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An investigation of the endocrine-disruptive effects of bisphenol a in human and rat fetal testes.

Ben Maamar M, Lesné L, Desdoits-Lethimonier C, Coiffec I, Lassurguère J, Lavoué V, Deceuninck Y, Antignac JP, Le Bizec B, Perdu E, Zalko D, Pineau C, Chevrier C, Dejucq-Rainsford N, Mazaud-Guittot S, Jégou B - PLoS ONE (2015)

Bottom Line: BPA concentrations of 10(-8)M and 10(-5)M for 72 h reduced testosterone production by the Sprague-Dawley fetal rat testes, while only 10-5M suppressed it in the Wistar strain.The suppressive effects at 10-5M were seen as early as 24h and 48 h in both strains.We concluded that (i) BPA can display anti-androgenic effects both in rat and human fetal testes; (ii) it is essential to ascertain that the divergent effects of endocrine disruptors between species in vitro do not result from the culture conditions used, and/or the rodent strain selected; (iii) the optimization of each in vitro assay for a given species should be a major objective rather than the search of an hypothetical trans-species consensual model-system, as the organization of the testis is intrinsically different between mammalian species; (iv) due to the uncertainty existing on the internal exposure of the human fetal testis to BPA, and the insufficient number of epidemiological studies on the endocrine disruptive effects of BPA, caution should be taken in the extrapolation of our present results to the human reproductive health after fetal exposure to BPA.

View Article: PubMed Central - PubMed

Affiliation: Inserm (Institut national de la santé et de la recherche médicale), IRSET, U1085, SFR Biosit, Campus de Beaulieu, Rennes, CEDEX, France; Université de Rennes I, Campus de Beaulieu, Rennes, CEDEX, France.

ABSTRACT
Few studies have been undertaken to assess the possible effects of bisphenol A (BPA) on the reproductive hormone balance in animals or humans with often contradictory results. We investigated possible direct endocrine disruption by BPA of the fetal testes of 2 rat strains (14.5-17.5 days post-coitum) and humans (8-12 gestational weeks) and under different culture conditions. BPA concentrations of 10(-8)M and 10(-5)M for 72 h reduced testosterone production by the Sprague-Dawley fetal rat testes, while only 10-5M suppressed it in the Wistar strain. The suppressive effects at 10-5M were seen as early as 24h and 48 h in both strains. BPA at 10(-7)-10(-5)M for 72 h suppressed the levels of fetal rat Leydig cell insulin-like factor 3 (INSL3). BPA exposure at 10(-8)M, 10(-7)M, and 10(-5)M for 72 h inhibited testosterone production in fetal human testes. For the lowest doses, the effects observed occurred only when no gonadotrophin was added to the culture media and were associated with a poorly preserved testicular morphology. We concluded that (i) BPA can display anti-androgenic effects both in rat and human fetal testes; (ii) it is essential to ascertain that the divergent effects of endocrine disruptors between species in vitro do not result from the culture conditions used, and/or the rodent strain selected; (iii) the optimization of each in vitro assay for a given species should be a major objective rather than the search of an hypothetical trans-species consensual model-system, as the organization of the testis is intrinsically different between mammalian species; (iv) due to the uncertainty existing on the internal exposure of the human fetal testis to BPA, and the insufficient number of epidemiological studies on the endocrine disruptive effects of BPA, caution should be taken in the extrapolation of our present results to the human reproductive health after fetal exposure to BPA.

