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

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 access

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

Open this paper in CoChat — free account Open PDF

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.

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

Crossref · 10.1172/jci34241

Cites

63 of 63 references verified0 citation errors · 0 not checkable

Statistics

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

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

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.

Sorted by citations

Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility
Skakkebæk, N. E., Meyts, E. R., Louis, G. M. B., Toppari, J., Andersson, A., Eisenberg, M. L., Jensen, T. K., Jørgensen, N., Swan, S. H., Sapra, K. J., et al. (2015) · Physiological Reviews · doi:10.1152/physrev.00017.2015 · Cited by 1,030
Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans
Swan, S. H. (2008) · Environmental Research · doi:10.1016/j.envres.2008.08.007 · Cited by 879
A new chapter in the bisphenol A story: bisphenol S and bisphenol F are not safe alternatives to this compound
Eladak, S., Grisin, T., Moison, D., Guerquin, M.-J., N’Tumba-Byn, T., Pozzi-Gaudin, S., Benachi, A., Livera, G., Rouiller, V., & Habert, R. (2014) · Fertility and Sterility · doi:10.1016/j.fertnstert.2014.11.005 · Cited by 713
Recent decline in age at breast development: The Copenhagen Puberty Study
Aksglaede, L., Sørensen, K., Petersen, J. H., Skakkebæk, N. E., & Juul, A. (2009) · Pediatrics · doi:10.1542/peds.2008-2491 · Cited by 626
The Impact of Nutrition and Environmental Epigenetics on Human Health and Disease
Tiffon, C. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113425 · Cited by 534
“The male offspring born to mothers treated with DES during pregnancy displayed feminization [62,63] and developmental malformations of the genital tract, infertility, and obesity [64].”
Environmental factors in declining human fertility
Skakkebæk, N. E., Lindahl-Jacobsen, R., Levine, H., Andersson, A.-M., Jørgensen, N., Main, K. M., Lidegaard, Ø., Priskorn, L., Holmboe, S. A., Bräuner, E. V., et al. (2022) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00598-8 · Cited by 389
State-of-the-science of endocrine disrupting chemicals, 2012
Bergman, Å., Heindel, J., Jobling, S., Kidd, K., & Zoeller, R. T. (2012) · Toxicology Letters · doi:10.1016/j.toxlet.2012.03.020 · Cited by 1,388
Environmental/lifestyle effects on spermatogenesis
Sharpe, R. M. (2010) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2009.0206 · Cited by 361
“2002) based on measurement of anogenital distance (Welsh et al. 2008).”
First trimester phthalate exposure and anogenital distance in newborns
Swan, S. H., Sathyanarayana, S., Barrett, E. S., Janssen, S. J., Liu, F., Nguyen, R. H. N., Redmon, J. B., the TIDES Study Team, the TIDES Study Team, Liu, F., et al. (2015) · Human Reproduction · doi:10.1093/humrep/deu363 · Cited by 358
“Urine samples were collected during the first trimester (mean gestational age 11 weeks), corresponding to the male programming window for genital development (Welsh et al., 2008).”
Steroidogenesis in the Fetal Testis and Its Susceptibility to Disruption by Exogenous Compounds
Scott, H. M., Mason, J. I., & Sharpe, R. M. (2009) · Endocrine Reviews · doi:10.1210/er.2009-0016 · Cited by 366
“The masculinization process in humans and rodents is remarkably similar, and, insofar as we understand them, the mechanisms involved and their complete dependence on androgen production/action are more or less the same (9).”
Influential
Sex differences in developmental programming models.
Aiken, C., & Ozanne, S. (2013) · Reproduction · doi:10.1530/rep-11-0489 · Cited by 336
