Adverse effects of endocrine disruptors on the foetal testis development: focus on the phthalates.

Habert, R.; Muczynski, Vincent; Lehraiki, Abdelali; Lambrot, Romain; LĂŠcureuil, Charlotte; Levacher, Christine; Coffigny, Hervé; Pairault, Catherine; Moison, Delphine; Frydman, R.; Rouiller-Fabre, Virginie

doi:10.2478/v10042-009-0056-5

Cited by 35 publications

(34 citation statements)

References 82 publications

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“…Specifically, the higher occurrence of hypospadias and cryptorchidism may result from alterations of the function of fetal Leydig cells. Indeed, Leydig cells produce testosterone that is responsible for the masculinization of the male urogenital system and external genitalia (26,(34)(35)(36)(37). An important finding in relation to the TDS hypothesis is that androgens must act before the phenotypic masculinization (38,39).…”

Section: Fetal Testis Is a Major Target Of Endocrine Disruptorsmentioning

confidence: 99%

A new chapter in the bisphenol A story: bisphenol S and bisphenol F are not safe alternatives to this compound

Eladak

Grisin

Moison

et al. 2015

Fertility and Sterility

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558

278

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Bisphenol A (BPA) is a widely studied typical endocrine-disrupting chemical, and one of the major new issues is the safe replacement of this commonly used compound. Bisphenol S (BPS) and bisphenol F (BPF) are already or are planned to be used as BPA alternatives. With the use of a culture system that we developed (fetal testis assay [FeTA]), we previously showed that 10 nmol/L BPA reduces basal testosterone secretion of human fetal testis explants and that the susceptibility to BPA is at least 100-fold lower in rat and mouse fetal testes. Here, we show that addition of LH in the FeTA system considerably enhances BPA minimum effective concentration in mouse and human but not in rat fetal testes. Then, using the FeTA system without LH (the experimental conditions in which mouse and human fetal testes are most sensitive to BPA), we found that, as for BPA, 10 nmol/L BPS or BPF is sufficient to decrease basal testosterone secretion by human fetal testes with often nonmonotonic dose-response curves. In fetal mouse testes, the dose-response curves were mostly monotonic and the minimum effective concentrations were 1,000 nmol/L for BPA and BPF and 100 nmol/L for BPS. Finally, 10,000 nmol/L BPA, BPS, or BPF reduced Insl3 expression in cultured mouse fetal testes. This is the first report describing BPS and BPF adverse effects on a physiologic function in humans and rodents.

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Section: Fetal Testis Is a Major Target Of Endocrine Disruptorsmentioning

confidence: 99%

A new chapter in the bisphenol A story: bisphenol S and bisphenol F are not safe alternatives to this compound

Eladak

Grisin

Moison

et al. 2015

Fertility and Sterility

Self Cite

558

278

View full text Add to dashboard Cite

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“…DEHP/MEHP induces germ cell loss and MNGs in vitro using human fetal testis explants (Chauvigné et al 2009; Habert et al 2009; Lambrot et al 2009; Lehraiki et al 2009; Muczynski et al 2012), and DBP exposure induces MNGs in human fetal testis xenografts (Heger et al 2012). However, none of these studies determined whether the phthalate effects were dependent on the stage of germ cell differentiation, which appears to be critical in vivo in rats.…”

Section: Introductionmentioning

confidence: 99%

Comparative Effects of Di( n -Butyl) Phthalate Exposure on Fetal Germ Cell Development in the Rat and in Human Fetal Testis Xenografts

