Assessment of the in vitro developmental toxicity of diethylstilbestrol and estradiol in the zebrafish embryotoxicity test

• Published in: Toxicology in vitro Vol. 72; p. 105088
• Main Authors: Adam, Aziza Hussein Bakheit, de Haan, Laura H.J., Louisse, Jochem, Rietjens, Ivonne M.C.M., Kamelia, Lenny
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2021; Elsevier Science Ltd
• Subjects: 17β-Estradiol; Biocompatibility; Danio rerio; Developmental toxicity; Diethylstilbestrol; Edema; Embryo cells; Embryos; Estrogen receptor alpha (ERα, ESR1); Fulvestrant; Growth rate; In vivo methods and tests; Mode of action; Mortality; Sex hormones; Stem cells; Toxicants; Toxicity; Zebrafish; Diethylstilbestrol; Estrogen receptor alpha (ERα, ESR1); 17β-estradiol; Developmental toxicity
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2021.105088

The present study investigated the developmental toxicity of diethylstilbestrol (DES) in the zebrafish embryotoxicity test (ZET). This was done to investigate whether the ZET would better capture the developmental toxicity of DES than the embryonic stem cells test (EST) that was previously shown to underpredict the DES-induced developmental toxicity as compared to in vivo data, potentially because the EST does not capture late events in the developmental process. The ZET results showed DES-induced growth retardation, cumulative mortality and dysmorphisms (i.e. induction of pericardial edema) in zebrafish embryos while the endogenous ERα agonist 17β-estradiol (E2) showed only growth retardation and cumulative mortality with lower potency compared to DES. Furthermore, the DES-induced pericardial edema formation in zebrafish embryos could be counteracted by co-exposure with ERα antagonist fulvestrant, indicating that the ZET captures the role of ERα in the mode of action underlying the developmental toxicity of DES. Altogether, it is concluded that the ZET differentiates DES from E2 with respect to their developmental toxicity effects, while confirming the role of ERα in mediating the developmental toxicity of DES. Furthermore, comparison to in vivo data revealed that, like the EST, in a quantitative way also the ZET did not capture the relatively high in vivo potency of DES as a developmental toxicant. •Developmental toxicity of DES and E2 were evaluated in the zebrafish embryotoxicity test (ZET)•DES and E2 induced growth retardation and cumulative mortality, and additionally DES also induced malformations in zebrafish embryos.•DES-induced pericardial edema in zebrafish embryos could be counteracted by co-exposure with the ERα antagonist fulvestrant