Non-additive hepatic gene expression elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) co-treatment in C57BL/6 mice
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824 (United States)
- Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298-0032 (United States)
- Wellington Laboratories Inc., Guelph ON, Canada N1G 3M5 (Canada)
- Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824 (United States)
Interactions between environmental contaminants can lead to non-additive effects that may affect the toxicity and risk assessment of a mixture. Comprehensive time course and dose-response studies with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), non-dioxin-like 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) and their mixture were performed in immature, ovariectomized C57BL/6 mice. Mice were gavaged once with 30 {mu}g/kg TCDD, 300 mg/kg PCB153, a mixture of 30 {mu}g/kg TCDD with 300 mg/kg PCB153 (MIX) or sesame oil vehicle for 4,12, 24,72 or 168 h. In the 24 h dose-response study, animals were gavaged with TCDD (0.3,1, 3, 6, 10, 15, 30, 45 {mu}g/kg), PCB153 (3,10, 30, 60, 100, 150, 300, 450 mg/kg), MIX (0.3 + 3, 1 + 10, 3 + 30, 6 + 60, 10 + 100, 15 + 150, 30 + 300, 45 {mu}g/kg TCDD + 450 mg/kg PCB153, respectively) or vehicle. All three treatments significantly increased relative liver weights (RLW), with MIX eliciting significantly greater increases compared to TCDD and PCB153 alone. Histologically, MIX induced hepatocellular hypertrophy, vacuolization, inflammation, hyperplasia and necrosis, a combination of TCDD and PCB153 responses. Complementary lipid analyses identified significant increases in hepatic triglycerides in MIX and TCDD samples, while PCB153 had no effect on lipids. Hepatic PCB153 levels were also significantly increased with TCDD co-treatment. Microarray analysis identified 167 TCDD, 185 PCB153 and 388 MIX unique differentially expressed genes. Statistical modeling of quantitative real-time PCR analysis of Pla2g12a, Serpinb6a, Nqo1, Srxn1, and Dysf verified non-additive expression following MIX treatment compared to TCDD and PCB153 alone. In summary, TCDD and PCB153 co-treatment elicited specific non-additive gene expression effects that are consistent with RLW increases, histopathology, and hepatic lipid accumulation. - Graphical abstract: Display Omitted Highlights: > MIX (TCDD:PCB153 at 1:10,000 ratio) exposure leads to non-additive gene expression. > MIX-induced liver weights are significantly greater relative to single chemicals. > MIX exposure leads to potentiation of hepatic PCB153 levels compared to TCDD. > MIX synergistically induces expression of Nqo1, Dysf, Pla2g12a, Serpinb6a, and Srxn1. > Non-additive gene expression supports putative non-additive phenotypic responses.
- OSTI ID:
- 21587860
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 256, Issue 2; Other Information: DOI: 10.1016/j.taap.2011.08.002; PII: S0041-008X(11)00293-6; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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ADDITIVES
DIOXIN
DOSES
GENES
HYPERTROPHY
INFLAMMATION
INTERACTIONS
LIVER
MICE
MIXTURES
NECROSIS
POLYMERASE CHAIN REACTION
RISK ASSESSMENT
SESAME OIL
SIMULATION
TRIGLYCERIDES
ANIMALS
BODY
DIGESTIVE SYSTEM
DISPERSIONS
ESTERS
GENE AMPLIFICATION
GLANDS
HETEROCYCLIC COMPOUNDS
LIPIDS
MAMMALS
OILS
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
OTHER ORGANIC COMPOUNDS
PATHOLOGICAL CHANGES
RODENTS
SYMPTOMS
VEGETABLE OILS
VERTEBRATES