cited by 82
Wu, Y., Zhong, G., Chen, S., Zheng, C., Liao, D., & Xie, M. (2017) · Human Reproduction · doi:10.1093/humrep/dex042 · Cited by 86
“In previous animal models studies, masculinization of the AGD was only observed when exogenous androgen exposure occurred during the presumptive MPW both in female rhesus monkeys (Abbott et al., 2005) and in rats (Welsh et al., 2008).”
Sunman, B., Yurdakök, K., Giray, B., Özyüncü, Ö., Akbıyık, F., Balcı, A., Özkemahlı, G., Erkekoğlu, P., & Yurdakök, M. (2019) · Reproductive Toxicology · doi:10.1016/j.reprotox.2019.05.065 · Cited by 81
Watkins, D. J., Sánchez, B. N., Téllez‐Rojo, M. M., Lee, J. M., Mercado‐García, A., Blank-Goldenberg, C., Peterson, K. E., & Meeker, J. D. (2017) · Environmental Health · doi:10.1186/s12940-017-0278-5 · Cited by 81
“Indeed, both animal and human studies have demonstrated that exposure to androgens, anti-androgens, or estrogens during different periods of in utero development have different effects on the newborn male reproductive tract [13, 18, 19, 39, 40].”
Tyndall, V., Broyde, M., Sharpe, R. M., Welsh, M., Drake, A. J., & McNeilly, A. S. (2011) · Reproduction · doi:10.1530/rep-11-0239 · Cited by 80
“To avoid foetal mortality that can be brought about by dystocia (Welsh et al. 2008), foetuses from TP-treated dams were delivered by caesarean and crossfostered to untreated dams that had delivered within the last 6 h (Welsh et al. 2010).”
InfluentialSelf-citationAndrogens During Infancy, Childhood, and Adolescence: Physiology and Use in Clinical Practice
Mason, K. A., Schoelwer, M. J., & Rogol, A. D. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnaa003 · Cited by 87
Pasterski, V., Acerini, C., Dunger, D., Ong, K., Hughes, I., Thankamony, A., & Hines, M. (2015) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.01.002 · Cited by 69
Lehraiki, A., Racine, C., Krust, A., Habert, R., & Levacher, C. (2009) · Toxicological Sciences · doi:10.1093/toxsci/kfp153 · Cited by 78
“Androgens mediate a wide range of developmental and physiological responses that are critical for the male reproductive and nonreproductive system (Sharpe, 2006; Welsh et al., 2008).”
In utero exposure to diisononyl phthalate caused testicular dysgenesis of rat fetal testis
Li, L., Bu, T., Su, H., Chen, Z., Liang, Y., Zhang, G., Zhu, D., Shan, Y., Xu, R.-A., Hu, Y., et al. (2014) · Toxicology Letters · doi:10.1016/j.toxlet.2014.11.024 · Cited by 76
“, 2004), and a decrease in testosterone production as well as gene expressions for androgen biosynthesis (Hannas et al., 2011; Lin et al., 2008; Parks et al., 2000; Scott et al., 2008; Thompson et al., 2004; Welsh et al., 2008).”
Phthalate exposure and semen quality in fertile US men
Thurston, S. W., Mendiola, J., Bellamy, A. R., Levine, H., Wang, C., Sparks, A. E., Redmon, J. B., Drobnis, E. Z., & Swan, S. H. (2015) · Andrology · doi:10.1111/andr.12124 · Cited by 76
“Animal studies have shown that exposure to certain phthalates during fetal sexual differentiation reduces fetal testosterone (Welsh et al., 2008).”
