Early developmental exposure to bisphenol A and bisphenol S disrupts socio-cognitive function, isotocin equilibrium, and excitation-inhibition balance in developing zebrafish.

Dysregulation of the oxytocinergic system and excitation/inhibition (E/I) balance in synaptic transmission and neural circuits are common hallmarks of various neurodevelopmental disorders. Several experimental and epidemiological studies have shown that perinatal exposure to endocrine-disrupting chemicals bisphenol A (BPA) and bisphenol S (BPS) may contribute to a range of childhood neurodevelopmental disorders. However, the effects of BPA and BPS on social-cognitive development and the associated mechanisms remain largely unknown. In this study, we explored the impacts of early developmental exposure (2hpf-5dpf) to environmentally relevant concentrations of BPA, and its analog BPS (0.001, 0.01, and 0.1 µM), on anxiety, social behaviors, and memory performance in 21 dpf zebrafish larvae. Our results revealed that early-life exposure to low concentrations of BPA and BPS elevated anxiety-like behavior, while fish exposed to higher concentrations of these chemicals displayed social deficits and impaired object recognition memory. Additionally, we found that co-exposure with an aromatase inhibitor antagonized BPA- and BPS-induced effects on anxiety levels and social behaviors, while the co-exposure to an estrogen receptor antagonist restored recognition memory in zebrafish larvae. These results indicate that BPA and BPS may affect social-cognitive function through distinct mechanisms. On the other hand, exposure to low BPA/BPS concentrations increased both the mRNA and protein levels of isotocin (zebrafish oxytocin) in the zebrafish brain, whereas a reduction in its mRNA level was observed at higher concentrations. Further, alterations in the transcript abundance of chloride transporters, and molecular markers of gamma-aminobutyric acid (GABA) and glutamatergic systems, were observed in the zebrafish brain, suggesting possible E/I imbalance following BPA or BPS exposure. Collectively, the results of this study demonstrate that early-life exposure to low concentrations of the environmental contaminants BPA and BPS can interfere with the isotocinergic signaling pathway and disrupts the establishment of E/I balance in the developing brain, subsequently leading to the onset of a suite of behavioral deficits and neurodevelopmental disorders.

The sensory-motor responses to environmental acidosis in larval zebrafish: Influences of neurotransmitter and water chemistry.

The sensory-motor function in larval zebrafish (Danio rerio) following exposure to low water pH was investigated. The results suggested that acid exposure (pH 4.0-5.0; control: pH 7.4) significantly reduced the touch-evoked escape response of larval zebrafish at 3 days post fertilization (dpf). A significant number of pH 4.0-exposed larvae also exhibited a lack of escape response. Treatment with neurotransmitters showed that serotonin or acetylcholine, but not dopamine, reduced the adverse effects of acid exposure on the escape response of larvae. Co-exposure to serotonin and acetylcholine did not further improve the escape response of acid-exposed larvae, suggesting no additive effect by these neurotransmitters. Interestingly, the negative effects of acid exposure on the escape response could be completely rescued by elevating the water levels of Ca2+, but not NaCl. Collectively, these results suggested that acid-induced disruption in Ca2+ balance suppressed the serotonin- and acetylcholine-mediated neuronal signaling, thereby affecting the sensory-motor function and escape response of larval zebrafish. Findings from the present study may have important implication for the survival (e.g., escape from adverse conditions) of larval fish in acid-impacted environments, particularly during early development when they are still incapable of spontaneous swimming.