Applications of gene arrays in environmental toxicology: fingerprints of gene regulation associated with cadmium chloride, benzo(a)pyrene, and trichloroethylene.

Abstract

Toxicity testing of unknown chemicals currently uses a number of short-term bioassays. These tests are costly and time consuming, require large numbers of animals, and generally focus on a single end point. The recent development of DNA arrays provides a potential mechanism for increasing the efficiency of standard toxicity testing through genome-wide assessments of gene regulation. In this study, we used DNA arrays containing 148 genes for xenobiotic metabolizing enzymes, DNA repair enzymes, heat shock proteins, cytokines, and housekeeping genes to examine gene expression patterns in the liver in response to cadmium chloride, benzo(a)pyrene (BaP), and trichloroethylene (TCE). Dose-response studies were carried out in mice for each chemical; each produced a unique pattern of gene induction. As expected, CdCl2 markedly up-regulated metallothionine I and II (5- to 10,000-fold at the highest doses) and several of the heat shock/stress response proteins and early response genes. In contrast, administration of BaP up-regulated only Cyp1a1 and Cyp1a2 genes and produced no significant increases in any of the stress response genes or any of the DNA repair genes present on the array. Likewise, TCE-induced gene induction was highly selective; only Hsp 25 and 86 and Cyp2a were up-regulated at the highest dose tested. Microarray analysis with a highly focused set of genes is capable of discriminating between different classes of toxicants and has potential for differentiating highly noxious versus more subtle toxic agents. These data suggest that use of microarrays to evaluate the potential hazards of unknown chemicals or chemical mixtures must include multiple doses and time points to provide effective assessments of potential toxicity of these substances.

In Vivo Pharmacokinetics and Regulation of Gene Expression Profiles by Isothiocyanate Sulforaphane in the Rat

“…In vertebrate, MT gene promoters contain metal (Buhler and Kagi, 1974) and glucocorticoid response elements ( Kelly et al, 1997), and also ARE (Dalton et al, 1994). Previous gene arrays studies with cadmium chloride but not benzo[a]pyrene nor ticholoroethylene induced high expression of MT-1 and MT-II as well as several heat shock/stress response genes and early response genes (Bartosiewicz et al, 2000(Bartosiewicz et al, , 2001. However, for SUL, the latter genes were not found to be modulated.…”

Comparison of gene expression profiles in HepG2 cells exposed to arsenic, cadmium, nickel, and three model carcinogens for investigating the mechanisms of metal carcinogenesis

“…As mentioned previously, it has been reported that carcinogenic metals including Cd and Ni exhibited different patterns of gene expressions and had different carcinogenic mechanisms [Bartosiewicz et al, 2001;Andrew et al, 2003]. Hence, the gene alterations that were considered to be associated with carcinogenesis have not been shown directly.…”

“…Until now, some DNA microarray analyses have been performed with animal tissues and cultured cells exposed to metals, and the specific gene expression patterns have been compared with the ones obtained after exposure to the known carcinogenic chemicals. Bartosiewicz et al [2001] have shown that cadmium chroride, Benzo[a]pyrene, and trichloroethylene exhibited different patterns of gene expression in the livers of exposed mice. Likewise, Andrew et al [2003] reported that cadmium chloride, sodium dichromate, and nickel subsulfide altered only a few genes that overlapped with DNA-cross-linker mitomycin C in human lung cells.…”

Antibodies against heat shock proteins in environmental stresses and diseases: friend or foe?

“…Although many environmental xenobiotics induce the synthesis of Hsps, some like benzo(a)pyrene, a ubiquitous environmental pollutant and a potent procarcinogen and mutagen that can elicit tumors, inhibits their synthesis. This points to the special toxicity of these xenobiotics and at potential mechanisms of diseases caused by this chemical (Bartosiewicz et al 2001;Gao et al 2004).…”