“5–17.5 in the rat (Welsh et al. 2008).”
Influential
Personal care products and endocrine disruption: A critical review of the literature
Witorsch, R. J., & Thomas, J. A. (2010) · Critical Reviews in Toxicology · doi:10.3109/10408444.2010.515563 · Cited by 334
“Since the female phenotype is default, impairment of either testosterone production or action prior to the late phase leads to feminizing characteristics such as reduced AGD and hypospadias (Welsh et al., 2008).”
Influential
Testis Development.
Mäkelä, J.-A., Koskenniemi, J., Virtanen, H., & Toppari, J. (2018) · Endocrine reviews · doi:10.1210/er.2018-00140 · Cited by 278
Exposure to phthalates: Reproductive outcome and children health. A review of epidemiological studies
Jurewicz, J., & Hanke, W. (2011) · International Journal of Occupational Medicine and Environmental Health · doi:10.2478/s13382-011-0022-2 · Cited by 320
Update of the risk assessment of di‐butylphthalate (DBP), butyl‐benzyl‐phthalate (BBP), bis(2‐ethylhexyl)phthalate (DEHP), di‐isononylphthalate (DINP) and di‐isodecylphthalate (DIDP) for use in food contact materials
EFSA Panel on Food Contact Materials, E. A. P. A. (., Silano, V., Baviera, J. M. B., Bolognesi, C., Chesson, A., Cocconcelli, P. S., Crebelli, R., Gott, D. M., Grob, K., Lampi, E., et al. (2019) · EFSA Journal · doi:10.2903/j.efsa.2019.5838 · Cited by 332
Long‐term adverse effects of paracetamol – a review
McCrae, J. C., Morrison, E. E., MacIntyre, I. M., Dear, J. W., & Webb, D. J. (2018) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.13656 · Cited by 308
“This is an interesting paradoxical observation given this time frame represents the human fetal programming window, disruption of which has previously been linked to reduced male infant ano-genital distance [138, 145].”
The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis
Bonde, J. P., Flachs, E. M., Rimborg, S., Glazer, C. H., Giwercman, A., Ramlau‐Hansen, C. H., Hougaard, K. S., Høyer, B. B., Hærvig, K. K., Petersen, S. B., et al. (2016) · Human Reproduction Update · doi:10.1093/humupd/dmw036 · Cited by 305
“Most studies measured the contaminants late in pregnancy, at birth or during lactation and not precisely at the time of differentiation of the male gonads, that based upon animal studies in the rat, is assumed to take place in gestational week 8–14 (Welsh et al., 2008; Macleod et al., 2010).”
Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat
Kristensen, D. M., Hass, U., Lesné, L., Lottrup, G., Jacobsen, P. R., Lethimonier, C., Boberg, J., Petersen, J. H., Toppari, J., Jensen, T. K., et al. (2010) · Human Reproduction · doi:10.1093/humrep/deq323 · Cited by 299
Anogenital Distance or Digit Length Ratio as Measures of Fetal Androgen Exposure: Relationship to Male Reproductive Development and Its Disorders
Dean, A., & Sharpe, R. M. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-4057 · Cited by 286
“Only early (MPW) androgen exposure virilized AGD in exposed females, as expected (11), and this treatment (but not late gestation androgen exposure) also increased length of digit 2, making it more male-like whereas it failed to have a ‘male-like’ effect on digit 4.”
Influential
Urinary excretion of phthalate metabolites, phenols and parabens in rural and urban Danish mother–child pairs
Frederiksen, H. W., Nielsen, J. K. S., Mørck, T. A., Hansen, P. W., Jensen, J. F., Nielsen, O., Andersson, A., & Knudsen, L. E. (2013) · International Journal of Hygiene and Environmental Health · doi:10.1016/j.ijheh.2013.02.006 · Cited by 267
Mechanisms of action of phthalate esters, individually and in combination, to induce abnormal reproductive development in male laboratory rats
Howdeshell, K. L., Rider, C. V., Wilson, V. S., & Gray, L. E. (2008) · Environmental Research · doi:10.1016/j.envres.2008.08.009 · Cited by 264
