Maternal Exposure to Environmentally Relevant Concentrations of Tris(2,4-di-<i>tert</i>-butylphenyl) Phosphate-Induced Developmental Toxicity in Zebrafish Offspring via Disrupting foxO1/<i>ripor2</i> Signaling

Abnormal development and mortality in early life stages pose significant threats to the growth and continuation of fish populations. Tris(2,4-di-<i>tert</i>-butylphenyl) phosphate (TDtBPP) is a novel organophosphate ester contaminant detected in natural waters. However, the potential effects of maternal exposure to TDtBPP on the early development of offspring embryos in fish remain unknown. Here, 30-day-old zebrafish were exposed to TDtBPP at 0, 50, 500, or 5000 ng/L for 180 days, and the exposed females were spawned with unexposed males. TDtBPP accumulation was detected in offspring embryos, accompanied by an increased malformation rate and mortality. The developmental abnormality of offspring embryos was identified to originate from the gastrula stage. Furthermore, based on transcriptome analysis, the down-regulation of RHO family interacting cell polarization regulator 2 gene (<i>ripor2</i>) was considered as a key toxic event, and this was confirmed in the subsequent knockdown experiment. Moreover, molecular docking studies and forkhead box O1 (foxO1) transcription factor inhibitor (AS1842856) exposure experiments demonstrated that the blockade of foxO1 transcriptional regulation was responsible for the decreased expression of <i>ripor2</i>. The results of this study demonstrated that the occurrence of developmental malformation and mortality in zebrafish offspring embryos following maternal TDtBPP exposure were triggered by the blockade of foxO1 transcriptional regulation and the consequent down-regulation of <i>ripor2</i>.