Long-term exposure to hexavalent chromium inhibits expression of tumor suppressor genes in cultured cells and in mice

Abstract

We have used mouse hepatoma cells in culture to study acute, short-term high-dose effects of hexavalent chromium on gene regulation directed by the polycyclic aromatic hydrocarbon benzo[a]pyrene (BaP). We find that the mixture engages three major signaling pathways: (i) activation of detoxification genes; (ii) induction of signal transduction effectors; and (iii) epigenetic modification of chromatin marks. Preliminary results in mice exposed to mixtures of low doses of Cr(VI) plus BaP indicate that all three pathways are likely to be engaged also in long-term effects resulting from exposure to environmentally relevant doses of the mixture that inhibit the expression of tumor suppressor genes. Given the toxicity and carcinogenicity of these mixtures, we expect that a two-way analytical approach, from cells in culture to biological effects in vivo and vice versa, will provide a better understanding of the molecular mechanisms responsible for the biological effects of mixtures. By focusing both the in vivo and the in vitro work into long-term, low-dose, environmentally relevant exposures, we expect to develop much needed information pertinent to the type of diseases found in human populations exposed to mixtures of environmental toxicants.

Figure 1. mRNA expression levels in Mouse hepatoma Hepa-1 cells grown in the presence of 0.25 μM K₂CrO₄ for 5 or 15 passages and then treated with 1 μM BaP or vehicle for 8 h

The ordinate denotes the ratio of mRNA levels in cells treated with Cr or Cr+BaP relative to the levels in cells propagated for the same number of generations in the absence of Cr.

Figure 2. mRNA expression levels in livers of mice exposed to the indicated doses of Cr(VI) (as Sodium chromate dihydrate) in drinking water for 8 weeks followed by corn oil control or 50 mg/kg BaP for 24 h

(A) mRNA levels for the genes shown in the abscissa. (B) mRNA of tumor suppressor genes after 8 weeks of the indicated Cr(VI) doses. (C) Same Cr(VI) as in (A) but treated with 50 mg/kg BaP for 24 h.