Androgen action in the masculinization programming window and development of male reproductive organs
MacLeod, D. J., Sharpe, R. M., Welsh, M., Fisken, M., Scott, H. M., Hutchison, G. R., Drake, A. J., & van den Driesche, S. (2009) · International Journal of Andrology · doi:10.1111/j.1365-2605.2009.01005.x · Cited by 262
Self-citation
Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders
Schwartz, C. L., Christiansen, S., Vinggaard, A. M., Axelstad, M., Hass, U., & Svingen, T. (2018) · Archives of Toxicology · doi:10.1007/s00204-018-2350-5 · Cited by 251
Anogenital distance as a marker of androgen exposure in humans
Thankamony, A., Pasterski, V., Ong, K. K., Acerini, C. L., & Hughes, I. A. (2016) · Andrology · doi:10.1111/andr.12156 · Cited by 238
“Hypospadias and cryptorchidism are relevant clinical disorders to evaluate the possible role of endocrine disruption, for which there is ample evidence from animal studies (Welsh et al., 2008; van den Driesche et al., 2012).”
Influential
Paracetamol use during pregnancy — a call for precautionary action
Bauer, A. Z., Swan, S. H., Kriebel, D., Liew, Z., Taylor, H. S., Bornehag, C.-G., Andrade, A. M., Olsen, J., Jensen, R. H., Mitchell, R. T., et al. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00553-7 · Cited by 228
Human urinary excretion of non-persistent environmental chemicals: an overview of Danish data collected between 2006 and 2012
Frederiksen, H., Jensen, T. K., Jørgensen, N., Kyhl, H. B., Husby, S., Skakkebæk, N. E., Main, K. M., Juul, A., & Andersson, A.-M. (2014) · Reproduction · doi:10.1530/rep-13-0522 · Cited by 219
Associations of in Utero Exposure to Perfluorinated Alkyl Acids with Human Semen Quality and Reproductive Hormones in Adult Men
Vested, A., Ramlau‐Hansen, C. H., Olsen, S. F., Bonde, J. P., Kristensen, S. L., Halldorsson, T. I., Becher, G., Haug, L. S., Ernst, E. H., & Toft, G. V. (2013) · Environmental Health Perspectives · doi:10.1289/ehp.1205118 · Cited by 222
“In addition, rat studies have suggested the existence of a male programming window—corresponding to gestational weeks 8–14 in humans—during which xeno biotic exposure may affect reproductive hormone balance and impact normal male reproductive develop ment (Welsh et al. 2008).”
Androgens in pregnancy: roles in parturition
Makieva, S., Saunders, P. T. K., & Norman, J. E. (2014) · Human Reproduction Update · doi:10.1093/humupd/dmu008 · Cited by 232
“Androgens are critically important for the development of the male reproductive tract during fetal life and the maintenance of male secondary sexual characteristics in adulthood (Scott et al., 2007; Welsh et al., 2008; Macleod et al., 2010).”
Dose-Response Assessment of Fetal Testosterone Production and Gene Expression Levels in Rat Testes Following InUtero Exposure to Diethylhexyl Phthalate, Diisobutyl Phthalate, Diisoheptyl Phthalate, and Diisononyl Phthalate
Hannas, B. R., Lambright, C. S., Furr, J., Howdeshell, K. L., Wilson, V. S., & Gray, L. E. (2011) · Toxicological Sciences · doi:10.1093/toxsci/kfr146 · Cited by 217
Shorter Anogenital Distance Predicts Poorer Semen Quality in Young Men in Rochester, New York
Mendiola, J., Stahlhut, R. W., Jørgensen, N., Liu, F., & Swan, S. H. (2011) · Environmental Health Perspectives · doi:10.1289/ehp.1103421 · Cited by 216
“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.”
Foetal exposure to phthalate esters and anogenital distance in male newborns
Suzuki, Y., Yoshinaga, J., Mizumoto, Y., Serizawa, S., & Shiraishi, H. (2011) · International Journal of Andrology · doi:10.1111/j.1365-2605.2011.01190.x · Cited by 211
Synergistic Disruption of External Male Sex Organ Development by a Mixture of Four Antiandrogens
