Hepatic transcriptomic responses to TCDD in dioxin-sensitive and dioxin-resistant rats during the onset of toxicity

Area of Science:

• Toxicology and Pharmacology
• Molecular Biology
• Genetics

Background:

• 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elicits toxic effects via the aryl hydrocarbon receptor (AHR).
• Han/Wistar (Kuopio) (H/W) rats exhibit remarkable resistance to TCDD toxicity, attributed to a variant AHR with a deleted transactivation domain.
• Despite resistance, H/W rats' variant AHR can still upregulate dioxin-inducible genes.

Purpose of the Study:

• To compare the hepatic transcriptional responses to TCDD in TCDD-sensitive (Long-Evans, L-E) and resistant (H/W) rats.
• To investigate the breadth and core set of dioxin-inducible genes in different rat strains.
• To assess the impact of TCDD exposure duration and feed restriction on gene expression.

Main Methods:

• TCDD treatment (100 μg/kg) or corn-oil control for 4 or 10 days in L-E and H/W rats.
• Hepatic gene expression profiling using microarrays.
• Validation of microarray data via RT-PCR for 41 selected genes.

Main Results:

• A core set of genes (e.g., CYP1A1, CYP1A2, CYP1B1) were consistently altered in both strains.
• L-E rats exhibited a significantly broader transcriptional response to TCDD compared to H/W rats (three-fold more genes altered).
• At 10 days, nearly all expressed genes were dysregulated in L-E rats, suggesting emerging toxicity; feed restriction had minimal impact.

Conclusions:

• The variant AHR in H/W rats, despite its deletion, retains functionality in upregulating key dioxin-responsive genes.
• Rat strain differences in AHR structure significantly influence the breadth of TCDD-induced transcriptional changes.
• TCDD-induced gene dysregulation in sensitive rats extends broadly, potentially reflecting systemic toxicity, and is largely independent of feed restriction.