Driesche

McKinnell

Calarrão

et al. 2015

Environ Health Perspect

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BackgroundPhthalate exposure induces germ cell effects in the fetal rat testis. Although experimental models have shown that the human fetal testis is insensitive to the steroidogenic effects of phthalates, the effects on germ cells have been less explored.ObjectivesWe sought to identify the effects of phthalate exposure on human fetal germ cells in a dynamic model and to establish whether the rat is an appropriate model for investigating such effects.MethodsWe used immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction to examine Sertoli and germ cell markers on rat testes and human fetal testis xenografts after exposure to vehicle or di(n-butyl) phthalate (DBP). Our study included analysis of germ cell differentiation markers, proliferation markers, and cell adhesion proteins.ResultsIn both rat and human fetal testes, DBP exposure induced similar germ cell effects, namely, germ cell loss (predominantly undifferentiated), induction of multinucleated gonocytes (MNGs), and aggregation of differentiated germ cells, although the latter occurred rarely in the human testes. The mechanism for germ cell aggregation and MNG induction appears to be loss of Sertoli cell–germ cell membrane adhesion, probably due to Sertoli cell microfilament redistribution.ConclusionsOur findings provide the first comparison of DBP effects on germ cell number, differentiation, and aggregation in human testis xenografts and in vivo in rats. We observed comparable effects on germ cells in both species, but the effects in the human were muted compared with those in the rat. Nevertheless, phthalate effects on germ cells have potential implications for the next generation, which merits further study. Our results indicate that the rat is a human-relevant model in which to explore the mechanisms for germ cell effects.Citationvan den Driesche S, McKinnell C, Calarrão A, Kennedy L, Hutchison GR, Hrabalkova L, Jobling MS, Macpherson S, Anderson RA, Sharpe RM, Mitchell RT. 2015. Comparative effects of di(n-butyl) phthalate exposure on fetal germ cell development in the rat and in human fetal testis xenografts. Environ Health Perspect 123:223–230; http://dx.doi.org/10.1289/ehp.1408248

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“…This reinforces the general concept that the fetal/neonatal testis has its specific endocrine regulations and that it is not a “mini-adult” testis. A better understanding of the endocrinology of fetal testis is now required, especially because it is a very sensitive target of endocrine disruptors [55], [56].…”

Section: Discussionmentioning

confidence: 99%

Mouse Testis Development and Function Are Differently Regulated by Follicle-Stimulating Hormone Receptors Signaling During Fetal and Prepubertal Life

et al. 2012

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It is currently admitted that Follicle-Stimulating Hormone (FSH) is physiologically involved in the development and function of fetal/neonatal Sertoli cells in the rat but not the mouse. However, FSH is produced by both species from late fetal life onwards. We thus reinvestigated the role of FSH in mouse testis development at day 0 (birth) 6, 8 and 10 post-partum (dpp) by using mice that lack functional FSH receptors (FSH-R−/−). At birth, the number and proliferative index of Sertoli cells were significantly lower in FSH-R−/− mice than in wild type neonates. Claudin 11 mRNA expression also was significantly reduced in FSH-R−/− testes at 0 and 8 dpp, whereas the mRNA levels of other Sertoli cell markers (Transferrin and Desert hedgehog) were comparable in FSH-R−/− and wild type testes. Conversely, AMH mRNA and protein levels were higher at birth, comparable at 6 dpp and then significantly lower in FSH-R−/− testes at 8–10 dpp in FSH-R−/− mice than in controls. Although the plasma concentration of LH and the number of Leydig cells were similar in FSH-R−/− and control (wild type), testosterone concentration and P450c17 mRNA expression were significantly increased in FSH-R−/− testes at birth. Conversely, at 10 dpp when adult Leydig cells appear, expression of the steroidogenic genes P450scc, P450c17 and StAR was lower in FSH-R−/− testes than in controls. In conclusion, our results show that 1) like in the rat, signaling via FSH-R controls Sertoli cell development and function during late fetal life in the mouse as well; 2) paracrine factors produced by Sertoli cells are involved in the FSH-R-dependent regulation of the functions of fetal Leydig cells in late fetal life; and 3) the role of FSH-R signaling changes during the prepubertal period.

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Adverse effects of endocrine disruptors on the foetal testis development: focus on the phthalates.

Cited by 35 publications

References 82 publications

A new chapter in the bisphenol A story: bisphenol S and bisphenol F are not safe alternatives to this compound

A new chapter in the bisphenol A story: bisphenol S and bisphenol F are not safe alternatives to this compound

Comparative Effects of Di( n -Butyl) Phthalate Exposure on Fetal Germ Cell Development in the Rat and in Human Fetal Testis Xenografts

Mouse Testis Development and Function Are Differently Regulated by Follicle-Stimulating Hormone Receptors Signaling During Fetal and Prepubertal Life

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