Christiansen, S., Scholze, M., Dalgaard, M., Vinggaard, A. M., Axelstad, M., Kortenkamp, A., & Hass, U. (2009) · Environmental Health Perspectives · doi:10.1289/ehp.0900689 · Cited by 210
Prenatal phthalate exposure and reduced masculine play in boys
Swan, S. H., Liu, F., Hines, M., Kruse, R. L., Wang, C., Redmon, J. B., Sparks, A., & Weiss, B. (2010) · International Journal of Andrology · doi:10.1111/j.1365-2605.2009.01019.x · Cited by 257
“…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).”
Influential
Female Reproductive Disorders, Diseases, and Costs of Exposure to Endocrine Disrupting Chemicals in the European Union
Hunt, P. A., Sathyanarayana, S., Fowler, P., & Trasande, L. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-2873 · Cited by 205
Maternal Use of Acetaminophen, Ibuprofen, and Acetylsalicylic Acid During Pregnancy and Risk of Cryptorchidism
Lindhard, M. S., Rebordosa, C., Thulstrup, A. M., Toft, G. V., Sørensen, H. T., Bonde, J. P., Henriksen, T. B., & Olsen, J. (2010) · Epidemiology · doi:10.1097/ede.0b013e3181f20bed · Cited by 200
“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
Kristensen, D. M., Mazaud‐Guittot, S., Gaudriault, P., Lesné, L., Serrano, T., Main, K. M., & Jégou, B. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.55 · Cited by 188
The Regulation of Testicular Descent and the Effects of Cryptorchidism
Hutson, J. M., Southwell, B. R., Li, R., Lie, G., Ismail, K. A., Harisis, G., & Chen, N. (2013) · Endocrine Reviews · doi:10.1210/er.2012-1089 · Cited by 199
Phthalates Impair Germ Cell Development in the Human Fetal Testis in Vitro without Change in Testosterone Production
Lambrot, R., Muczynski, V., Lécureuil, C., Angenard, G., Coffigny, H., Pairault, C., Moison, D., Frydman, R., Habert, R., & Rouiller, V. (2008) · Environmental Health Perspectives · doi:10.1289/ehp.11146 · Cited by 190
“( 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
Kilcoyne, K. R., Smith, L. B., Atanassova, N. N., Macpherson, S., McKinnell, C., van den Driesche, S., Jobling, M. S., Chambers, T. J. G., Gendt, K. D., Verhoeven, G., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1320735111 · Cited by 190
“5 in rats when intratesticular testosterone levels are high/increasing (33, 40).”
Testicular dysgenesis syndrome: foetal origin of adult reproductive problems
Wohlfahrt‐Veje, C., Main, K. M., & Skakkebæk, N. E. (2009) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2009.03545.x · Cited by 189
Male Reproductive Disorders, Diseases, and Costs of Exposure to Endocrine-Disrupting Chemicals in the European Union
Hauser, R. B., Skakkebæk, N. E., Hass, U., Toppari, J., Juul, A., Andersson, A., Kortenkamp, A., Heindel, J. J., & Trasande, L. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-4325 · Cited by 189
“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
O’Shaughnessy, P. J., Antignac, J. P., Le Bizec, B., Morvan, M.-L., Svechnikov, K., Söder, O., Savchuk, I., Monteiro, A., Soffientini, U., Johnston, Z. C., et al. (2019) · PLOS Biology · doi:10.1371/journal.pbio.3000002 · Cited by 177
Regional differences and temporal trends in male reproductive health disorders: Semen quality may be a sensitive marker of environmental exposures
Nordkap, L., Joensen, U. N., Jensen, M. B., & Jørgensen, N. (2011) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.05.048 · Cited by 176
“In the ‘‘vulnerable’’ period of masculinization, corresponding to 8–14 week of gestation in humans, these processes are possible targets of endocrine disruption (Welsh et al., 2008).”
Factors controlling testis descent
Hughes, I. A., & Acerini, C. L. (2008) · European Journal of Endocrinology · doi:10.1530/eje-08-0458 · Cited by 169
“dams and demonstrating undescended testes, hypospadias and reduced anogenital distance in male offspring ( 48 ).”
Possible fetal determinants of male infertility
