Mechanisms of Developmental Toxicity of Dioxins and Related Compounds

• Published in: International journal of molecular sciences Vol. 20; no. 3; p. 617
• Main Authors: Yoshioka, Wataru, Tohyama, Chiharu
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 31.01.2019; MDPI
• Subjects: Cleft lip/palate; cleft palate; dioxin; Dioxins; E-cadherin; Epidermal growth factor; Epidermal growth factor receptors; Fetuses; Fibroblast growth factor receptor 1; Gene expression; Growth factors; heart; hydronephrosis; Hydrostatic pressure; jaw; Laboratory animals; malformation; Mutation; Parenchyma; Pathogenesis; prostate; Proteins; Review; TCDD; terata; Toxicity; Urinary tract; Urine; Urogenital system; α-Catenin; β-Catenin; jaw; dioxin; hydronephrosis; TCDD; malformation; cleft palate; prostate; terata; heart
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20030617

Dioxins and related compounds induce morphological abnormalities in developing animals in an aryl hydrocarbon receptor (AhR)-dependent manner. Here we review the studies in which 2,3,7,8-tetrachlorodibenzo- -dioxin (TCDD) is used as a prototypical compound to elucidate the pathogenesis of morphological abnormalities. TCDD-induced cleft palate in fetal mice involves a delay in palatogenesis and dissociation of fused palate shelves. TCDD-induced hydronephrosis, once considered to be caused by the anatomical obstruction of the ureter, is now separated into TCDD-induced obstructive and non-obstructive hydronephrosis, which develops during fetal and neonatal periods, respectively. In the latter, a prostaglandin E₂ synthesis pathway and urine concentration system are involved. TCDD-induced abnormal development of prostate involves agenesis of the ventral lobe. A suggested mechanism is that AhR activation in the urogenital sinus mesenchyme by TCDD modulates the wingless-type MMTV integration site family (WNT)/β-catenin signaling cascade to interfere with budding from urogenital sinus epithelium. TCDD exposure to zebrafish embryos induces loss of epicardium progenitor cells and heart malformation. AHR2-dependent downregulation of Sox9b expression in cardiomyocytes is a suggested underlying mechanism. TCDD-induced craniofacial malformation in zebrafish is considered to result from the AHR2-dependent reduction in SRY-box 9b (SOX9b), probably partly via the noncoding RNA , resulting in the underdevelopment of chondrocytes and cartilage.