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Bisphenol A induces otolith malformations during vertebrate embryogenesis.

Gibert Y, Sassi-Messai S, Fini JB, Bernard L, Zalko D, Cravedi JP, Balaguer P, Andersson-Lendahl M, Demeneix B, Laudet V - BMC Dev. Biol. (2011)

Bottom Line: Here, we investigated BPA effects during embryonic development using the zebrafish and Xenopus models.As no effects on otolith development were seen with exposure to micromolar concentrations of thyroid hormone, 17-ß-estradiol or of the estrogen receptor antagonist ICI 182,780 we conclude that the effects of BPA are independent of estrogen receptors or thyroid-hormone receptors.The data suggest that the spectrum of BPA action is wider than previously expected and argue for a systematic survey of the developmental effects of this endocrine disruptor.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut de Génomique Fonctionnelle de Lyon; Université de Lyon; Université Lyon 1; CNRS; INRA; Ecole Normale Supérieure de Lyon; 46 allée d'Italie, 69364 Lyon Cedex 07, France. vincent.laudet@ens-lyon.fr

ABSTRACT

Background: The plastic monomer and plasticizer bisphenol A (BPA), used for manufacturing polycarbonate plastic and epoxy resins, is produced at over 2.5 million metric tons per year. Concerns have been raised that BPA acts as an endocrine disruptor on both developmental and reproductive processes and a large body of evidence suggests that BPA interferes with estrogen and thyroid hormone signaling. Here, we investigated BPA effects during embryonic development using the zebrafish and Xenopus models.

Results: We report that BPA exposure leads to severe malformations of the otic vesicle. In zebrafish and in Xenopus embryos, exposure to BPA during the first developmental day resulted in dose-dependent defects in otolith formation. Defects included aggregation, multiplication and occasionally failure to form otoliths. As no effects on otolith development were seen with exposure to micromolar concentrations of thyroid hormone, 17-ß-estradiol or of the estrogen receptor antagonist ICI 182,780 we conclude that the effects of BPA are independent of estrogen receptors or thyroid-hormone receptors. Na+/K+ ATPases are crucial for otolith formation in zebrafish. Pharmacological inhibition of the major Na+/K+ ATPase with ouabain can rescue the BPA-induced otolith phenotype.

Conclusions: The data suggest that the spectrum of BPA action is wider than previously expected and argue for a systematic survey of the developmental effects of this endocrine disruptor.

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BPA effect on otolith development is estrogen receptor-independent. Morphology of the inner ear of zebrafish embryos at 48 hpf following exposure to BPA with or without ER antagonists (ICI 182 780) or agonists (17-β estradiol, E2). Treatment with either 1 μM ICI (A) or 1 μM 17-β estradiol (B) from 5 to 48 hpf does not induce any malformation of the developing semi-circular canals nor otoliths. Moreover, the BPA-induced otolith phenotype is not rescued when embryos are co-treated with BPA 5 μM +ICI 1 μM (A) or BPA 5 μM +βE2 1 μM (B). Interestingly, co-treatment with BPA 5 μM +ICI 1 μM lead to in increased ratio of affected otolith than a treatment with BPA 5 μM alone (A). On the other hand co-treatment with BPA 5 μM +βE2 1 μM gives a similar ratio than a treatment with BPA 5 μM alone (B).
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Figure 4: BPA effect on otolith development is estrogen receptor-independent. Morphology of the inner ear of zebrafish embryos at 48 hpf following exposure to BPA with or without ER antagonists (ICI 182 780) or agonists (17-β estradiol, E2). Treatment with either 1 μM ICI (A) or 1 μM 17-β estradiol (B) from 5 to 48 hpf does not induce any malformation of the developing semi-circular canals nor otoliths. Moreover, the BPA-induced otolith phenotype is not rescued when embryos are co-treated with BPA 5 μM +ICI 1 μM (A) or BPA 5 μM +βE2 1 μM (B). Interestingly, co-treatment with BPA 5 μM +ICI 1 μM lead to in increased ratio of affected otolith than a treatment with BPA 5 μM alone (A). On the other hand co-treatment with BPA 5 μM +βE2 1 μM gives a similar ratio than a treatment with BPA 5 μM alone (B).

Mentions: We next examined if the otolith phenotype was linked to an alteration of the estrogen signalling pathway. A first approach was to test whether the ER agonist, E2, or the ER antagonist, ICI, modified BPA effects on otolith morphology (Figure 4). Zebrafish embryos were exposed to BPA with or without either 1 μM E2 or 1 μM ICI. As shown in Figure 4A and B, neither ICI nor E2 treatment alone induced phenotypic alteration of the otoliths (0%, n=120). However, whereas E2 had absolutely no effect on BPA-induced phenotype in terms of morphology or frequency, ICI exhibited a certain level of synergy with BPA, since there were consistently more affected embryos after co-treatment than with BPA alone (Figure 4A; 56.7%, n = 120 of otoliths affected upon BPA exposure 5.10-6 M alone versus 73.3%, n = 120 of otoliths affected upon BPA exposure 5.10-6 M supplemented with ICI 10-6 M). However, in this case the severity of the morphological phenotype was unaltered. Taken together, these results indicate that the BPA action on otic vesicle development is not mediated primarily by ERs but that, to some extent, modulation of ERs may alter the frequency of the BPA-induced effect.


