Characterization of 2,3,7,8-tetrachlorodibenzofuran-dependent suppression and AH receptor pathway gene expression in the developing mouse mammary gland

The AH receptor (AHR) is a ligand-activated transcription factor and member of a growing family of homologous proteins implicated in development, In this study we have characterized the actions of 2,3,7,8-tetrachlorodibenzofuran (TCDF), a well-studied AHR ligand, and the expression of AHR and selected AHR signal transduction pathway genes in the developing mouse mammary gland. High levels of AHR protein were observed in the mammary glands of C57Bl/6J (AHR +/+) mice during estrous-stimulated growth and branching of terminal end buds (TEBs). Comparative analysis of mammary gland development in AHR -/- and +/+ littermates revealed a 50% reduction in TEBs and an increase in blunt-ended terminal ducts in the AHR null animals, Treatment of mammary glands, removed from estrogen/progesterone-primed C57Bl/6J mice and maintained in organ culture, with TCDF suppressed lobule development (greater than twofold decreases in lobule number and size), with a concomitant suppression of DNA synthesis, as judged by a 35 to 45% decrease in [H-3]thymidine incorporation in the TEBs. Immunohistochemical staining patterns for AHR, aryl hydrocarbon nuclear translocator (ARNT; the heterodimerization partner of AHR), and two AHR-regulated genes, Cyp1A1 and Cyp1B1, were similar and not altered by treatment of mammary glands in organ culture with TCDF, The observed differences in the development of mammary glands from AHR +/+ and -/- mice, associated expression of the AHR protein with hormone-dependent lobule development, and suppressive actions of TCDF support the position that, in C57Bl/6J mice, development of the mammary gland is at least in part AHR dependent. Development occurs in the absence of exogenous AHR ligand, suggesting that the unoccupied receptor may function to support the proliferative stages required for full lobule development, (C) 1998 Academic Press.