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

Developmental toxicity of 4-octylphenol (OP), an estrogenic endocrine disruptor was verified using frog embryo teratogenesis assay Xenopus. LC, EC and EC 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.