2-Hydroxy-4-n-octyloxybenzophenone induces developmental neurotoxicity and multiple sclerosis-like symptoms through cacna1a regulated Ca2 + inward flow and microglial activation.

2-Hydroxy-4-n-octyloxybenzophenone (UV-531) is a UV absorber widely used in infrastructure, cosmetics, and rubber products. The previous study found that UV-531 exposure irritate the skin and interfere with androgen secretion. However, the developmental toxicity and neurotoxic effects of UV-531 are still at an exploratory stage, and the effects of UV-531 on the environment and living organisms need to be further explored. Here, we exposed zebrafish to environmental relevant doses of UV-531 (0.1, 0.2, 0.4, 0.8 and 1.6 μg/L) and observed no significant developmental toxicity, but significant neurotoxicity. We assessed locomotor ability and responsiveness of zebrafish by general locomotion and light/dark challenge. Changes in dopaminergic (DA) neurons were observed using transgenic zebrafish slc18a2:GFP. Changes in cerebral vessels and blood-brain barrier (BBB) were observed using transgenic zebrafish fli1:GFP. Gene expression was detected by transcriptome and real-time qPCR. The effect of UV-531 on calcium homeostasis was determined by measuring Ca2+ levels. Microglia status was assessed by in situ hybridization. It was observed that UV-531 treatment resulted in a reduced locomotor activity, DA neurons injury, cerebral vessels damage, BBB leakage, calcium homeostasis imbalance, and abnormal expression of genes related to neurodevelopment and function. RNA-seq results indicated that Ca2+ import across plasma membrane was highly associated with UV-531-induced developmental neurotoxicity and cacna1aa and cacna1ab were key regulators. These findings suggest that UV-531 induced calcium homeostasis imbalance caused by upregulating cacna1aa and cacna1ab may contribute to multiple sclerosis (MS). Accordingly, UV-531 exposure triggered neuroinflammation, injured myelin, ultimately leading to the development of MS-like symptoms, including decreased responsiveness to external stimuli, microglia activation, dysregulation of mbp and MS-related genes ahsg1, btg1, and grna. In summary, exposure to environmental relevant doses of UV-531 caused neurological damage and led to MS-like symptoms. Given the effects of UV-531 on the organisms, a safe dose range should be established.