Bisphenol A induces otolith malformations during vertebrate embryogenesis.

Gibert Y, Sassi-Messai S, Fini JB, Bernard L, Zalko D, Cravedi JP, Balaguer P, Andersson-Lendahl M, Demeneix B, Laudet V - BMC Dev. Biol. (2011)

BPA effect on otolith development is estrogen receptor-independent. Morphology of the inner ear of zebrafish embryos at 48 hpf following exposure to BPA with or without ER antagonists (ICI 182 780) or agonists (17-β estradiol, E2). Treatment with either 1 μM ICI (A) or 1 μM 17-β estradiol (B) from 5 to 48 hpf does not induce any malformation of the developing semi-circular canals nor otoliths. Moreover, the BPA-induced otolith phenotype is not rescued when embryos are co-treated with BPA 5 μM +ICI 1 μM (A) or BPA 5 μM +βE2 1 μM (B). Interestingly, co-treatment with BPA 5 μM +ICI 1 μM lead to in increased ratio of affected otolith than a treatment with BPA 5 μM alone (A). On the other hand co-treatment with BPA 5 μM +βE2 1 μM gives a similar ratio than a treatment with BPA 5 μM alone (B).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3040707&req=5

Figure 4: BPA effect on otolith development is estrogen receptor-independent. Morphology of the inner ear of zebrafish embryos at 48 hpf following exposure to BPA with or without ER antagonists (ICI 182 780) or agonists (17-β estradiol, E2). Treatment with either 1 μM ICI (A) or 1 μM 17-β estradiol (B) from 5 to 48 hpf does not induce any malformation of the developing semi-circular canals nor otoliths. Moreover, the BPA-induced otolith phenotype is not rescued when embryos are co-treated with BPA 5 μM +ICI 1 μM (A) or BPA 5 μM +βE2 1 μM (B). Interestingly, co-treatment with BPA 5 μM +ICI 1 μM lead to in increased ratio of affected otolith than a treatment with BPA 5 μM alone (A). On the other hand co-treatment with BPA 5 μM +βE2 1 μM gives a similar ratio than a treatment with BPA 5 μM alone (B).
Mentions: We next examined if the otolith phenotype was linked to an alteration of the estrogen signalling pathway. A first approach was to test whether the ER agonist, E2, or the ER antagonist, ICI, modified BPA effects on otolith morphology (Figure 4). Zebrafish embryos were exposed to BPA with or without either 1 μM E2 or 1 μM ICI. As shown in Figure 4A and B, neither ICI nor E2 treatment alone induced phenotypic alteration of the otoliths (0%, n=120). However, whereas E2 had absolutely no effect on BPA-induced phenotype in terms of morphology or frequency, ICI exhibited a certain level of synergy with BPA, since there were consistently more affected embryos after co-treatment than with BPA alone (Figure 4A; 56.7%, n = 120 of otoliths affected upon BPA exposure 5.10-6 M alone versus 73.3%, n = 120 of otoliths affected upon BPA exposure 5.10-6 M supplemented with ICI 10-6 M). However, in this case the severity of the morphological phenotype was unaltered. Taken together, these results indicate that the BPA action on otic vesicle development is not mediated primarily by ERs but that, to some extent, modulation of ERs may alter the frequency of the BPA-induced effect.

Bottom Line: Here, we investigated BPA effects during embryonic development using the zebrafish and Xenopus models.As no effects on otolith development were seen with exposure to micromolar concentrations of thyroid hormone, 17-ß-estradiol or of the estrogen receptor antagonist ICI 182,780 we conclude that the effects of BPA are independent of estrogen receptors or thyroid-hormone receptors.The data suggest that the spectrum of BPA action is wider than previously expected and argue for a systematic survey of the developmental effects of this endocrine disruptor.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut de Génomique Fonctionnelle de Lyon; Université de Lyon; Université Lyon 1; CNRS; INRA; Ecole Normale Supérieure de Lyon; 46 allée d'Italie, 69364 Lyon Cedex 07, France. vincent.laudet@ens-lyon.fr

ABSTRACT

Background: The plastic monomer and plasticizer bisphenol A (BPA), used for manufacturing polycarbonate plastic and epoxy resins, is produced at over 2.5 million metric tons per year. Concerns have been raised that BPA acts as an endocrine disruptor on both developmental and reproductive processes and a large body of evidence suggests that BPA interferes with estrogen and thyroid hormone signaling. Here, we investigated BPA effects during embryonic development using the zebrafish and Xenopus models.

Results: We report that BPA exposure leads to severe malformations of the otic vesicle. In zebrafish and in Xenopus embryos, exposure to BPA during the first developmental day resulted in dose-dependent defects in otolith formation. Defects included aggregation, multiplication and occasionally failure to form otoliths. As no effects on otolith development were seen with exposure to micromolar concentrations of thyroid hormone, 17-ß-estradiol or of the estrogen receptor antagonist ICI 182,780 we conclude that the effects of BPA are independent of estrogen receptors or thyroid-hormone receptors. Na+/K+ ATPases are crucial for otolith formation in zebrafish. Pharmacological inhibition of the major Na+/K+ ATPase with ouabain can rescue the BPA-induced otolith phenotype.

Conclusions: The data suggest that the spectrum of BPA action is wider than previously expected and argue for a systematic survey of the developmental effects of this endocrine disruptor.

Show MeSH
Related in: MedlinePlus