Genetic Evidence\nfor Estrogenic Effects of Benzophenone‑2\non Zebrafish Neurodevelopment and Its Signaling Mechanism

Estrogens play a crucial role in regulating various biological\nresponses during the early stages of neurodevelopment. Benzophenone-2\n(BP2), a widely used organic ultraviolet (UV) filter, has been proven\nas an estrogenic compound, whereas the estrogenic effects of BP2 on\nneurodevelopment remain largely unknown. Here, we investigated the\nneurodevelopmental toxicity of BP2 by exposing zebrafish embryos from\n2 to 120 h postfertilization (hpf) at environmentally relevant concentrations.\nWe demonstrated that early life exposure to BP2 induced multiple concentration-dependent\nimpairments in the nervous system, including hypoactivity, abnormal\nbrain morphology, impaired neurocyte proliferation, shortened axon,\nand increased neurocyte apoptosis. Moreover, metabolomic profiling\nrevealed a decrease in dopamine (DA) and its metabolites in BP2-treated\nlarvae. Using E2 treatment and morpholino knockdown assays, we provided\nstrong genetic evidence that the BP2-induced behavioral disorders\nwere associated with estrogen-dependent signaling, especially estrogen\nreceptors 2a and 2b (<i>esr2</i>). Subsequently, transcriptomic\nprofiling indicated that the activation of <i>esr2</i> further\ninhibited the expression of LIM homeobox transcription factor 1 β\na (<i>lmx1ba)</i>, which is vital for normal neurodevelopment.\nConsistently, the overexpression of <i>lmx1ba</i> and inhibition\nof <i>esr2</i> obviously alleviated BP2-caused neurotoxicity,\nuncovering a seminal role of <i>esr2</i> and <i>lmx1ba</i> in BP2-induced neurodevelopmental toxicity. Our findings provide\nthe first evidence in fish that BP2 can induce neurodevelopmental\ndeficits and brain dysfunction and offer novel insights into the mechanisms\nof toxicity of BP2 as well as other emerging benzophenones.