Altered gene expression in response to toxicants

Environmental Health Sciences

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Abstract

Drug-induced liver and cardiotoxicity represents an important healthcare issue because it causes significant morbidity and mortality and can be extremely difficult to predict. Elucidating the mechanism(s) of drug-induced liver toxicity, therefore, is essential for the design of safer therapeutic agents. The antipyretic and analgesic drug, acetaminophen (APAP), has been the most widely studied of all drugs with hepatotoxic potential. It continues to be a significant cause of liver injury and lethality in humans. Studies have suggested that APAP-induced liver injury may be related to protein arylation, oxidative stress, disruption of calcium and mitochondrial homeostasis, alteration of transcription pathways, and the induction of cell death pathways. However, the precise molecular events occurring within the liver following APAP insult have still not been deciphered, and only a limited number of pathways involved in controlling toxicity progression have been identified. Using the NIEHS cDNA microarray technique, we conducted an in vivo gene expression profiling approach for studying the mechanism(s) of APAP-induced hepatotoxicity. We have evaluated mRNA from target tissues (liver and kidney) as well as from blood in order to ascertain the usefulness of blood to serve as a biomarker for tissue-specific toxicity. Many of the genes have not previously been reported and/or thoroughly investigated in the context of drug toxicity and, therefore, represent novel factors for further study of the mechanism(s) of APAP-induced liver injury. Similar factors may also play a role in the hepatotoxic potential of other drugs or environmental agents we will study in the future. Currently, we are expanding the toxicogenomic profiles for cardiotoxins and pulmonary toxins. Heart disease is the leading cause of mortality, and the leading health care cost in the United States. NIEHS has developed models for heart disease, and using these models we propose to characterize cardiotoxicity and susceptibilities to cardiotoxicity. The bis(2-chloroethoxymethane) (CEM) model of heart disease is an efficient model to characterize susceptibility to heart toxicity in different rodent strains, because disease occurs after only a few days of dosing. CEM is a synthetic compound used in the production of polysulfide elastomers. It is widely used in sealant applications because of its resistance to solvents and high temperature degradation. It has been identified in industrial waste from metal finishing, plastics, rubber and chemical manufacturers and steam electric power industries. It has been detected in water from inland highways. The most likely route for human exposure is dermal. In rodents, CEM-cardiotoxicity consists of a time-related development of myofiber vacuolation, necrosis, mononuclear-cell infiltration, fibrosis, and atrial thrombosis. Changes are pronounced at day 2, increase in severity at day 3, but in young rats may resolve by study-day 16 (corresponding to 12 exposure days). As dosing is continued in older rodents, the heart damage once again occurs. [unreadable] [unreadable] Ultrastructural analysis of hearts from CEM-treated rats shows that the primary site of damage is the mitochondrion. There are two types of vacuolation in the mitochondrion. One that forms as damaged mitochondria became devoid of cristae and their bounding double membranes become reduced to singleness. Another manifested as distention of the sarcoplasmic reticulum. The heart can apparently launch a protective mechanisms enabling it to cope with the continued CEM exposure while eliminating some damaged myofibers.[unreadable] [unreadable] Other chemicals metabolized to thiodiglycolic acid also produce heart toxicity in rodents and/or humans including the drug Ifosfamid, monochloroacetic acid, chloroacetaldehyde, trichloroethane, trichloroethylene,1-dichloroethylene, cyclophosphamide, vinylidene chloride, and vinyl chloride. Thiodiglycolic acid is a metabolic product of chemicals in humans and/or rodents, and, thus, the CEM cardiotoxicity model may also serve as an investigative tool for other chemical-induced heart damage.