Clarification of Molecular Targets of Dioxin Toxicity

Abstract

Health effects associated with exposure to various chemicals have been extensively studied. However, in most cases, the molecular basis of the underlying mechanism has been elusive. Dioxin toxicity, which has raised a significant concern in society, was discovered to be mediated by a high-affinity receptor, aryl hydrocarbon receptor (AhR), more than three decades ago. This receptor has been established to be essential for the manifestation of various toxicities, such as carcinogenicity, reproductive toxicity, developmental neurotoxicity, and immunotoxicity. However, it has not been clarified how AhR mediates such a wide variety of dioxin toxicities through AhR-dependent mechanisms. In recent years, several lines of experimental evidence have provided clues for opening the "black box" that contains the molecular mechanisms of dioxin action. In this review, I focus on dioxin toxicity phenotypes for which downstream molecular targets have begun to be elucidated. The toxicity phenotypes include impaired prostate development and hydronephrosis in mouse fetuses and pups, respectively, as well as abnormality in organogenesis in zebrafish embryos and adults. As the molecular basis of the tissue-specific endpoints of dioxin toxicity, dysregulation of AhR downstream pathways, such as signaling of prostanoid synthesis, Wnt/β-catenin signaling, and signaling by receptors for inflammatory cytokines, are discussed. The new findings on the molecular targets of dioxin may provide clues to the prospective discovery of new molecular events associated with the growth and development of organs and pathogenesis of diseases.