Reprod Toxicol 2025 Sep 04;:109046. doi: 10.1016/j.reprotox.2025.109046.

Caffeic acid phenethyl ester disrupts germ layer specification in Xenopus embryos.

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Xenopus embryo serves as an ideal model for teratogenesis assays to observe the effects of any compounds on the cellular processes crucial for early development and adult tissue homeostasis. In our screening of a chemical library with frog embryo, caffeic acid phenethyl ester (CAPE) was found to upregulate the FGF/MAPK pathway, disrupting germ layer formation in early development. Exposure to CAPE interfered with the formation of anterior-posterior body axis and of ectodermal derivatives such as eyes, dorsal fin and pigment cells. These inhibitory effects were achieved by promoting paraxial mesodermal specification and neural differentiation concomitant with a repression of epidermal and neural crest cell fates. This compound also induced the caudalization of anterior neural fate, thereby recapitulating the activity of the FGF/MAPK signals in the anterior-posterior patterning of neural tissue. Consistently, phosphorylation of extracellular signal-regulated kinase (ERK) was elevated in CAPE-treated cells, which was mediated by the FGFR1 and FGFR4 pathway. Together, these results suggest that CAPE functions as an activator of the FGF/MAPK signaling pathway, generating severe teratogenic effects on germ layer specification in vertebrate early development.

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Species referenced: Xenopus laevis
Genes referenced: bmp4 chd1 egr2 en2 fgf8 fgfr1 fgfr4 hoxb9 krt12.4 myod1 nog otx2 snai2 sox2 tbxt

Phenotypes: Xla wt + CAPE [1uM] (NF1-37/38) (Fig. 1A) [+]