Dalsager, L., Christensen, L. E., Kongsholm, M. G., Kyhl, H. B., Nielsen, F., Schoeters, G. E. R., Jensen, T. K., & Andersen, H. R. (2017) · Reproductive Toxicology · doi:10.1016/j.reprotox.2017.12.008 · Cited by 76
Pointis, G., Gilleron, J., Carette, D., & Segretain, D. (2011) · Spermatogenesis · doi:10.4161/spmg.1.4.18392 · Cited by 74
Regulation of masculinization: androgen signalling for external genitalia development
Matsushita, S., Suzuki, K., Murashima, A., Kajioka, D., Acebedo, A. R., Miyagawa, S., Haraguchi, R., Ogino, Y., & Yamada, G. (2018) · Nature Reviews Urology · doi:10.1038/s41585-018-0008-y · Cited by 72
Dioxin-Induced Changes in Epididymal Sperm Count and Spermatogenesis
Foster, W. G., Maharaj-Briceño, S., & Cyr, D. G. (2009) · Environmental Health Perspectives · doi:10.1289/ehp.0901084 · Cited by 73
“Welsh et al. (2008) suggested a window of programming for the male reproductive tract during embryonic development and described the presence of early (GD15.”
Papadopoulou, E., Vafeiadi, M., Agramunt, S., Basagaña, X., Mathianaki, K., Karakosta, P., Spanaki, A., Koutis, A. D., Chatzi, L., Vrijheid, M., et al. (2012) · Paediatric and Perinatal Epidemiology · doi:10.1111/ppe.12022 · Cited by 72
Fetal Testis Dysgenesis and Compromised Leydig Cell Function in Tgfbr3 (Betaglycan) Knockout Mice1
Sarraj, M. A., Escalona, R. M., Umbers, A. J., Chua, H. K., Small, C. L., Griswold, M., Loveland, K. L., Findlay, J. K., & Stenvers, K. L. (2009) · Biology of Reproduction · doi:10.1095/biolreprod.109.078766 · Cited by 72
The role of sonic hedgehog-Gli2 pathway in the masculinization of external genitalia.
Miyagawa, S., Matsumaru, D., Murashima, A., Omori, A., Satoh, Y., Haraguchi, R., Motoyama, J., Iguchi, T., Nakagata, N., Hui, C.-C., et al. (2011) · Endocrinology · doi:10.1210/en.2011-0263 · Cited by 78
Mitchell, R. T., Mungall, W., McKinnell, C., Sharpe, R. M., Cruickshanks, L., Milne, L., & Smith, L. B. (2014) · Endocrinology · doi:10.1210/en.2014-1534 · Cited by 72
“However, androgens are also important drivers of this growth (4, 5, 19), and although previous studies have implied that AGD could exhibit plasticity postnatally (20–22), the concept of AGD plasticity in adulthood has not previously been explored directly.”
Karmaus, A. L., Ding, Q., Jaremba, R. G., Huhtaniemi, I. T., Rahman, N. A., & Zacharewski, T. R. (2012) · Toxicological Sciences · doi:10.1093/toxsci/kfs121 · Cited by 71
“, 2006), and throughout gestation in humans, with a similar programming window for androgen-dependent masculinization extrapolated between humans and rodents (Welsh et al., 2008).”
Timing of prenatal phthalate exposure in relation to genital endpoints in male newborns
Martino‐Andrade, A. J., Liu, F., Sathyanarayana, S., Barrett, E. S., Redmon, J. B., Nguyen, R. H. N., Levine, H., Swan, S. H., & the TIDES Study Team (2016) · Andrology · doi:10.1111/andr.12180 · Cited by 70
“588 Andrology, 2016, 4, 585–593 © 2016 American Society of Andrology and European Academy of Andrology (Gray et al., 2000; Welsh et al., 2008; van den Driesche et al., 2011; O’Shaughnessy & Fowler, 2011).”
Endocrine-Disrupting Chemicals and Human Growth and Maturation
Fudvoye, J., Bourguignon, J.-P., & Parent, A. (2014) · Vitamins and hormones · doi:10.1016/b978-0-12-800095-3.00001-8 · Cited by 77
“Indeed, it has been shown that normal development of the male reproductive system depends on the crucial role of androgen within an early fetal time window, called the mas-culinization programming window (Welsh et al., 2008), which influences the reproductive capacity throughout life.”