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Effects of BPA on testosterone production after 72h of culture of 7–12 GW human fetal testis explants.A) Dose-dependent effects of BPA—diluted in DMSO or ethanol—with hLH on testosterone production by human fetal testis explants (RTP; RTP, %Ctrl): BPA was diluted in DMSO or ethanol and the media collected after 72 hr of culture were assayed. Results are expressed as normalized production of testosterone of treated samples as the percentage of that of the respective untreated first day of culture sample (RTP) (top) and as the percentage of that of the respective untreated first day of culture sample and control (RTP, %Ctrl) (bottom). Values are mean +/- SEM of testosterone from the respective untreated first day of culture basal sample and control. The number of testes (n) is indicated below the graphic for each condition. Dose-responses were analyzed for significance with a Wilcoxon test. The effects of the vehicle were analyzed with two-way ANOVA. *p<0.05. B) Testosterone production after culture of human fetal testis in the presence of BPA and hCG, hLH or no gonadotrophin (-gonado) supplementing the medium (RTP). n = 7–13 testes for the hCG group, n = 3–20 testes for hLH group and n = 9–21 in the absence of gonadotrophin. *p<0.05, ***p<0.001 (two-way ANOVA followed by a Holm-Sidak test or a Wilcoxon test to compare matched samples). C) Testosterone production represented as a fold change from the respective first day of culture sample and control (RTP, %Ctrl). Results are expressed as normalized production of testosterone of treated samples as the percentage of that of the respective untreated first day of culture sample (RTP) and control (RTP, %Ctrl). n = 7–13 testes for the hCG group, n = 3–20 testes for hLH group and n = 9–21 in the absence of gonadotrophin. *p<0.05, ***p<0.001 (two-way ANOVA followed by a Holm-Sidak test or a Wilcoxon test to compare matched samples).
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pone.0117226.g003: Effects of BPA on testosterone production after 72h of culture of 7–12 GW human fetal testis explants.A) Dose-dependent effects of BPA—diluted in DMSO or ethanol—with hLH on testosterone production by human fetal testis explants (RTP; RTP, %Ctrl): BPA was diluted in DMSO or ethanol and the media collected after 72 hr of culture were assayed. Results are expressed as normalized production of testosterone of treated samples as the percentage of that of the respective untreated first day of culture sample (RTP) (top) and as the percentage of that of the respective untreated first day of culture sample and control (RTP, %Ctrl) (bottom). Values are mean +/- SEM of testosterone from the respective untreated first day of culture basal sample and control. The number of testes (n) is indicated below the graphic for each condition. Dose-responses were analyzed for significance with a Wilcoxon test. The effects of the vehicle were analyzed with two-way ANOVA. *p<0.05. B) Testosterone production after culture of human fetal testis in the presence of BPA and hCG, hLH or no gonadotrophin (-gonado) supplementing the medium (RTP). n = 7–13 testes for the hCG group, n = 3–20 testes for hLH group and n = 9–21 in the absence of gonadotrophin. *p<0.05, ***p<0.001 (two-way ANOVA followed by a Holm-Sidak test or a Wilcoxon test to compare matched samples). C) Testosterone production represented as a fold change from the respective first day of culture sample and control (RTP, %Ctrl). Results are expressed as normalized production of testosterone of treated samples as the percentage of that of the respective untreated first day of culture sample (RTP) and control (RTP, %Ctrl). n = 7–13 testes for the hCG group, n = 3–20 testes for hLH group and n = 9–21 in the absence of gonadotrophin. *p<0.05, ***p<0.001 (two-way ANOVA followed by a Holm-Sidak test or a Wilcoxon test to compare matched samples).

Mentions: Human fetal testis. As described above in rats, human fetal testosterone levels did not differ significantly whether the testes were cultured with DMSO or ethanol in control conditions (Fig. 3A). BPA, whether diluted in DMSO or ethanol, did not significantly change testosterone production levels (Relative Testosterone Production, or RTP) at any concentration (Fig. 3A: p = 0.404). The same pattern of BPA-induced effects on testosterone was observed when the data were expressed as testosterone production normalized to the D0 of the same well and to the control (RTP, %Ctrl, p = 0.206). BPA at 10-5M induced a significant decrease of the RTP, %Ctrl whatever the solvent (Fig. 3A: -28% when diluted in DMSO, p<0.05; -35% in ethanol, p<0.05).


