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Herbivores regularly ingest natural toxins produced by plants as a defence against herbivory. Recent work suggests that compound toxicity is exacerbated at higher ambient temperatures. This phenomenon, known as temperature-dependent toxicity (TDT), is the likely result of decreased liver function at warmer temperatures; however, the underlying cause of TDT remains speculative. In the present study, we compared the effects of temperature and dietary plant toxins on differential gene expression in the liver of an herbivorous rodent (Neotoma lepida), using species-specific microarrays. Expression profiles revealed a greater number of differentially expressed genes at an ambient temperature below the thermal neutral zone for N. lepida (22 degrees C) compared to one within (27 degrees C). Genes and pathways upregulated at 22 degrees C were related to growth and biosynthesis, whereas those upregulated at 27 degrees C were associated with gluconeogenesis, apoptosis and protein misfolding, suggestive of a stressed state for the liver. Additionally, few genes associated with xenobiotic metabolism were induced when woodrats ingested plant toxins compared to nontoxic diets, regardless of temperature. Taken together, the results highlight the important role of ambient temperature on gene expression profiles in the desert woodrat. Temperatures just below the thermal neutral zone might be a favourable state for liver metabolism. Furthermore, the reduction in the number of genes expressed at a temperature within the thermal neutral zone indicates that liver function may be reduced at temperatures that are not typically considered as thermally stressful. Understanding how herbivorous mammals will respond to ambient temperature is imperative to accurately predict the impacts of climate change.