Aryl Hydrocarbon Receptor Activation in Genital Tubercle, Palate, and Other Embryonic Tissues in 2,3,7,8-Tetrachlorodibenzo-p-Dioxin-ResponsivelacZMice

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates the toxicity of 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons. Although the normal function and endogenous ligand for this receptor are not known, it is thought to have a role in growth regulation processes. The AhR has been found in both adult and certain developing tissues, and AhR agonists like the environmental contaminant TCDD cause a number of developmental anomalies. We sought to determine whether the AhR is directly activated to a transcriptionally functional form in tissues known to be adversely affected by AhR agonist exposure. To this end, a transgenic mouse model was developed that could be used to indicate the temporal and spatial context of transcriptionally active AhR following agonist exposure in vivo. A synthetic promoter containing two dioxin-responsive elements (DREs) and a minimal TATA box was strongly induced by TCDD in transfected cells when linked to the lacZ or luciferase reporter gene. Transgenic mice harboring the lacZ construct had TCDD-inducible beta-galactosidase activity in tissues following adult and in utero exposure. Embryonic lacZ expression was induced in hard and soft palates, genital tubercle, certain facial regions, shoulder, as well as other tissues by in utero exposure to 30 microg TCDD/kg at Gestational Day 13. The most intense reporter response was observed in the genital tubercle. Histopathology of…