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

Abstract

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 mu M, respectively. In tadpoles, despite the low teratogenic index, 2 mu M OP significantly inhibited head cartilage development and tail malformation. The total length of tadpole was significantly increased at 5 mu M and decreased at 10 mu M OP. In OP-treated tadpoles, head cartilages were frequently missed and col2a1 mRNA was decreased at 2 mu M, indicating a chondrogenic defect in developing head. In the head skin of 1 mu M 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 mu M significantly increased lipid hydroperoxide and induced spliced xbp1 mRNA, an IRE1 pathway endoplasmic reticulum stress (ERS) marker and p-eIF2 alpha protein, a PERK pathway ERS marker. OP at 10 mu M induced CHOP mRNA, proapoptotic 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 mu M 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.