TCDD Disrupts Gene Expression in the Developing Mouse Kidney

Dioxins such as the potent 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are persistent environmental contaminants, exposure to which results in a number of toxic effects in several species. In mice, TCDD-induced hydronephrosis of the kidney is among the most sensitive of developmental abnormalities. It is widely accepted that the toxic effects of dioxins such as TCDD are mediated by the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor expressed in virtually all tissues. Though it is known that activation of the AHR during development is likely the first step in TCDD-induced hydronephrosis, genetic events occurring downstream of AHR activation remain to be elucidated. To this end, we investigated the effect of TCDD on gene expression during development of the mouse kidney through use of expression arrays. Our analysis indicates that TCDD alters the expression of genes involved in the developmentally-critical Wnt signaling pathway and genes involved in cell cycle and cell proliferation. Further investigation of the effect of TCDD on Wnt pathway gene expression using an mRNA expression time course and in situ hybridization to characterize localized mRNA changes suggests that TCDD inhibits canonical Wnt signaling in the developing kidney. Consistent with our expression array finding that TCDD downregulates genes involved in cell proliferation, we also report a decrease in cell proliferation that coincides with regions of the kidney where inhibitors of canonical Wnt signaling are induced in response to TCDD. TCDD-induced disruption of Wnt pathway gene expression is not limited to the kidney, and alteration of Wnt gene expression is tissue-specific with varying effects observed in the heart, lung, liver, skin, and brain. Preliminary evidence also indicates that exposure to TCDD during development can alter the expression of microRNAs predicted to target Wnt pathway genes, suggesting a new mechanism for TCDD-induced disruption of gene expression. Taken together, our findings suggest that TCDD may disrupt an important pathway that is critical to the normal development of several organs in numerous species.Ph