Kilcoyne, K. R., & Mitchell, R. T. (2019) · Human Reproduction Update · doi:10.1093/humupd/dmz004 · Cited by 69
“Moreover, effects primarily result from exposure during the MPW (Welsh et al., 2008; Kilcoyne et al., 2014; van den Driesche et al., 2017) which is believed to equate to ~8–14 weeks gestation in humans (Scott et al., 2009; Fowler et al., 2011).”
InfluentialDorman, D. C., Chiu, W. A., Hales, B. F., Hauser, R. B., Johnson, K. J., Mantus, E., Martel, S., Robinson, K. A., Rooney, A. A., Rudel, R. A., et al. (2018) · Journal of Toxicology and Environmental Health Part B · doi:10.1080/10937404.2018.1505354 · Cited by 68
“Phthalate exposure measurements performed in the first trimester were preferred over the second trimester, which was preferred over the third trimester, because the male programming window is approximately gestation weeks 8–14 in the human (Welsh et al. 2008).”
Lind, D. V., Priskorn, L., Lassen, T. H., Nielsen, F., Kyhl, H. B., Kristensen, D. M., Christesen, H. T., Jørgensen, J. S., Grandjean, P., & Jensen, T. K. (2016) · Reproductive Toxicology · doi:10.1016/j.reprotox.2016.08.019 · Cited by 69
“higher in utero androgen exposure results in longer AGD (Welsh et al., 2008).”
Tharmalingam, M. D., Matilionyte, G., Wallace, W. H., Stukenborg, J., Jahnukainen, K., Oliver, E., Goriely, A., Lane, S. M., Guo, J., Cairns, B. R., et al. (2020) · BMC Medicine · doi:10.1186/s12916-020-01844-y · Cited by 67
“Foetal life is a critical period for programming subsequent testicular development and reproductive function [34].”
Falco, M. D., Forte, M., & Laforgia, V. (2015) · Frontiers in Environmental Science · doi:10.3389/fenvs.2015.00003 · Cited by 62
Effects of environmental pollutants on the reproduction and welfare of ruminants
Rhind, S. M., Evans, N. P., Bellingham, M., Sharpe, R. M., Cotinot, C., Mandon‐Pepin, B., Loup, B., Sinclair, K. D., Lea, R. G., Pocar, P., et al. (2010) · animal · doi:10.1017/s1751731110000595 · Cited by 67
“A similar time window applies to domestic ruminants, the best characterised being in the sheep (Wood and Foster, 1998), and is thought, by analogy to the rat and human, to start when testosterone production by the foetal testis first commences (Welsh et al., 2008).”
InfluentialEnvironmental toxicants and male fertility
Rodprasert, W., Toppari, J., & Virtanen, H. E. (2022) · Best Practice & Research Clinical Obstetrics & Gynaecology · doi:10.1016/j.bpobgyn.2022.102298 · Cited by 66
Hutson, J. M. (2013) · Journal of Pediatric Surgery · doi:10.1016/j.jpedsurg.2013.02.001 · Cited by 66
Gaspari, L., Sampaio, D. R., Paris, F., Audran, F., Orsini, M., Neto, J. B. P., & Sultan, C. (2012) · International Journal of Andrology · doi:10.1111/j.1365-2605.2011.01241.x · Cited by 66
“5) that ensures normal formation and subsequent development of the penis and reproductive tract (Clark et al., 1993; Welsh et al., 2008).”
InfluentialBarrett, E. S., Sathyanarayana, S., Mbowe, O., Thurston, S. W., Redmon, J. B., Nguyen, R. H. N., & Swan, S. H. (2017) · Environmental Health Perspectives · doi:10.1289/ehp875 · Cited by 65
“In this case, the timing of urine and blood collection was outside of the period of greatest relevance, the reproductive programming window (estimated to be approximately 8–14weeksgestation), during which AGD appears to be most responsive to exposures (Welsh et al. 2008).”
