aldrin and Chemical-and-Drug-Induced-Liver-Injury

Topics: Adipose Tissue; Aldrin; Animals; Central Nervous System Diseases; Chemical and Drug Induced Liver Injury; Chlordan; DDT; Dieldrin; Dogs; Drug Synergism; Endrin; Environmental Pollution; Female; Heptachlor; Hexachlorocyclohexane; Humans; Hydrocarbons, Halogenated; Malaria; Male; Methoxychlor; Mice; Mice, Inbred Strains; Pesticides; Rats; Rats, Inbred Strains; Reproduction; Toxaphene; Typhus, Epidemic Louse-Borne

Predicting the potential human health risk posed by chemical stressors has long been a major challenge for toxicologists, and the use of microarrays to measure responses to toxicologically relevant genes, and to identify selective, sensitive biomarkers of toxicity is a major application of predictive and discovery toxicology. To investigate this possibility, we investigated whether carcinogens (at doses known to induce liver tumors in chronic exposure bioassays) deregulate characteristic sets of genes in mice. Male C3H/He mice were dosed with two hepatocarcinogens (vinyl chloride (VC, 50-25 mg/kg), aldrin (AD, 0.8-0.4 mg/kg)), or two non-hepatocarcinogens (copper sulfate (CS, 150-60 mg/kg), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T, 150-60 mg/kg)). Large-scale molecular changes elicited by these four hepatotoxicants in liver tissues were analyzed using DNA microarray. Three days after administration, no significant phenotypic changes were induced by these four different hepatotoxicants in terms of histological examination or blood biochemical assay. However, unsupervised hierarchical analysis of gene expressional changes induced by hepatotoxicants resulted in two major gene subclusters on dendrogram, i.e., a carcinogen (VN, AD) and non-carcinogen group (CS, 2,4,5-T), and also revealed that distinct molecular signatures exist. These signatures were founded on well-defined functional gene categories and may differentiate genotoxic and non-genotoxic carcinogens. Furthermore, Venn diagram analysis allowed us to identify carcinogen and non-carcinogen-associated molecular signatures. Using statistical methods, we analyzed outlier genes for four different classes (genotoxic-, non-genotoxic-carcinogen, genotoxic-, non-genotoxic non-carcinogen) in terms of their potential to predict different modes-of-action. In conclusion, the identification of large-scale molecular changes in different hepatocarcinogen exposure models revealed that different types of hepatotoxicants are associated with different epigenetic changes and molecular pathways and that these large-scale characteristic molecular changes could be used as predictable toxicity markers.

Topics: 2,4,5-Trichlorophenoxyacetic Acid; Aldrin; Animals; Carcinogens; Chemical and Drug Induced Liver Injury; Copper Sulfate; Data Interpretation, Statistical; Gene Expression Profiling; In Situ Hybridization; Insecticides; Liver Neoplasms; Male; Mice; Mice, Inbred C3H; Microarray Analysis; Organ Size; RNA; Vinyl Chloride

The development of hyperplastic and neoplastic lesions of parenchymal cells of the liver adjacent to central veins was observed in C3H mice ingesting the chlorinated hydrocarbons, dieldrin or aldrin, in the diet. Lesions could be followed from pericentral hyperplasia to areas of hyperplasia, nodules of hyperplasia, small hepatocellular carcinomas, and large well-developed carcinomas, occasionally with metastases. Sometimes pericentral hyperplasia was diffuse throughout most or all of one lobe of the liver. These hyperplastic cells collided to become one large nodule and also one large carcinoma. The carcinomas were well-differentiated or moderately well-differentiated and grew on transplantation to isologous hosts. Histologically, the hyperplastic cells adjacent to central veins were increased in size, frequently with double nuclei. Carcinoma cells varied in size and shape and were huge with large nuclei, prominent nucleoli, and eosinophilic cytoplasm. Similar hepatocellular carcinomas were seen previously with carbon tetrachloride, another organochlorine chemical.

Topics: Aldrin; Animals; Carcinoma, Hepatocellular; Chemical and Drug Induced Liver Injury; Dieldrin; Female; Hepatic Veins; Hyperplasia; Liver Diseases; Liver Neoplasms; Male; Mice; Mice, Inbred C3H

Topics: Aldrin; Chemical and Drug Induced Liver Injury; Dieldrin; Dogs; Hepatitis; Hepatitis A; Insecticides; Kidney Diseases; Pathology; Poisoning; Rats; Research; Statistics as Topic; Toxicology