Perfluoroheptanoic acid affects amphibian embryogenesis by inducing the phosphorylation of ERK and JNK.

Perfluoroalkyl compounds (PFCs) are globally distributed synthetic compounds that are known to adversely affect human health. Developmental toxicity assessment of PFCs is important to facilitate the evaluation of their environmental impact. In the present study, we assessed the developmental toxicity and teratogenicity of PFCs with different numbers of carbon atoms on Xenopus embryogenesis. An initial frog embryo teratogenicity assay-Xenopus (FETAX) assay was performed that identified perfluorohexanoic (PFHxA) and perfluoroheptanoic (PFHpA) acids as potential teratogens and developmental toxicants. The mechanism underlying this teratogenicity was also investigated by measuring the expression of tissue-specific biomarkers such as phosphotyrosine­binding protein, xPTB (liver); NKX2.5 (heart); and Cyl18 (intestine). Whole­mount in situ hybridization, reverse transcriptase­polymerase chain reaction (RT-PCR), and histologic analyses detected severe defects in the liver and heart following exposure to PFHxA or PFHpA. In addition, immunoblotting revealed that PFHpA significantly increased the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), while PFHxA slightly increased these, as compared with the control. These results suggest that PFHxA and PFHpA are developmental toxicants and teratogens, with PFHpA producing more severe effects on liver and heart development through the induction of ERK and JNK phosphorylation.

Pick1 modulates ephrinB1-induced junctional disassembly through an association with ephrinB1.

Members of the Eph family have been implicated in the formation of cell-cell boundaries, cell movement, and positioning during development in the context of cancer progression. De-regulation of this signaling system is linked to the promotion of more aggressive and metastatic tumor phenotypes in a large variety of human cancers, including breast, lung, and prostate cancer, melanoma, and leukemia. Thus, it is interesting to consider the case of cancer progression where de-regulation of the Eph/ephrin signaling system results in invasion and metastasis. Here, we present evidence that Pick1, one of the essential components of the adherens junction, recovers ephrinB1-induced cell-cell de-adhesion. Loss of Pick1 leads to dissociation of epithelial cells via disruption of the adherens junction, a phenotype similar to ephrinB1 overexpression. In addition, overexpressed ephrinB1-induced disruption of the adherens junction is rescued via binding to Pick1. These data indicate that Pick1 is involved in regulating the cell-cell junction in epithelial cells, and this may influence therapeutic strategy decisions with regards to cell adhesion molecules in metastatic disease.

In vivo evaluation and comparison of developmental toxicity and teratogenicity of perfluoroalkyl compounds using Xenopus embryos.

Perfluoroalkyl compounds (PFCs) are environmental toxicants that persistently accumulate in human blood. Their widespread detection and accumulation in the environment raise concerns about whether these chemicals might be developmental toxicants and teratogens in ecosystem. We evaluated and compared the toxicity of PFCs of containing various numbers of carbon atoms (C8-11 carbons) on vertebrate embryogenesis. We assessed the developmental toxicity and teratogenicity of various PFCs. The toxic effects on Xenopus embryos were evaluated using different methods. We measured teratogenic indices (TIs), and investigated the mechanisms underlying developmental toxicity and teratogenicity by measuring the expression of organ-specific biomarkers such as xPTB (liver), Nkx2.5 (heart), and Cyl18 (intestine). All PFCs that we tested were found to be developmental toxicants and teratogens. Their toxic effects were strengthened with increasing length of the fluorinated carbon chain. Furthermore, we produced evidence showing that perfluorodecanoic acid (PFDA) and perfluoroundecanoic acid (PFuDA) are more potent developmental toxicants and teratogens in an animal model compared to the other PFCs we evaluated [perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA)]. In particular, severe defects resulting from PFDA and PFuDA exposure were observed in the liver and heart, respectively, using whole mount in situ hybridization, real-time PCR, pathologic analysis of the heart, and dissection of the liver. Our studies suggest that most PFCs are developmental toxicants and teratogens, however, compounds that have higher numbers of carbons (i.e., PFDA and PFuDA) exert more potent effects.