Hannas, B. R., Furr, J., Lambright, C. S., Wilson, V. S., Foster, P. M. D., & Gray, L. E. (2010) · Toxicological Sciences · doi:10.1093/toxsci/kfq386 · Cited by 65
Kortenkamp, A. (2019) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2019.110581 · Cited by 65
Genetic pathway of external genitalia formation and molecular etiology of hypospadias
Kojima, Y., Kohri, K., & Hayashi, Y. (2009) · Journal of Pediatric Urology · doi:10.1016/j.jpurol.2009.11.007 · Cited by 64
“showed that androgen-driven masculinization is programmed by androgen action earlier in fetal life (10e14 gestational weeks) before morphological differentiation occurs, and deficient androgen action only within this early programming window can induce hypospadias [24].”
den bergh, C. V., Åberg, K. M., Svartengren, M., Emenius, G., & Östman, C. E. (2011) · Journal of Environmental Monitoring · doi:10.1039/c1em10152h · Cited by 64
What should it take to describe a substance or product as 'sperm-safe'
Mortimer, D., Barratt, C. L. R., Björndahl, L., de Jager, C., Jequier, A. M., & MULLER, C. H. (2013) · Human Reproduction Update · doi:10.1093/humupd/dmt008 · Cited by 64
“Intrauterine exposure has been linked to abnormal reproductive development as the sensitive reproductive programming window may be influenced by androgen deficiency, resulting in cryptorchidism, hypospadias and compromised fertility (Welsh et al., 2008).”
Manipulation of pre and postnatal androgen environments and anogenital distance in rats
Kita, D. H., Meyer, K. B., Venturelli, A. C., Adams, R., Machado, D. L. B., de Morais, R. N., Swan, S. H., Gennings, C., & Martino‐Andrade, A. J. (2016) · Toxicology · doi:10.1016/j.tox.2016.08.021 · Cited by 63
Draskau, M. K., & Svingen, T. (2022) · Frontiers in Toxicology · doi:10.3389/ftox.2022.883254 · Cited by 68
Chauvigné, F., Plummer, S. M., Lesné, L., Cravedi, J., Dejucq‐Rainsford, N., Fostier, A., & Jégou, B. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027172 · Cited by 63
van den Driesche, S., Kolovos, P., Platts, S., Drake, A. J., & Sharpe, R. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030111 · Cited by 63
Adibi, J. J., Lee, M. K., Naimi, A. I., Barrett, E. S., Nguyen, R. H. N., Sathyanarayana, S., Zhao, Y., Thiet, M.-P., Redmon, J. B., & Swan, S. H. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-2370 · Cited by 65
“This is consistent with the presence of the masculinization programming window between 8 and 12 weeks’ gestation (35).”
Cryptorchidism as Part of the Testicular Dysgenesis Syndrome: The Environmental Connection
Main, K. M., k, N. E. S. A., & Toppari, J. (2009) · Endocrine development · doi:10.1159/000207485 · Cited by 62
Effects of endocrine disruptors on fetal testis development, male puberty, and transition age
Cargnelutti, F., Nisio, A. D., Pallotti, F., Šabović, I., Spaziani, M., Tarsitano, M. G., Paoli, D., & Foresta, C. (2020) · Endocrine · doi:10.1007/s12020-020-02436-9 · Cited by 61
Sexually dimorphic expression of Mafb regulates masculinization of the embryonic urethral formation
Suzuki, K., Numata, T., Suzuki, H., Raga, D. D., Ipulan, L. A., Yokoyama, C., Matsushita, S., Hamada, M., Nakagata, N., Nishinakamura, R., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1413273111 · Cited by 59
“Several works have identified the critical time window for masculinization of external genitalia (3, 6, 27).”
Axelstad, M., Christiansen, S., Boberg, J., Scholze, M., Jacobsen, P. R., Isling, L. K., Kortenkamp, A., & Hass, U. (2013) · Reproduction · doi:10.1530/rep-13-0447 · Cited by 61
“…previous toxicity studies, the effects on AGD and NR are highly predictive for increased risk of adverse reproductive toxicity effects later in life, including increased incidence of hypospadias after puberty (McIntyre et al. 2001, Bowman et al. 2003, Welsh et al. 2008, Christiansen et al. 2009).”
