Mechanisms of Developmental Toxicity of Dioxins and Related Compounds

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.

Developmental 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin exposure of either parent enhances the risk of necrotizing enterocolitis in neonatal mice

“…In support of this theory, several studies report an increased incidence in premature birth among women residing near solid waste incinerators (Candela et al, 2013; Lin, Li, & Mao, 2006; Santoro et al, 2016) while other studies linked maternal smoking during pregnancy to an increased risk of NEC in their infants (G. Ding et al, 2017; Downard et al, 2012). Cigarette smoke and incinerator smoke are both known to contain a wide array of toxicants, many of which bind the aryl hydrocarbon receptor (AhR), an orphan nuclear receptor expressed on numerous cells throughout the body (Bock, 2019; Yoshioka & Tohyama, 2019). Inappropriate activation of the AhR during development has been associated with reproductive, immune, neurological, and metabolic disorders in adulthood (Bruner‐Tran et al, 2017; Guo et al, 2018; Lawrence & Vorderstrasse, 2013; Warner et al, 2020).…”

Cellular and molecular mechanisms in the development of a cleft lip and/or cleft palate; insights from zebrafish (Danio rerio)

“…Further evidence that teratogens induce CLP on the zebrafish model include studies performed on anti‐epileptics, steroid drugs, and cold medications (Cohen, Lachappelle, Walker, & Lassiter, 2014; Lai et al, 2017). Toxic compounds, such as dioxins, fungicides, and herbicides, were found to cause long‐term birth defects and zebrafish have been widely used in identifying the mechanism of action of these agents on cranial cartilage morphogenesis, including defects in cartilage of the neurocranium that mimic the cleft palate (Yoshioka & Tohyama, 2019; Zoupa et al, 2020). In the era of epigenetic research, zebrafish will be a forefront model in identifying how teratogenic agents induce CLP development.…”

Correlation between TGF-β2/3 promoter DNA methylation and Smad signaling during palatal fusion induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin

“…6 Some studies reported that females exposed to TCDD during pregnancy can induce CP. 7,8 Histone modification and DNA methylation are the primary epigenetic factors that regulated gene expression, 9 and recent work suggests that in murine model systems, TCDD can influence palatogenesis by modulating DNA methylation and thereby causing CP. 10 The genome contains large GC-rich unmethylated regions known as CpG islands, and the methylation of those CpG islands located with the gene promoter regions can suppress gene expression.…”