A systematic comparison of neurotoxicity of bisphenol A and its derivatives in zebrafish

As more and more countries have prohibited the manufacture and sale of plastic products with bisphenol A (BPA), a number of bisphenol analogues (BPs), including BPS, BPF and BPAF, have gradually been used as its primary substitutes. Ideally, substitutes used to replace chemicals with environmental risks should be inert, so it makes sense that the risk of the similar chemical substitutes (BPS, BPF, and BPAF) should be assessed before they used. Therefore, in the present study, the neurotoxicity of four BPs at environmentally relevant concentration (200 μg/L) were systematically compared using zebrafish as a model. Our results showed that the four BPs (BPA, BPS, BPF and BPAF) exhibited no obvious effect on the hatchability, survival rate and body length of zebrafish larvae, noteworthily a significant inhibitory effect on spontaneous movement at 24 hpf was observed in the BPA, BPF and BPAF treatment groups. Behavioral tests showed that BPAF, BPF and BPA exposure significantly reduced the locomotor activity of the larvae. Additionally, BPAF treatment adversely affected motor neuron axon length in transgenic lines hb9-GFP zebrafish and decreased central nervous system (CNS) neurogenesis in transgenic lines HuC-GFP zebrafish. Intriguingly, BPAF displayed the strongest effects on the levels and metabolism of neurotransmitters, followed by BPF and BPA, while BPS showed the weakest effects on neurotransmitters. In conclusion, our study deciphered that environmentally relevant concentrations of BPs exposure exhibited differential degrees of neurotoxicity, which ranked as below: BPAF > BPF ≈ BPA > BPS. The possible mechanisms can be partially ascribed to the dramatical changes of multiple neurotransmitters and the inhibitory effects on neuronal development. These results suggest that BPAF and BPF should be carefully considered as alternatives to BPA.