Neurodevelopmental toxicity of bisphenol AF in zebrafish larvae and the protective effects of curcumin

Abstract

Bisphenol AF (BPAF) is one of the most commonly used alternatives of bisphenol A in the plastics industry. The effects of BPAF on nervous development are unclear. Curcumin (CUR) has been determined to be an anti‐inflammatory and antioxidant agent. In this study, the effects of BPAF on neurotoxicity of zebrafish embryos/larvae and whether CUR could reverse effects induced by BPAF were investigated. The results showed that BPAF treatment induced deficits in locomotor behavior, altered the larval brain development, caused aberrant expression of neurogenesis related genes (elavl3, zn5, α‐tubulin, syn2a, and gap43), decreased acetylcholinesterase (AChE) activity, and induced oxidative stress, cell apoptosis, and neuroinflammation in zebrafish larvae. CUR addition could block the adverse effects of BPAF on nervous development by attenuated oxidative stress and cell apoptosis induced by BPAF in zebrafish, enhanced the activity of AChE, and increased the expression of genes involved in the pro‐inflammatory cytokines (IL‐6, IL‐1β, TNF‐α, and IL‐8). The results of this study indicate that BPAF could induce aberrant development on nervous system. However, CUR exerts neuroprotective effects on BPAF‐induced neurotoxicity in zebrafish larvae.

Regrettable Substitutes and the Brain: What Animal Models and Human Studies Tell Us about the Neurodevelopmental Effects of Bisphenol, Per- and Polyfluoroalkyl Substances, and Phthalate Replacements

“…Regarding mechanisms of action, increases in oxidative stress are a consistent mechanism to which alterations to neurodevelopment and behavior through bisphenols, similar to results for BPA, are attributed [73,[82][83][84]98]. ↓ Larvae locomotion at 10-1000 ug/L ↑ Hypothalamus and mesencephalon degeneration at 100 and 1000 ug/L, with no change in other brain regions ↑ T3 hormone and T3/T4 hormone ratio at 10-1000 ug/L ↓ T4 hormone at 1000 ug/L ↑ Expression of dio1, dio2 and trhr1 at 1-1000 ug/L; tg, ttr, thrα at 10-1000 ug/L; thrβ at 100-1000 ug/L (genes related to the HPG axis) ↓ Expression of tshβ and trh at 1-1000 ug/L, (genes related to the HPG axis) ↓ Expression of α1-tubulin, myelin basic protein, syn2a, elavl3, zn5 at 1-1000 ug/L; gap43 at 100-1000 ug/L (genes related to neurodevelopment) ↑ Time and distance in well peripheral zone at 0.001 μM ↓ Time in "social" zone at 0.1 μM ↓ Exploration of novel object in memory task at 0.01 and 0.1 μM ↑ Expression of esr1, esr2a, it, slc12a5a, slc12a5b, slc12a2 at 0.001 μM (genes related to brain signaling pathways) ↓ Expression of esr2b at 0.01 and 0.1; it and slc12a2 at 0.1 μM (genes Naderi et al, 2022 [88] related to brain signaling pathways) ↑ Expression of gad1b, slc32a1, slc6a1a, gabra1 at 0.001 μM; slc17a7a, grla1a, grin1a at 0.1 μM (genes associated with GABA and glutamate signaling) ↓ Expression of slc6a1a and gabra1 at 0.1 μM; grabra2 at 0.01 and 0.1 ↓ Embryo spontaneous movement at all doses ↓ Larvae locomotion at 0.5 mg/L and above ↓ Neurogenesis in larvae brain at 0.5 mg/L and above ↓ Larvae motor-neuron length at 0.5 mg/L and above ↓ Dopamine neuron development at all doses ↓ Expression of syn2a and gafp expression at 0.5 mg/L and above (genes related to neurodevelopment) ↑ Expression of th1 and th2 at 0.24 mg/L and above (genes related to neurodevelopment)…”

“…Embryonic and larval BPA analogue exposure has neurotoxic effects in zebrafish (Table 2). In general, embryonic and larval exposure to bisphenols decreases embryo spontaneous movement and larvae locomotion [26,74,[79][80][81][82][83][84][85][86][87], with the exception of BPS, which produced mixed results. According to multiple comparison studies, BPAF leads to the most severe alterations in locomotion, followed by BPF, which is similar to BPA, and then BPS [80,81].…”

“…It is clear from the zebrafish studies that exposure to many BPA analogues leads to disrupted neuronal development, with immunohistochemistry and gene expression studies demonstrating decreased motor neuron lengths [80,87,91,92], alterations in neuron differentiation [79,93,94], neurogenesis [26,73,80,83,95], and neural maturation [93], in addition to a rise in brain degeneration [85] and neuron apoptosis [86]. Specific neurotransmitters including GABA, glutamine, glutamate, dopamine, serotonin, acetylcholine, and isotocin (oxytocin-family peptide) also show changes with perinatal analogue exposure [26,80,87,88].…”