Juul, A., Almstrup, K., Andersson, A., Jensen, T. K., Jørgensen, N., Main, K. M., Meyts, E. R., Toppari, J., & Skakkebæk, N. E. (2014) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2014.97 · Cited by 168
Polybrominated diphenyl ethers in paired samples of maternal and umbilical cord blood plasma and associations with house dust in a Danish cohort
Frederiksen, M., Thomsen, C., Frøshaug, M., Vorkamp, K., Thomsen, M., Becher, G., & Knudsen, L. E. (2010) · International Journal of Hygiene and Environmental Health · doi:10.1016/j.ijheh.2010.04.008 · Cited by 165
Hormone Regulation in Testicular Development and Function
Li, L., Lin, W., Wang, Z., Huang, R., Xia, H., Li, Z., Deng, J., Ye, T., Huang, Y., & Yan, Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25115805 · Cited by 204
“5, while in humans, it is postulated to be between 8 and 14 weeks of gestation [69].”
Paracetamol, Aspirin, and Indomethacin Induce Endocrine Disturbances in the Human Fetal Testis Capable of Interfering With Testicular Descent
Mazaud‐Guittot, S., Nicolaz, C. N., Lethimonier, C., Coiffec, I., Maamar, M. B., Balaguer, P., Kristensen, D. M., Chevrier, C., Lavoué, V., Poulain, P., et al. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-2531 · Cited by 161
Genital anomalies in boys and the environment
Main, K. M., Skakkebæk, N. E., Virtanen, H. E., & Toppari, J. (2010) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2009.10.003 · Cited by 161
Hypogonadism and Cryptorchidism
Rodprasert, W., Virtanen, H. E., Mäkelä, J., & Toppari, J. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00906 · Cited by 153
“5 in rats (equivalent to GW 7–15 in humans) is related to the occurrence of cryptorchidism (9, 18, 146, 147).”
In utero exposure to bisphenol-A and anogenital distance of male offspring
Miao, M., Yuan, W., He, Y., Zhou, Z., Wang, J., Gao, E., Li, G., & Li, D. (2011) · Birth Defects Research Part A Clinical and Molecular Teratology · doi:10.1002/bdra.22845 · Cited by 150
“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).”
Effects of endocrine disrupting chemicals on gonad development: Mechanistic insights from fish and mammals
Delbès, G., Blázquez, M., Fernandino, J. I., Grigorova, P., Hales, B. F., Metcalfe, C. D., Navarro‐Martín, L., Parent, L., Robaire, B., Rwigemera, A., et al. (2021) · Environmental Research · doi:10.1016/j.envres.2021.112040 · Cited by 152
High urinary phthalate concentration associated with delayed pubarche in girls
Frederiksen, H., Sørensen, K., Mouritsen, A., Aksglaede, L., Hagen, C. P., Petersen, J. H., Skakkebaek, N. E., Andersson, A. ‐., & Juul, A. (2012) · International Journal of Andrology · doi:10.1111/j.1365-2605.2012.01260.x · Cited by 160
Of Mice and Men (and Rats): Phthalate-Induced Fetal Testis Endocrine Disruption Is Species-Dependent
Johnson, K. J., Heger, N. E., & Boekelheide, K. (2012) · Toxicological Sciences · doi:10.1093/toxsci/kfs206 · Cited by 147
“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…”
Influential
Gonadal Maldevelopment as Risk Factor for Germ Cell Cancer: Towards a Clinical Decision Model
van der Zwan, Y. G., Biermann, K., Wolffenbuttel, K. P., Cools, M., & Looijenga, L. H. J. (2014) · European Urology · doi:10.1016/j.eururo.2014.07.011 · Cited by 145
“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.”
Relationship between Androgen Action in the “Male Programming Window,” Fetal Sertoli Cell Number, and Adult Testis Size in the Rat
Scott, H. M., Hutchison, G. R., Jobling, M. S., McKinnell, C., Drake, A. J., & Sharpe, R. M. (2008) · Endocrinology · doi:10.1210/en.2008-0413 · Cited by 145
Gonadal tumours and DSD
Looijenga, L. H. J., Hersmus, R., de Leeuw, B. H. C. G. M., Stoop, H., Cools, M., Oosterhuis, J. W., Drop, S. L. S., & Wolffenbuttel, K. P. (2010) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2009.10.002 · Cited by 142
Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model
van den Driesche, S., Macdonald, J., Anderson, R. A., Johnston, Z. C., Chetty, T., Smith, L. B., McKinnell, C., Dean, A., Homer, N. Z. M., Jørgensen, A., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa4097 · Cited by 142
“intratesticular testosterone (ITT) can result in a subsequent male reproductive disorder (2, 3).”
Influential
Anogenital Distance and Penile Length in Infants with Hypospadias or Cryptorchidism: Comparison with Normative Data
Thankamony, 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 146
Intrauterine exposure to mild analgesics during pregnancy and the occurrence of cryptorchidism and hypospadia in the offspring: the Generation R Study
Snijder, C. A., Kortenkamp, A., Steegers, E. A. P., Jaddoe, V. W. V., Albert Hofman, D., Hass, U., & Burdorf, A. (2012) · Human Reproduction · doi:10.1093/humrep/der474 · Cited by 140
A critical assessment of the endocrine susceptibility of the human testis to phthalates from fetal life to adulthood
Albert, O., & Jégou, B. (2013) · Human Reproduction Update · doi:10.1093/humupd/dmt050 · Cited by 133
“…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).”
Influential
Regulation of testicular descent
Hutson, J. M., Li, R., Southwell, B. R., Newgreen, D. F., & Cousinery, M. (2015) · Pediatric Surgery International · doi:10.1007/s00383-015-3673-4 · Cited by 133
Paracetamol (acetaminophen), aspirin (acetylsalicylic acid) and indomethacin are anti‐androgenic in the rat foetal testis
Kristensen, D. M., Lesné, L., Fol, V. L., Lethimonier, C., Dejucq‐Rainsford, N., Leffers, H. C. B., & Jégou, B. (2012) · International Journal of Andrology · doi:10.1111/j.1365-2605.2012.01282.x · Cited by 131
Tissue- and cell-specific functions of the androgen receptor revealed through conditional knockout models in mice
Gendt, K. D., & Verhoeven, G. (2011) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.08.008 · Cited by 128
Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window
van den Driesche, S., Kilcoyne, K. R., Wagner, I., Rebourcet, D., Boyle, A. K., Mitchell, R. T., McKinnell, C., Macpherson, S., Donat, R., Shukla, C. J., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.91204 · Cited by 130
Presence of benzophenones commonly used as UV filters and absorbers in paired maternal and fetal samples
Krause, M., Frederiksen, H. W., Sundberg, K., Jørgensen, F. S., Jensen, L. N., Nørgaard, P., Jørgensen, C., Ertberg, P., Juul, A., Drzewiecki, K. T., et al. (2017) · Environment International · doi:10.1016/j.envint.2017.10.005 · Cited by 130
Human infertility: are endocrine disruptors to blame?
Marques-Pinto, A., & Carvalho, D. M. (2013) · Endocrine Connections · doi:10.1530/ec-13-0036 · Cited by 129
Fetal programming of sexual development and reproductive function
Zambrano, E., Guzmán, C., Rodríguez-González, G. L., Durand-Carbajal, M., & Nathanielsz, P. W. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.09.008 · Cited by 128
Obstetrical outcomes and biomarkers to assess exposure to phthalates: A review
Marie, C., Vendittelli, F., & Sauvant‐Rochat, M. (2015) · Environment International · doi:10.1016/j.envint.2015.06.003 · Cited by 128
Hormones as epigenetic signals in developmental programming
Fowden, A. L., & Forhead, A. J. (2009) · Experimental Physiology · doi:10.1113/expphysiol.2008.046359 · Cited by 123
“…of hormones in developmental programming in mammals, The 2008 Joan Mott Prize Lecture was given on Sunday 13th July at the Physiological Society Meeting in Cambridge, UK. although androgens control the phenotype that develops from the sex chromosomes inherited at conception (Welsh et al. 2008).”
Influential
