BENZO(A)PYRENE-INDUCED ALTERATIONS IN GROWTH-RELATED GENE-EXPRESSION AND SIGNALING IN PRECISION-CUT ADULT-RAT LIVER AND KIDNEY SLICES

Benzo(a)pyrene (BaP) and related aromatic hydrocarbons are suspected c arcinogens; however, the molecular basis underlying tumorigenesis rema ins unclear. To identify acute molecular targets of BaP within the liv er and kidney, precision-cut slices harvested from naive, adult female Sprague-Dawley rats were challenged with BaP (0.3-30 mu M) for 0.5 to 24 h. BaP did not elicit cytotoxicity, as assessed by intracellular K + and ATP content and histological evaluation over the 24-h period. To determine if molecular signaling pathways were maintained in precisio n-cut slices, induction of the aryl hydrocarbon receptor (AhR) pathway was assessed following BaP challenge. Induction of cytochrome P450IA1 (P450IA1) mRNA and protein expression was observed in both liver and kidney slices, c-fos and c-Ha-ras gene expression was enhanced in live r, but not kidney, slices by BaP. c-jun mRNA levels were decreased in liver and kidney slices, although the effect was earlier (0.5 h) in li ver slices compared to kidney slices. BaP increased the DNA binding of nuclear proteins to the AP-1 consensus recognition element in liver, but decreased DNA binding in kidney slices. In contrast, DNA binding o f NF-kappa B was not affected by BaP in either liver or kidney slices. These results suggest that acute BaP challenge is associated with alt ered expression of several growth-related genes and AP-1 signaling and establish precision-cut slices as a useful in vitro system to investi gate the molecular basis of BaP-induced tumorigenesis, including organ -specific differences. (C) 1998 Academic Press.