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Abstract
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-p-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 slincR, resulting in the underdevelopment of chondrocytes and cartilage.
Highlights
Dioxins and related compounds are a group of structurally related chemicals composed of two coplanar benzene rings
The present review focuses on the recent progress reported on the mechanisms of developmental toxicity, in terms of teratogenicity, malformation, and morphological changes in laboratory animals exposed to TCDD
While TCDD-induced upregulation of the COX-2/mPGES-1/prostaglandin E2 (PGE2) pathway depends on cPLA2α, TCDD-induced increase in the expression of other genes, such as those coding for cytochrome P450 1A1 (CYP1A1), aryl hydrocarbon receptor (AhR) repressor (AhRR), and insulin-like growth factor binding protein 1 (IGFBP-1), does not depend on cPLA2α in the pup kidneys [48]
Summary
Dioxins and related compounds are a group of structurally related chemicals composed of two coplanar benzene rings These compounds induce a similar spectrum of toxicity phenotypes with a wide degree of potency. Aryl hydrocarbon receptor (AhR, or dioxin receptor), a ligand-activated transcription factor (see reviews [3,4] for molecular biology of AhR and history), is indispensable for the manifestation of TCDD teratogenicity. This pivotal role for AhR was demonstrated using AhR-null mice [5,6] and AHR2-null zebrafish [7]. The present review focuses on the recent progress reported on the mechanisms of developmental toxicity, in terms of teratogenicity, malformation, and morphological changes in laboratory animals exposed to TCDD
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