Time- and Dose-Related Effects of Di-(2-ethylhexyl) Phthalate and Its Main Metabolites on the Function of the Rat Fetal Testis in Vitro
Chauvigné, 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
Do Phthalates Affect Steroidogenesis by the Human Fetal Testis? Exposure of Human Fetal Testis Xenografts to Di-n-Butyl Phthalate
Mitchell, R. T., Childs, A. J., Anderson, R. A., van den Driesche, S., Saunders, P. T. K., McKinnell, C., Wallace, W. H., Kelnar, C. J. H., & Sharpe, R. M. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-2411 · Cited by 120
Prenatal exposure to phthalates is associated with decreased anogenital distance and penile size in male newborns
Bustamante-Montes, L. P., Hernández-Valero, M., Flores-Pimentel, D., García-Fábila, M., Amaya-Chávez, A., Barr, D., & Borja-Aburto, V. (2013) · Journal of Developmental Origins of Health and Disease · doi:10.1017/s2040174413000172 · Cited by 110
Genetic Interactions of the Androgen and Wnt/β-Catenin Pathways for the Masculinization of External Genitalia
Miyagawa, S., Satoh, Y., Haraguchi, R., Suzuki, K., Iguchi, T., Taketo, M. M., Nakagata, N., Μatsumoto, T., Takeyama, K., Kato, S., et al. (2009) · Molecular Endocrinology · doi:10.1210/me.2008-0478 · Cited by 117
Impaired puberty, fertility, and final stature in 45,X/46,XY mixed gonadal dysgenetic patients raised as boys
Martinerie, L., Morel, Y., Gay, C.-L., Pienkowski, C., de Kerdanet, M., Cabrol, S., Lecointre, C., Coutant, R., Baron, S., Colle, M., et al. (2012) · European Journal of Endocrinology · doi:10.1530/eje-11-0756 · Cited by 115
Sperm counts and fertility in men: a rocky road ahead
Sharpe, R. M. (2012) · EMBO Reports · doi:10.1038/embor.2012.50 · Cited by 114
Prenatal environmental risk factors for genital malformations in a population of 1442 French male newborns: a nested case-control study
Gaspari, L., Paris, F., Jandel, C., Kalfa, N., Orsini, M., Daurès, J., & Sultan, C. (2011) · Human Reproduction · doi:10.1093/humrep/der283 · Cited by 114
“…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).”
Influential
Metformin 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 120
“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
Sharpe, R. M. (2020) · Biochemical Society Transactions · doi:10.1042/bst20200200 · Cited by 118
Food safety involving ingestion of foods and beverages prepared with phthalate-plasticizer-containing clouding agents
Yen, T., Lin‐Tan, D., & Lin, J. (2011) · Journal of the Formosan Medical Association · doi:10.1016/j.jfma.2011.09.002 · Cited by 110
Cryptorchidism and endocrine disrupting chemicals
Virtanen, H. E., & Adamsson, A. (2011) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.11.015 · Cited by 109
Prenatal phthalate exposure and reproductive function in young men
Axelsson, J., Rylander, L., Rignell-Hydbom, A., Lindh, C. H., Jönsson, B. A. G., & Giwercman, A. (2015) · Environmental Research · doi:10.1016/j.envres.2015.02.024 · Cited by 107
The diversity of sex steroid action: novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models
Saloniemi, T., Jokela, H., Strauss, L., Pakarinen, P., & POUTANEN, M. H. (2011) · Journal of Endocrinology · doi:10.1530/joe-11-0315 · Cited by 116
Low-dose effects of bisphenol A on early sexual development in male and female rats
Christiansen, S., Axelstad, M., Boberg, J., Vinggaard, A. M., Pedersen, G. A., & Hass, U. (2014) · Reproduction · doi:10.1530/rep-13-0377 · Cited by 108
The Impact of Environmental and Occupational Exposures on Reproductive Health
Chalupka, S. M., & Chalupka, A. N. (2010) · Journal of Obstetric, Gynecologic & Neonatal Nursing · doi:10.1111/j.1552-6909.2009.01091.x · Cited by 108
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
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
“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).”
Influential
