You are here:
CHANGES IN GENE EXPRESSION PROFILE FOLLOWING SHORT-TERM EXPOSURE TO AN ENVIRONMENTALLY RELEVANT MIXTURE OF PHAHS
Citation:
Khan, M A., K M. Crofton, B. Sen, D C. Wolf, AND S D. Hester. CHANGES IN GENE EXPRESSION PROFILE FOLLOWING SHORT-TERM EXPOSURE TO AN ENVIRONMENTALLY RELEVANT MIXTURE OF PHAHS. Presented at Society of Toxicologic Pathology Annual Meeting, Savannah, Ga, 06/15-19/03.
Description:
Changes in gene expression profile following short-term exposure to an environmentally relevant mixture of PHAHs
Polyhalogenated aromatic hydrocarbons (PHAH) including, polychlorinated biphenyls (PCBs), polychlorinated dibenzodioxins (PCDDS) and polychlorinated dibenzofurans (PCDFs) are highly lipophilic and persistent global contaminants. These chemicals cause disruption of the endocrine system, including alteration in pituitary-thyroid homeostasis. Most of the information documenting harmful effects of PHAH and related compounds in human and wildlife comes from studies focused on exposure to single chemicals. However, humans and wildlife are usually exposed to mixtures of chemicals. Limited information is available on how mixtures of chemicals, present in the environment, affect the pituitary-thyroid axis and produce toxicity. Two or more compounds may show additive, antagonistic, or synergistic interactions involving single or multiple mechanisms. A short-term study was conducted to examine the effects of an environmental mixture of PHAHs on the thyroid hormone homeostasis. Twenty-eight day old female Long-Evans rats were administered orally with various doses of a PHAH mixture, which contained environmentally relevant concentration of 18 different dibenzodioxins, dibenzofurans, and coplanar and non-coplanar PCB congeners. The study was terminated after 4 days of exposure and several biochemical and molecular endpoints were examined in order to explore possible mechanism(s) by which the PHAH mixture may affect the thyroid homeostasis. Gene expression profiles were examined in liver samples from a dose that decreased T4 (30%) and increased hepatic P450 CYP 1A1 activity (~ 35 fold), CYP 2B activity (~ 4 fold) and UGT- T4 glucuronidation (~ 4 fold). Liver samples were analyzed using AgilentTM cDNA microarrays containing 14000 genes and ESTs. Total RNA was extracted from liver samples and assayed by using a two dye labeling protocol was used to incorporate fluorescence tags into the cDNA. Gene expression as a function of fluorescent signal intensity ratio was generated using an Axon scanner. Analysis was performed using GeneSpringTM software. Gene expression profiles showed a 2-fold or greater upregulation in a number of genes including the sodium/iodide symporter, cytochrome P450s 1A1, 2B1, 2B12, type II deiodinase, and glutathione S-transferase enzymes. These genes are known to regulate thyroid hormone homeostasis. Mixtures of these endocrine-active compounds appear to act through multiple mechanisms.
(This abstract does not reflect the policies or opinions of the USEPA).