Strain differences in tissue repair response to 1,2-dichlorobenzene

Kulkarni, Swarupa G.; Duong, Hoan; Gomila, Remi; Mehendale, Harihara M.; Conway, Eadaoin

doi:10.1007/s002040050332

Cited by 26 publications

(16 citation statements)

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“…Lower liver injury at earlier points was also observed in a dose-response study with TA, where liver injury at 600 mg/kg dose was significantly lower at 12 and 24 h compared to that observed after 50, 150, or 300 mg/kg doses (Mangipudy et al, 1995a). Kulkarni et al (1996) reported similar delay in maximum liver injury in Sprague-Dawley and Fischer 344 rats treated with higher doses of 1,2-dichlorobenzene.…”

Section: Discussionsupporting

confidence: 54%

Temporal Changes in Tissue Repair Permit Survival of Diet-Restricted Rats from an Acute Lethal Dose of Thioacetamide

Ramaiah¹

1998

Toxicological Sciences

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Section: Discussionsupporting

confidence: 54%

Temporal Changes in Tissue Repair Permit Survival of Diet-Restricted Rats from an Acute Lethal Dose of Thioacetamide

Ramaiah¹

1998

Toxicological Sciences

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“…Tissue repair stimulated in response to different doses of o-DCB (6-fold dose range) was compared between these two strains. These studies indicated that tissue repair response in the F344 rat is approximately 4 to 10 times higher than the S-D rat, suggesting that higher injury in F344 rat livers is of no consequence to animal survival because an exacting level of tissue repair stimulation rescues these animals (42). Similar to these studies, marked differences in CC14 toxicity among four strains of mice have been reported to be due to differential tissue repair (62,63).…”

Section: Previous Studiesmentioning

confidence: 72%

“…In addition to the use of the dose-response curve for prediction of the ultimate outcome in individual subjects, such a response can also be used for prediction in a population. To test this concept, we conducted studies with model hepatotoxicants (8,(41)(42)(43) (42). In contrast to the reported 75-fold higher liver injury, we found only 10-to 15-fold higher injury in F344 rats compared to S-D rats (60,61).…”

Section: Previous Studiesmentioning

confidence: 83%

“…Between the two threshold doses there is a dose-related incremental biologic compensatory mechanism that effectively and promptly restrains tissue injury, permitting recovery from toxic injury. Stimulated cell division and tissue repair are the foundations of the biologic compensatory response (2,8,(41)(42)(43) The resulting consequences of toxicity are well known and well described in the toxicologic literature.…”

Section: Implications To Therapeutic Strategiesmentioning

confidence: 99%

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Role of tissue repair in toxicologic interactions among hepatotoxic organics.

Soni

Mehendale

1998

Environ Health Perspect

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It is widely recognized that exposure to combinations or mixtures of chemicals may result in highly exaggerated toxicity even though individual chemicals might not be toxic at low doses. Chemical mixtures may also cause additive or less than additive toxicity. From the perspective of public health, highly exaggerated toxicity is of significant concern. Assessment of risk from exposure to chemical mixtures requires knowledge of the underlying mechanisms. Previous studies from this laboratory have shown that nontoxic doses of chlordecone (10 ppm, 15 days) and carbon tetrachloride (CCl4) (100 microliters/kg) interact at the biologic interface, resulting in potentiated liver injury and 67-fold amplification of CCl4 lethality. In contrast, although interaction between phenobarbital and CCl4 leads to even higher injury, animal survival is unaffected because of highly stimulated compensatory tissue repair. A wide variety of additional experimental evidence confirms the central role of stimulated tissue repair as a decisive determinant of the final outcome of liver injury inflicted by hepatotoxicants. These findings led us to propose a two-stage model of toxicity. In this model, tissue injury is inflicted in stage one by the well-described mechanisms of toxicity, whereas in stage two the ultimate toxic outcome is determined by whether timely and sufficient tissue repair response accompanies this injury. In an attempt to validate this model, dose-response relationships for injury and tissue repair as opposing responses have been developed for model hepatotoxicants. Results of these studies suggest that tissue repair increases in a dose-dependent manner, restraining injury up to a threshold dose, whereupon it is inhibited, allowing an unrestrained progression of injury. These findings indicate that tissue repair is a quantifiable response to toxic injury and that inclusion of this response in risk assessment may help in fine-tuning prediction of toxicity outcomes. Images Figure 3 Figure 4 Figure 6

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“…There is ample evidence that those strains vary in their susceptibilities to various toxicants or mutagens (Asamoto et al 1989; Kulkarni et al 1996). Therefore, we investigated whether a model built with Wistar rat expression profiles would be predictive for treatment effects in Sprague-Dawley rats.…”

Section: Discussionmentioning

confidence: 99%

Discriminating Different Classes of Toxicants by Transcript Profiling

Steiner

Suter

Boess

et al. 2004

Environ Health Perspect

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Male rats were treated with various model compounds or the appropriate vehicle controls. Most substances were either well-known hepatotoxicants or showed hepatotoxicity during preclinical testing. The aim of the present study was to determine if biological samples from rats treated with various compounds can be classified based on gene expression profiles. In addition to gene expression analysis using microarrays, a complete serum chemistry profile and liver and kidney histopathology were performed. We analyzed hepatic gene expression profiles using a supervised learning method (support vector machines; SVMs) to generate classification rules and combined this with recursive feature elimination to improve classification performance and to identify a compact subset of probe sets with potential use as biomarkers. Two different SVM algorithms were tested, and the models obtained were validated with a compound-based external cross-validation approach. Our predictive models were able to discriminate between hepatotoxic and nonhepatotoxic compounds. Furthermore, they predicted the correct class of hepatotoxicant in most cases. We provide an example showing that a predictive model built on transcript profiles from one rat strain can successfully classify profiles from another rat strain. In addition, we demonstrate that the predictive models identify nonresponders and are able to discriminate between gene changes related to pharmacology and toxicity. This work confirms the hypothesis that compound classification based on gene expression data is feasible.

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Strain differences in tissue repair response to 1,2-dichlorobenzene

Cited by 26 publications

References 0 publications

Temporal Changes in Tissue Repair Permit Survival of Diet-Restricted Rats from an Acute Lethal Dose of Thioacetamide

Temporal Changes in Tissue Repair Permit Survival of Diet-Restricted Rats from an Acute Lethal Dose of Thioacetamide

Role of tissue repair in toxicologic interactions among hepatotoxic organics.

Discriminating Different Classes of Toxicants by Transcript Profiling

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