Relative importance of prenatal and postnatal androgen action in determining growth of the penis and anogenital distance in the rat before, during and after puberty
van 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
“, 2009), consistent with occurrence of an MPW in humans (Welsh et al., 2008).”
Influential
Androgen Receptor Expression in the Caput Epididymal Epithelium Is Essential for Development of the Initial Segment and Epididymal Spermatozoa Transit
O’Hara, L., Welsh, M., Saunders, P. T. K., & Smith, L. B. (2010) · Endocrinology · doi:10.1210/en.2010-0928 · Cited by 107
Self-citation
Bisphenol A: developmental toxicity from early prenatal exposurea
Golub, M. S., Wu, K. L., Kaufman, F. L., Li, L., Moran, F. M., Zeise, L. A., Alexeeff, G. V., & Donald, J. M. (2010) · Birth Defects Research Part B Developmental and Reproductive Toxicology · doi:10.1002/bdrb.20275 · Cited by 106
“In rodents, AGD is a marker for other abnormalities of genital differentiation (Welsh et al., 2008).”
Differential Effects of Bisphenol A and Diethylstilbestrol on Human, Rat and Mouse Fetal Leydig Cell Function
N’Tumba-Byn, T., Moison, D., Lacroix, M. Z., Lécureuil, C., Lesage, L., Prud’homme, S. M., Pozzi-Gaudin, S., Frydman, R., Benachi, A., Livera, G., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0051579 · Cited by 106
“normal phenotypic masculinization [11,12].”
Prenatal paracetamol exposure is associated with shorter anogenital distance in male infants
Fisher, B. G., Thankamony, A., Hughes, I. A., Ong, K. K., Dunger, D. B., & Acerini, C. L. (2016) · Human Reproduction · doi:10.1093/humrep/dew196 · Cited by 105
“…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).”
Influential
The Masculinization Programming Window
Welsh, M., Suzuki, H., & Yamada, G. (2014) · Endocrine development · doi:10.1159/000363609 · Cited by 105
Self-citation
Endocrinology of the mammalian fetal testis
O’Shaughnessy, P. J., & Fowler, P. (2010) · Reproduction · doi:10.1530/rep-10-0365 · Cited by 104
“…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).”
Influential
Endocrine Disrupting Chemicals and Reproductive Health in Boys and Men
Rodprasert, W., Toppari, J., & Virtanen, H. E. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.706532 · Cited by 102
Presence of parabens, phenols and phthalates in paired maternal serum, urine and amniotic fluid
Bräuner, E. V., Uldbjerg, C. S., Lim, Y., Gregersen, L. S., Krause, M., Frederiksen, H. W., & Andersson, A. (2021) · Environment International · doi:10.1016/j.envint.2021.106987 · Cited by 103
“, 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
“Elsewhere, Cd was also found to lead to the disruption of the blood–testis barrier (Chung and Cheng 2001; Wong et al. 2004).”
Human testicular (non)seminomatous germ cell tumours: the clinical implications of recent pathobiological insights
Looijenga, L. H. J. (2009) · The Journal of Pathology · doi:10.1002/path.2522 · Cited by 100
Interpreting digit ratio (2D:4D)-behavior correlations: 2D:4D sex difference, stability, and behavioral correlates and their replicability in young children.
Wong, W. I., & Hines, M. (2016) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.10.022 · Cited by 93
Endocrine Disruption in Human Fetal Testis Explants by Individual and Combined Exposures to Selected Pharmaceuticals, Pesticides, and Environmental Pollutants
Gaudriault, P., Mazaud‐Guittot, S., Lavoué, V., Coiffec, I., Lesné, L., Dejucq‐Rainsford, N., Scholze, M., Kortenkamp, A., & Jégou, B. (2017) · Environmental Health Perspectives · doi:10.1289/ehp1014 · Cited by 99

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

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

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

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks