Dataset Information

Interstrain differences in the liver effects of trichloroethylene in a multistrain panel of inbred mice.

ABSTRACT: Trichloroethylene (TCE) is a widely used industrial chemical and a common environmental contaminant. It is a well-known carcinogen in rodents and a probable carcinogen in humans. Studies utilizing panels of mouse inbred strains afford a unique opportunity to understand both metabolic and genetic basis for differences in responses to TCE. We tested the hypothesis that strain- and liver-specific toxic effects of TCE are genetically controlled and that the mechanisms of toxicity and susceptibility can be uncovered by exploring responses to TCE using a diverse panel of inbred mouse strains. TCE (2100 mg/kg) or corn oil vehicle was administered by gavage to 6- to 8-week-old male mice of 15 mouse strains. Serum and liver were collected at 2, 8, and 24 h postdosing and were analyzed for TCE metabolites, hepatocellular injury, and gene expression of liver. TCE metabolism, as evident from the levels of individual oxidative and conjugative metabolites, varied considerably between strains. TCE treatment-specific effect on the liver transcriptome was strongly dependent on genetic background. Peroxisome proliferator-activated receptor-mediated molecular networks, consisting of the metabolism genes known to be induced by TCE, represent some of the most pronounced molecular effects of TCE treatment in mouse liver that are dependent on genetic background. Conversely, cell death, liver necrosis, and immune-mediated response pathways, which are altered by TCE treatment in liver, are largely genetic background independent. These studies provide better understanding of the mechanisms of TCE-induced toxicity anchored on metabolism and genotype-phenotype correlations that may define susceptibility or resistance.

SUBMITTER: Bradford BU

PROVIDER: S-EPMC3044200 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Interstrain differences in the liver effects of trichloroethylene in a multistrain panel of inbred mice.

Bradford Blair U BU Lock Eric F EF Kosyk Oksana O Kim Sungkyoon S Uehara Takeki T Harbourt David D DeSimone Michelle M Threadgill David W DW Tryndyak Volodymyr V Pogribny Igor P IP Bleyle Lisa L Koop Dennis R DR Rusyn Ivan I

Toxicological sciences : an official journal of the Society of Toxicology 20101206 1

Trichloroethylene (TCE) is a widely used industrial chemical and a common environmental contaminant. It is a well-known carcinogen in rodents and a probable carcinogen in humans. Studies utilizing panels of mouse inbred strains afford a unique opportunity to understand both metabolic and genetic basis for differences in responses to TCE. We tested the hypothesis that strain- and liver-specific toxic effects of TCE are genetically controlled and that the mechanisms of toxicity and susceptibility ...[more]

PMID: 21135412

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Project description:Depression is an extremely heterogeneous disorder. Diverse molecular mechanisms have been suggested to underlie its etiology. To understand the molecular mechanisms responsible for this complex disorder, researchers have been using animal models extensively, namely mice from various genetic backgrounds and harboring distinct genetic modifications. The use of numerous mouse models has contributed to enrich our knowledge on depression. However, accumulating data also revealed that the intrinsic characteristics of each mouse strain might influence the experimental outcomes, which may justify some conflicting evidence reported in the literature. To further understand the impact of the genetic background, we performed a multimodal comparative study encompassing the most relevant parameters commonly addressed in depression, in three of the most widely used mouse strains: Balb/c, C57BL/6, and CD-1. Moreover, female mice were selected for this study taken into account the higher prevalence of depression in women and the fewer animal studies using this gender. Our results show that Balb/c mice have a more pronounced anxious-like behavior than CD-1 and C57BL/6 mice, whereas C57BL/6 animals present the strongest depressive-like trait. Furthermore, C57BL/6 mice display the highest rate of proliferating cells and brain-derived neurotrophic factor (Bdnf) expression levels in the hippocampus, while hippocampal dentate granular neurons of Balb/c mice show smaller dendritic lengths and fewer ramifications. Of notice, the expression levels of inducible nitric oxide synthase (iNos) predict 39.5% of the depressive-like behavior index, which suggests a key role of hippocampal iNOS in depression. Overall, this study reveals important interstrain differences in several behavioral dimensions and molecular and cellular parameters that should be considered when preparing and analyzing experiments addressing depression using mouse models. It further contributes to the literature by revealing the predictive value of hippocampal iNos expression levels in depressive-like behavior, irrespectively of the mouse strain.

Project description:Trichloroethylene (TCE) is a common environmental toxicant linked with hypersensitivity and autoimmune responses in humans and animal models. While autoimmune diseases are more common in females, mechanisms behind this disparity are not clear. Recent evidence suggests that autoimmunity may be increasing in males, and occupational studies have shown that TCE-mediated hypersensitivity responses occur just as often in males. Previous experimental studies in autoimmune-prone MRL+/+ mice have focused on responses in females. However, it is important to include both males and females in order to better understand sex-disparity in autoimmune disease. In addition, because of an alarming increase in autoimmunity in adolescents, developmental and/or early life exposures to immune-enhancing environmental pollutants should also be considered. Using MRL+/+ mice, we hypothesized that TCE would alter markers related to autoimmunity to a greater degree in female mice relative to male mice, and that TCE would enhance these effects. Mice were continuously exposed to either TCE or vehicle beginning at gestation, continuing during lactation, and directly in the drinking water. Both male and female offspring were evaluated at 7 weeks of age. Sex-specific effects were evident. Female mice were more likely than males to show enhanced CD4+ T cell cytokine responses (e.g., IL-4 and IFN-γ). Although none of the animals developed pathological or serological signs of autoimmune hepatitis-like disease, TCE-exposed female mice were more likely than males in either group to express higher levels of biomarkers in the liver related to regeneration/repair and proliferation. Levels of bacterial populations in the intestinal ileum were also altered by TCE exposure and were more prominent in females as compared to males. Thus, our expectations were correct in that young adult female mice developmentally exposed to TCE were more likely to exhibit alterations in immunological and gut/liver endpoints compared to male mice.

Dataset Information

Interstrain differences in the liver effects of trichloroethylene in a multistrain panel of inbred mice.

Publications

Interstrain differences in the liver effects of trichloroethylene in a multistrain panel of inbred mice.

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