What question did this study set out to answer?

To determine whether hepatic Cyp1a1 and Cyp1a2 gene expression thresholds measured in short-term rat studies can differentiate tumorigenic from non-tumorigenic aryl hydrocarbon receptor (AhR) activation.

May 21, 2019Toxicological Sciences

AhR Activation in Pharmaceutical Development: Applying Liver Gene Expression Biomarker Thresholds to Identify Doses Associated With Tumorigenic Risks in Rats

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To determine whether hepatic Cyp1a1 and Cyp1a2 gene expression thresholds measured in short-term rat studies can differentiate tumorigenic from non-tumorigenic aryl hydrocarbon receptor (AhR) activation.
Treated Wistar Han rats in short-term studies with two AhR-activating carcinogens (TCDD and PCB126) at minimally carcinogenic and noncarcinogenic dose levels.
Treated rats with three AhR-activating noncarcinogens (omeprazole, mexiletine, and canagliflozin) at the top doses from their two-year rat carcinogenicity studies.
Evaluated liver gene expression and activity profiles of downstream AhR effectors Cyp1a1 and Cyp1a2 to evaluate signal strength and sustainability.
Identified a hepatic gene expression threshold that separated tumorigenic-strength AhR activation from statistically significant AhR activation that did not induce dioxin-like carcinogenicity.
Demonstrated that sustained AhR activation exceeding this biomarker threshold is necessary for compounds to display dioxin-like carcinogenic potential in rats.

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Implication

Animal study reveals a liver gene expression biomarker threshold in rats, suggesting short-term assays can distinguish tumorigenic AhR activation from non-carcinogenic drug exposures.

Cite This Study

Qin et al. (2019) studied this question.

synapsesocial.com/papers/6a030a2da3a0c1863b6513fa https://doi.org/10.1093/toxsci/kfz125

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Implication

Animal study reveals a liver gene expression biomarker threshold in rats, suggesting short-term assays can distinguish tumorigenic AhR activation from non-carcinogenic drug exposures.

AhR Activation in Pharmaceutical Development: Applying Liver Gene Expression Biomarker Thresholds to Identify Doses Associated With Tumorigenic Risks in Rats

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Discussion

Implication

Cite This Study

AhR Activation in Pharmaceutical Development: Applying Liver Gene Expression Biomarker Thresholds to Identify Doses Associated With Tumorigenic Risks in Rats

Key Points

Discussion

Implication

Cite This Study

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