An investigation of the endocrine-disruptive effects of bisphenol a in human and rat fetal testes.

Ben Maamar M, Lesné L, Desdoits-Lethimonier C, Coiffec I, Lassurguère J, Lavoué V, Deceuninck Y, Antignac JP, Le Bizec B, Perdu E, Zalko D, Pineau C, Chevrier C, Dejucq-Rainsford N, Mazaud-Guittot S, Jégou B - PLoS ONE (2015)

Effects of BPA on testosterone production after 72h of culture of 7–12 GW human fetal testis explants.A) Dose-dependent effects of BPA—diluted in DMSO or ethanol—with hLH on testosterone production by human fetal testis explants (RTP; RTP, %Ctrl): BPA was diluted in DMSO or ethanol and the media collected after 72 hr of culture were assayed. Results are expressed as normalized production of testosterone of treated samples as the percentage of that of the respective untreated first day of culture sample (RTP) (top) and as the percentage of that of the respective untreated first day of culture sample and control (RTP, %Ctrl) (bottom). Values are mean +/- SEM of testosterone from the respective untreated first day of culture basal sample and control. The number of testes (n) is indicated below the graphic for each condition. Dose-responses were analyzed for significance with a Wilcoxon test. The effects of the vehicle were analyzed with two-way ANOVA. *p<0.05. B) Testosterone production after culture of human fetal testis in the presence of BPA and hCG, hLH or no gonadotrophin (-gonado) supplementing the medium (RTP). n = 7–13 testes for the hCG group, n = 3–20 testes for hLH group and n = 9–21 in the absence of gonadotrophin. *p<0.05, ***p<0.001 (two-way ANOVA followed by a Holm-Sidak test or a Wilcoxon test to compare matched samples). C) Testosterone production represented as a fold change from the respective first day of culture sample and control (RTP, %Ctrl). Results are expressed as normalized production of testosterone of treated samples as the percentage of that of the respective untreated first day of culture sample (RTP) and control (RTP, %Ctrl). n = 7–13 testes for the hCG group, n = 3–20 testes for hLH group and n = 9–21 in the absence of gonadotrophin. *p<0.05, ***p<0.001 (two-way ANOVA followed by a Holm-Sidak test or a Wilcoxon test to compare matched samples).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4338204&req=5

pone.0117226.g003: Effects of BPA on testosterone production after 72h of culture of 7–12 GW human fetal testis explants.A) Dose-dependent effects of BPA—diluted in DMSO or ethanol—with hLH on testosterone production by human fetal testis explants (RTP; RTP, %Ctrl): BPA was diluted in DMSO or ethanol and the media collected after 72 hr of culture were assayed. Results are expressed as normalized production of testosterone of treated samples as the percentage of that of the respective untreated first day of culture sample (RTP) (top) and as the percentage of that of the respective untreated first day of culture sample and control (RTP, %Ctrl) (bottom). Values are mean +/- SEM of testosterone from the respective untreated first day of culture basal sample and control. The number of testes (n) is indicated below the graphic for each condition. Dose-responses were analyzed for significance with a Wilcoxon test. The effects of the vehicle were analyzed with two-way ANOVA. *p<0.05. B) Testosterone production after culture of human fetal testis in the presence of BPA and hCG, hLH or no gonadotrophin (-gonado) supplementing the medium (RTP). n = 7–13 testes for the hCG group, n = 3–20 testes for hLH group and n = 9–21 in the absence of gonadotrophin. *p<0.05, ***p<0.001 (two-way ANOVA followed by a Holm-Sidak test or a Wilcoxon test to compare matched samples). C) Testosterone production represented as a fold change from the respective first day of culture sample and control (RTP, %Ctrl). Results are expressed as normalized production of testosterone of treated samples as the percentage of that of the respective untreated first day of culture sample (RTP) and control (RTP, %Ctrl). n = 7–13 testes for the hCG group, n = 3–20 testes for hLH group and n = 9–21 in the absence of gonadotrophin. *p<0.05, ***p<0.001 (two-way ANOVA followed by a Holm-Sidak test or a Wilcoxon test to compare matched samples).
Mentions: Human fetal testis. As described above in rats, human fetal testosterone levels did not differ significantly whether the testes were cultured with DMSO or ethanol in control conditions (Fig. 3A). BPA, whether diluted in DMSO or ethanol, did not significantly change testosterone production levels (Relative Testosterone Production, or RTP) at any concentration (Fig. 3A: p = 0.404). The same pattern of BPA-induced effects on testosterone was observed when the data were expressed as testosterone production normalized to the D0 of the same well and to the control (RTP, %Ctrl, p = 0.206). BPA at 10-5M induced a significant decrease of the RTP, %Ctrl whatever the solvent (Fig. 3A: -28% when diluted in DMSO, p<0.05; -35% in ethanol, p<0.05).

