Fig. 5. Proposed model for the generation of a unique gene expression signature by Hg and TCDD co-exposure. Individual exposures to Hg and TCDD activate a number of genes primarily through AhR (TCDD) and Nrf2 (Hg) signaling. Upon Hg and TCDD co-exposure, both the AhR and Nrf2 signaling pathways are further activated, potentially through AhR–Nrf2 cross-talk and the ability of these molecules to regulate each other as well as their ability to activate master regulators such as ATF4. This results in the generation of a co-exposure specific unique transcriptional program through (i) additive interactions, where the expression of target genes is higher in co-exposed cells compared to single exposed cells, (ii) antagonistic interactions, where the effects of one toxicant on the gene expression are negated by the addition of the other toxicant, often resulting in a gene expression fold change that is an average of the fold change induced during the two individual exposures and (iii) differential expression of genes only by co-exposure. Moreover, anti-apoptotic signaling including IL9 signaling is significantly enriched in the co-exposed cells. This could provide the cells with the ability to survive under stress resulting in chronic inflammation and pathogenesis. Red dashed arrows represent interactions between transcription factors.