Expression Regulation of Hox and paraHox Genes by Perfluorochemicals in Mouse Liver

Abstract

Homeodomain proteins, encoded by Hox genes, play important roles in the development and morphological diversification of organisms. Perfluorochemicals (PFCs), which are persistent environmental pollutants and frequently detected in human blood, interfere with animal development. PFCs produce numerous adverse effects in the liver of research animals, such as hepatomegaly and hepatic dyslipidemia, primarily via activation of peroxisome proliferator‐activated receptors (PPARs) and/or constitutive androstane receptor (CAR). No report shows that PFCs alter the expression of Hox genes. This study was designed to determine the regulation of Hox (including Hox‐a to ‐d subfamily members) and paraHox (including Gsx, Pdx, and Cdx gene family members) gene expression by perfluorochemicals including perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) in mouse liver. A single dose of 0.1 mmole/kg PFOA, PFNA or PFDA was intraperitoneally administered to adult male C57BL/6 wild‐type mice, as well as age‐matched male PPARα‐null and male CAR‐null mice (n=6/genotype/treatment). Four days later, mouse livers were collected and processed. PFNA induced mRNA expression of Hoxa5, b7, c5, c8, and d10 in the livers of wild‐type and CAR‐null mice, but not in PPARα‐null mouse liver, indicating a PPARα‐dependent mechanism. In addition, PFOA, PFNA, and PFDA all induced mRNA expression of Hoxb7, c5, and d10 in wild‐type but not PPARα‐null mouse liver. Furthermore, Wy‐14643, a classical PPARα agonist, induced mRNA expression of Hoxc5 in wild‐type but not PPARα‐null mice. However, Wy‐14643 did not alter mRNA expression of Hoxa5, b7 or d10 in either wild‐type or PPARα‐null mouse liver. TCPOBOP, a classical CAR agonist, did not alter mRNA expression of Hoxa5, b7, c5 or d10 in mouse liver. Moreover, PFNA increased cytoplasmic levels of Hoxc5 protein in mouse liver. In conclusion, perfluorochemicals induced the expression of certain Hox genes such as Hoxc5, mainly via PPARα activation.