Comparative study on the acute and developmental toxicity of bisphenol S and F in medaka ( <i>Oryzias latipes</i> )

Due to the known adverse effects of bisphenol A (BPA), bisphenol F (BPF), and bisphenol S (BPS) have been widely adopted as substitutes. However, they are now detected at significant levels globally, often at levels rivaling or exceeding those of BPA, which raises concerns regarding their potential ecological and health risks. Our previous work indicated that BPS exhibits lower toxicity than BPF in Chinese medaka (Oryzias sinensis). To validate this, we compared their toxicity in Japanese medaka (Oryzias latipes) using both acute and developmental exposure tests. In the 96-hr acute test, embryos exposed to a concentration gradient showed a BPF median lethal concentration of 128 mg/L, whereas BPS exposure resulted in high survival even at the highest concentrations. Based on the observed acute toxicity, we investigated the underlying mechanism of BPF and evaluated vitamin C rescue. Vitamin C treatment effectively improved embryo survival rates. Subsequently, in a 15-day developmental exposure, 2 μg/L BPF significantly increased yolk sac edema and malformation rates. Bisphenol exposure did not show concentration-dependent malformation increases. Transcriptomic analysis revealed BPF induced more differentially expressed genes (DEGs) than BPS at the tested concentrations (0.02, 0.2, and 2 μg/L): 177, 14, and 24 DEGs were identified in BPF-treated groups, respectively. In contrast, only 4, 2, and 12 DEGs were detected in the corresponding BPS-treated groups. Further analysis of the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichments provided further insights into the potential toxicological mechanisms of BPF. This study provides a comparative toxicity assessment of BPF and BPS, elucidates BPF acute and developmental toxicity pathways, and offers toxicological data for risk assessment and regulation, which also provides a direction for in-depth research on toxicity mechanisms.