Genetic variation in chromosome Y regulates susceptibility to influenza A virus infection
Krementsov, D. N., Case, L. K., Dienz, O., Raza, A., Fang, Q., Ather, J. L., Poynter, M. E., Boyson, J. E., Bunn, J. Y., & Teuscher, C. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1620889114 · Cited by 60
Retinoic Acid Antagonizes Testis Development in Mice
Bowles, J., Feng, C.-W. A., Ineson, J., Miles, K. M., Spiller, C. M., Harley, V. R., Sinclair, A. H., & Koopman, P. A. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.06.111 · Cited by 60
Calvert, L., Green, M. P., Iuliis, G. N. D., Dun, M. D., Turner, B. D., Clarke, B. O., Eamens, A. L., Roman, S. D., & Nixon, B. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.799043 · Cited by 62
Zhao, F., & Yao, H. H. (2019) · Biology of Reproduction · doi:10.1093/biolre/ioz079 · Cited by 61
Effects of In Utero Exposure to Di-n-Butyl Phthalate on Testicular Development in Rat
Ma, T., Yin, X., Han, R., Ding, J., Zhang, H., Han, X., & Li, D. (2017) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph14101284 · Cited by 59
Barrett, E. S., Parlett, L. E., Sathyanarayana, S., Redmon, J. B., Nguyen, R. H. N., & Swan, S. H. (2015) · Paediatric and Perinatal Epidemiology · doi:10.1111/ppe.12264 · Cited by 58
Anogenital distance is determined during early gestation in humans
Jain, V. G., Goyal, V., Chowdhary, V., Swarup, N., Singh, R. J., Singal, A. K., & Shekhawat, P. (2018) · Human Reproduction · doi:10.1093/humrep/dey265 · Cited by 89
Endocrine disruptors and the male reproductive system
Stukenborg, J., Mitchell, R. T., & Söder, O. (2021) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2021.101567 · Cited by 55
Coadministration of active phthalates results in disruption of foetal testicular function in rats
Martino‐Andrade, A. J., de Morais, R. N., Botelho, G. G. K., Muller, G., Grande, S. W., Carpentieri, G. B., Leão, G. M. C., & Dalsenter, P. R. (2008) · International Journal of Andrology · doi:10.1111/j.1365-2605.2008.00939.x · Cited by 55
“, 2008), while the testosterone-driven ‘male programming window’ in rats occurs between days 15 and 18 of gestation (Welsh et al., 2008).”
Goodyer, C. G., Poon, S., Aleksa, K., Hou, L., Atehortua, V., Carnevale, A., Jednak, R., Emil, S. G. S., Bägli, D., Davé, S., et al. (2017) · Environmental Health Perspectives · doi:10.1289/ehp522 · Cited by 55
“…al. 2009) and have been linked to genitourinary malformations, including cryptorchidism, in animal studies (Auger et al. 2014; Chen et al. 2015; Christiansen et al. 2009; Christiansen et al. 2010; Christiansen et al. 2014; Emmen et al. 2000; van den Driesche et al. 2012; Welsh et al. 2008).”
Testicular cancer: biology and biomarkers
Looijenga, L. H. J., Stoop, H., & Biermann, K. (2014) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-013-1522-1 · Cited by 54
“The latter matches nicely with the socalled window of masculinization as defined by Philip Sharpe [145].”
Development of malignant germ cells - the genvironmental hypothesis
Looijenga, L. H. J., van Agthoven, T., & Biermann, K. (2013) · The International Journal of Developmental Biology · doi:10.1387/ijdb.130026ll · Cited by 53
“This matched nicely with the so-called window of masculinization as defined by Philip Sharpe (Welsh et al., 2008).”
