Environ Pollut 2021 Apr 01;274:116560. doi: 10.1016/j.envpol.2021.116560.

4-Octylphenol induces developmental abnormalities and interferes the differentiation of neural crest cells in Xenopus laevis embryos.

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Developmental toxicity of 4-octylphenol (OP), an estrogenic endocrine disruptor was verified using frog embryo teratogenesis assay Xenopus. LC50, EC50Malformtion and EC50Melanocyte-dysgenesis of OP were 9.9, 10.5, and 2.4 μM, respectively. In tadpoles, despite the low teratogenic index, 2 μM OP significantly inhibited head cartilage development and tail malformation. The total length of tadpole was significantly increased at 5 μM and decreased at 10 μM OP. In OP-treated tadpoles, head cartilages were frequently missed and col2a1 mRNA was decreased at 2 μM, indicating a chondrogenic defect in developing head. In the head skin of 1 μM OP-treated tadpoles, number of melanocytes and melanogenic pathway genes expression were significantly decreased. In the head-neck junction of stage 22 embryos, OP increased foxd3 and sox10 mRNA and SOX10(+) neural crest cells (NCCs) in somite mesoderm and endoderm, indicating the inhibition of chondrogenic differentiation, ectopic migration to endoderm, and undifferentiation of NCCs by OP. Together, OP-induced head dysplasia and inhibition of melanogenesis may be attributable to deregulation of neural crest cells in embryos. In tadpoles, OP at 1 μM significantly increased lipid hydroperoxide and induced spliced xbp1 mRNA, an IRE1 pathway endoplasmic reticulum stress (ERS) marker and p-eIF2α protein, a PERK pathway ERS marker. OP at 10 μM induced CHOP mRNA, pro-apoptotic genes expression, DNA fragmentation, and cleaved caspase-3, suggesting that OP differentially induced ERS and apoptosis according to the concentration in embryos. In 5-10 μM OP-treated stage 22 embryos and stage 45 tadpole heads, Ki67 was significantly increased, suggesting the apoptosis-induced proliferation of embryonic cells in the OP-treated embryos. Together, OP should be managed as a developmental toxicant altering the behavior of NCCs in vertebrates.

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Genes referenced: col2a1 dct ddit3 ern1 foxd3 kit mitf sox10 sox9 tyr XBP1
GO keywords: neural crest cell migration [+]


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