Developmental Effects and Estrogenicity of Bisphenol A Alternatives in a Zebrafish Embryo Model

Abstract

In order to understand the negative effects of bisphenol A (BPA) alternatives comprehensively, zebrafish embryos were used to assess the lethality, developmental effects, and estrogenic activity of bisphenol analogues. The in silico estrogenic activities of bisphenol analogues were assayed by binding simulation. According to our results, the lethality of bisphenol analogues decreased in order of bisphenol AF (BPAF) > BPA > bisphenol F (BPF) > bisphenol S (BPS). BPAF and BPF induced significant effects on zebrafish embryos, including decreased heart rate, hatching inhibition, and teratogenic effects. The binding potentials of bisphenol analogues toward zebrafish ERs (zfERS) decreased in the following order: BPAF > BPA > BPF > BPS. Among the three subtypes of zfERs, zfERβ2 showed the highest binding activity toward the bisphenols, followed by zfERα and zfERβ1. In vivo estrogenic activity tests showed that BPAF, BPA, and BPF significantly enhanced the protein levels of ERα along with the mRNA levels of esr1, esr2a, esr2b, and vtg1 in zebrafish embryos. Esr2b showed the strongest response to BPAF and BPA exposure among the three esrs. In contrast, BPS did not significantly regulate ER protein level or ER transcription. In conclusion, BPAF showed the highest lethality, developmental effects, and estrogenic activity (both in silico and in vivo) followed by BPA and BPF. BPS showed the weakest toxicity and estrogenic activity. zfERβ2 might act as the main target among the three ER subtypes of zebrafish after exposure to BPAF and BPA.

Bisphenol F has different effects on preadipocytes differentiation and weight gain in adult mice as compared with Bisphenol A and S

“…The National Health and Nutritional Survey (NHANES) done in 2013-2014 (Lehmler et al 2018) found detectable level of all three bisphenols (Mu et al 2018) in randomly selected urine samples collected from the U.S. population, indicating that the exposure to BPA and its substitutes is almost ubiquitous. The urinary levels of bisphenols were associated mainly with age, gender and race/ethnicity.…”

Immune Cells in the Uterine Remodeling: Are They the Target of Endocrine Disrupting Chemicals?

“…Companies increasingly advertise for their BPA-free products (Websites European chemicals agency, Umweltbundesamt). What the consumers do not know is, that BPA is replaced by other bisphenols like bisphenol F or S that show comparable or even worse harmful developmental effects and are able to cross the placenta (156,157). It was recently shown that the exposure of the population to BPA substitutes is almost ubiquitous (158).…”

Using zebrafish (Danio rerio) to study the behavioral impacts of early bisphenol F exposure reveals decreased swim speed, increased distance between fish, and increased freezing behaviors

“…BPF has been shown to significantly alter 56 different genes involved in the serotonin-dopamine pathway in the prefrontal cortex of female rats, changing the transcrip-tion of these genes (Castro et al, 2015). Studies with zebrafish embryos have revealed decreased heart rates, hatching inhibition, and disrupted development when treated with BPF (Mu et al, 2018). Similar to the mechanism proposed by the Kinch lab, BPF was shown to upregulate aromatase in the brain of embryonic zebrafish through estrogen receptors by acting as a full agonist in vivo (Le Fol et al, 2017).…”