Country‐specific chemical signatures of persistent environmental compounds in breast milk
Krysiak-Baltyn, K., Toppari, J., Skakkebæk, N. E., Jensen, T. S., Virtanen, H. E., Schramm, K., Shen, H., Vartiainen, T., Kiviranta, H., Taboureau, O., et al. (2009) · International Journal of Andrology · doi:10.1111/j.1365-2605.2009.00996.x · Cited by 53
Potential influence of the phthalates on normal liver function and cardiometabolic risk in males
Milosevic, N. P., Milić, N., Bosić, D. Ž., Bajkin, I. A., Perčić, I., Abenavoli, L., & Medic‐Stojanoska, M. (2017) · Environmental Monitoring and Assessment · doi:10.1007/s10661-017-6398-0 · Cited by 54
“Antiandrogen effect of phthalates is well described on animal models (Foster et al. 2001; Gray et al. 2000) since they inhibit the synthesis of testosterone (Welsh et al. 2008) followed by reduced anogenital distance and genital size (Foster 2006).”
Rebourcet, D., Mackay, R., Darbey, A. L., Curley, M. K., Jørgensen, A., Frederiksen, H. W., Mitchell, R. T., O’Shaughnessy, P. J., Nef, S., & Smith, L. B. (2020) · The FASEB Journal · doi:10.1096/fj.202000361r · Cited by 55
46,XX DSD: Developmental, Clinical and Genetic Aspects
Alkhzouz, C., Bucerzan, S., Miclaus, M., Mirea, A.-M., & Miclea, D. (2021) · Diagnostics · doi:10.3390/diagnostics11081379 · Cited by 54
The fetal ovary exhibits temporal sensitivity to a ‘real-life’ mixture of environmental chemicals
Lea, R. G., Amezaga, M. R., Loup, B., Mandon‐Pepin, B., Stefansdottir, A., Filis, P., Kyle, C., Zhang, Z., Allen, C. E., Purdie, L., et al. (2016) · Scientific Reports · doi:10.1038/srep22279 · Cited by 52
Wei, X., Wan, H. T., Zhao, Y. G., Wong, M. H., Giesy, J. P., & Wong, C. K. C. (2012) · Environmental Science and Pollution Research · doi:10.1007/s11356-012-0827-y · Cited by 51
Skakkebæk, N. E. (2016) · Hormone Research in Paediatrics · doi:10.1159/000443400 · Cited by 51
New Insights into the Role of Androgens in Wolffian Duct Stabilization in Male and Female Rodents
Welsh, M., Sharpe, R. M., Walker, M., Smith, L. B., & Saunders, P. T. K. (2009) · Endocrinology · doi:10.1210/en.2008-0529 · Cited by 51
“5, testosterone was present in the fetal testis but was barely detectable in the fetal ovary (12).”
Self-citationHolmboe, S. A., Beck, A. L., Andersson, A., Main, K. M., Jørgensen, N., Skakkebæk, N. E., & Priskorn, L. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1343887 · Cited by 50
“…of EDC exposure have demonstrated that anti-androgenic EDC exposure particularly during early fetal development, known as the masculinization programming window, can compromise suf fi cient androgen action and result in cryptorchidism and other signs of impaired male reproductive function (41, 44).”
Adverse effects of endocrine disruptors on the foetal testis development: focus on the phthalates.
Habert, R., Muczynski, V., Lehraiki, A., Lambrot, R., LĂŠcureuil, C., Levacher, C., Coffigny, H., Pairault, C., Moison, D., Frydman, R., et al. (2010) · Folia Histochemica et Cytobiologica · doi:10.2478/v10042-009-0056-5 · Cited by 50
“This early developmental period of the testis has been shown to be a critical window for the determination of the reproductive tract [77].”
Mesenchymal mechanisms in prostate organogenesis
Thomson, A. A. (2008) · Differentiation · doi:10.1111/j.1432-0436.2008.00296.x · Cited by 50
Prenatal exposure to bisphenols affects pregnancy outcomes and offspring development in rats
Kaimal, A., Mansi, M. H. A., Dagher, J. B., Pope, C., Varghese, M. G., Rudi, T. B., Almond, A. E., Cagle, L. A., Beyene, H. K., Bradford, W. T., et al. (2021) · Chemosphere · doi:10.1016/j.chemosphere.2021.130118 · Cited by 49
“A reduction in AGD suggests feminization of the male reproductive tract (Welsh et al., 2008).”
