ARYL-HYDROCARBON RECEPTOR ACTIVATION IN GENITAL TUBERCLE, PALATE, ANDOTHER EMBRYONIC-TISSUES IN 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN RESPONSIVE LACZ MICE

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcriptio n factor that mediates the toxicity of 2,3,7,8-tetra-chlorodibenzo-p-d ioxin (TCDD) and related halogenated aromatic hydrocarbons. Although t he normal function and endogenous ligand for this receptor are not kno wn, it is thought to have a role in growth regulation processes. The A hR has been found in both adult and certain developing tissues, and Ah R agonists like the environmental contaminant TCDD cause a number of d evelopmental anomalies. We sought to determine whether the AhR is dire ctly activated to a transcriptionally functional form in tissues known to be adversely affected by AhR agonist exposure. To this end, a tran sgenic mouse model was developed that could be used to indicate the te mporal and spatial context of transcriptionally active AhR following a gonist exposure in vivo. A synthetic promoter containing two dioxin-re sponsive elements (DREs) and a minimal TATA box was strongly induced b y TCDD in transfected cells when linked to the lacZ or luciferase repo rter gene. Transgenic mice harboring the lacZ construct had TCDD-induc ible beta-galactosidase activity in tissues following adult and in ute ro exposure. Embryonic lacZ expression was induced in hard and soft pa lates, genital tubercle, certain facial regions, shoulder, as well as other tissues by in utero exposure to 30 mu g TCDD/kg at Gestational D ay 13. The most intense reporter response was observed in the genital tubercle. Histopathology of the palate and tubercle demonstrated the r eporter gene activity to be both cell- and region-specific. This is th e first publication to correlate reported TCDD-elicited toxicity (e.g. , cleft palate in mice) with TCDD-dependent AhR activation. These data indicate the ability of TCDD to initiate a signal transduction proces s leading to a transcriptionally active AhR in these tissues, thereby identifying potential targets of dioxin-induced toxicity during develo pment. Weak activation of the reporter gene was consistently observed only in the genital tubercle in the absence of exogenous inducer. This indicates minimal or no endogenous AhR activators at the developmenta l stage examined. This mouse model will prove useful for both the exam ination of the endogenous role of the AhR in proliferation or differen tiation and of the developmental targets of dioxin-like compounds. (C) 1998 Academic Press.