Bottom Line: BPA concentrations of 10(-8)M and 10(-5)M for 72 h reduced testosterone production by the Sprague-Dawley fetal rat testes, while only 10-5M suppressed it in the Wistar strain.The suppressive effects at 10-5M were seen as early as 24h and 48 h in both strains.We concluded that (i) BPA can display anti-androgenic effects both in rat and human fetal testes; (ii) it is essential to ascertain that the divergent effects of endocrine disruptors between species in vitro do not result from the culture conditions used, and/or the rodent strain selected; (iii) the optimization of each in vitro assay for a given species should be a major objective rather than the search of an hypothetical trans-species consensual model-system, as the organization of the testis is intrinsically different between mammalian species; (iv) due to the uncertainty existing on the internal exposure of the human fetal testis to BPA, and the insufficient number of epidemiological studies on the endocrine disruptive effects of BPA, caution should be taken in the extrapolation of our present results to the human reproductive health after fetal exposure to BPA.

View Article: PubMed Central - PubMed

Affiliation: Inserm (Institut national de la santé et de la recherche médicale), IRSET, U1085, SFR Biosit, Campus de Beaulieu, Rennes, CEDEX, France; Université de Rennes I, Campus de Beaulieu, Rennes, CEDEX, France.

ABSTRACT
Few studies have been undertaken to assess the possible effects of bisphenol A (BPA) on the reproductive hormone balance in animals or humans with often contradictory results. We investigated possible direct endocrine disruption by BPA of the fetal testes of 2 rat strains (14.5-17.5 days post-coitum) and humans (8-12 gestational weeks) and under different culture conditions. BPA concentrations of 10(-8)M and 10(-5)M for 72 h reduced testosterone production by the Sprague-Dawley fetal rat testes, while only 10-5M suppressed it in the Wistar strain. The suppressive effects at 10-5M were seen as early as 24h and 48 h in both strains. BPA at 10(-7)-10(-5)M for 72 h suppressed the levels of fetal rat Leydig cell insulin-like factor 3 (INSL3). BPA exposure at 10(-8)M, 10(-7)M, and 10(-5)M for 72 h inhibited testosterone production in fetal human testes. For the lowest doses, the effects observed occurred only when no gonadotrophin was added to the culture media and were associated with a poorly preserved testicular morphology. We concluded that (i) BPA can display anti-androgenic effects both in rat and human fetal testes; (ii) it is essential to ascertain that the divergent effects of endocrine disruptors between species in vitro do not result from the culture conditions used, and/or the rodent strain selected; (iii) the optimization of each in vitro assay for a given species should be a major objective rather than the search of an hypothetical trans-species consensual model-system, as the organization of the testis is intrinsically different between mammalian species; (iv) due to the uncertainty existing on the internal exposure of the human fetal testis to BPA, and the insufficient number of epidemiological studies on the endocrine disruptive effects of BPA, caution should be taken in the extrapolation of our present results to the human reproductive health after fetal exposure to BPA.

Show MeSH
Related in: MedlinePlus