The Fate of Leydig Cells in Men with Spermatogenic Failure
Adamczewska, D., Słowikowska‐Hilczer, J., & Walczak-Jędrzejowska, R. (2022) · Life · doi:10.3390/life12040570 · Cited by 57
Cox, K., Kyriakou, A., Amjad, B., O’Toole, S., Flett, M. E., Welsh, M., Ahmed, S. F., & Cascio, S. (2016) · Journal of Pediatric Urology · doi:10.1016/j.jpurol.2016.08.006 · Cited by 49
“One documented factor in the development of hypospadias is reduced antenatal exposure to testosterone during the masculinisation-programming window (MPW) [5].”
Self-citationLe Moal, J., Sharpe, R. M., Jϕrgensen, N., Levine, H., Jurewicz, J., Mendiola, J., Swan, S. H., Virtanen, H., Christin-Maître, S., Cordier, S., et al. (2016) · The European Journal of Public Health · doi:10.1093/eurpub/ckv153 · Cited by 48
New Insights into Testosterone Biosynthesis: Novel Observations from HSD17B3 Deficient Mice
Lawrence, B. M., O’Donnell, L., Smith, L. B., & Rebourcet, D. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232415555 · Cited by 49
Béranger, R., Cornet, C. L., Schüz, J., & Fervers, B. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077130 · Cited by 48
“While uncertainties remain concerning the exact window of exposure associated with occurrence of TGCT, events during the ‘testicle programming period’ has been proposed to originate in cryptochidism and hypospadias in rats [92].”
Ben, Y., Li, X., Yang, Y., Li, L., Zheng, M., Wang, W., & Xu, X. (2013) · Environmental Science & Technology · doi:10.1021/es404106b · Cited by 48
Maternal effects in mammals: Broadening our understanding of offspring programming
Edwards, P. D., Lavergne, S. G., McCaw, L. K., Wijenayake, S., Boonstra, R., McGowan, P. O., & Holmes, M. M. (2021) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2021.100924 · Cited by 49
Jensen, D. V., Christensen, J. S., Virtanen, H. E., Skakkebæk, N. E., Main, K. M., Toppari, J., Wohlfahrt‐Veje, C., Andersson, A., Nielsen, F., Grandjean, P., et al. (2013) · Reproduction · doi:10.1530/rep-13-0444 · Cited by 47
Cryptorchidism and long-term consequences
Kurpisz, M. K., Havryluk, A., Nakonechnyj, A., Chopyak, V. V., & Kamieniczna, M. (2010) · Reproductive Biology · doi:10.1016/s1642-431x(12)60035-7 · Cited by 46
“Testicular dysgenesis syndrome, especially hypospadias and cryptorchidism, is programmed by insuffi cient androgen function early in fetal life [25].”
Endocrine disruption as an adverse effect of non-endocrine targeting pharmaceuticals
Sabir, S., Akhtar, M. F., & Saleem, A. (2018) · Environmental Science and Pollution Research · doi:10.1007/s11356-018-3774-4 · Cited by 47
Self-organising human gonads generated by a Matrigel-based gradient system
Oliver, E., Alves-Lopes, J. P., Harteveld, F., Mitchell, R. T., Åkesson, E., Söder, O., & Stukenborg, J. (2021) · BMC Biology · doi:10.1186/s12915-021-01149-3 · Cited by 46
“Based on timings in rats, the developmental window at risk of disruption in humans is thought to be approximately 8–14 weeks of gestation [41].”
Use of Glucocorticoids in Pregnancy
Lunghi, L., Pavan, B., Biondi, C., Paolillo, R., Valerio, A., Vesce, F., & Patella, A. (2010) · Current Pharmaceutical Design · doi:10.2174/138161210793797898 · Cited by 47
“Inappropriate GC exposure in utero alters the functioning of all the hypothalamic-pituitary endocrine axes [81-85], of the endocrine pancreas and the renin-angiotensin system, as well as the endocrine axes regulating appetite and energy balance in the adult offspring [86-88].”
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
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 ›
Are you an author, or do you see a problem with this page? Request a review
