2. To determine the overlap of these TCDD-responsive genes across the different strains/lines, we analyzed the number of responsive genes across strains. We merged the data from selleck RAT230-2 and RAE230-A microarrays by keeping genes common to both and visualized those that were TCDD-responsive (Fig. 3B). There is a log-decrease in the number of responsive genes as the number of strains increases, indicating very large inter-strain differences in the number of TCDD-responsive genes.

We found a set of 11 genes that responded significantly to TCDD in all six strains/lines (Fig. 3C). Outside of this core, strains differ significantly in their responses to TCDD and there is minimal overlap between them (Fig. 3D). Interestingly, F344 rats showed greater similarity to L-E rats (25.3% overlap) than to H/W rats (9.8% overlap); Wis rats had similar numbers of gene alterations as H/W rats but greater similarity in specific genes to L-E (41.8% overlap) than to H/W rats (22.4% overlap). We previously contrasted the transcriptomic responses to TCDD between L-E and H/W rats at 4 and 10 days following

TCDD treatment at 100 μg/kg and found considerable overlap between the two strains at both time points (Boutros et al., 2011). Similarly, we looked for overlap between different rat strains at an early time point (19 h) to identify genes that may have critical roles in triggering TCDD toxicity. Consistent with our previous data, the 11 genes p38 MAP Kinase pathway that exhibited the greatest magnitude of response and were most consistent across all 6 strains/lines at the onset of TCDD toxicity are classic AHR-regulated genes, such as Cyp1a1, Cyp1b1, Nqo1, and Tiparp. All 11 of these genes exhibited consistent Metalloexopeptidase directions and magnitudes of change across all six strains and lines ( Fig. 4A). We hypothesized that genes showing differential gene expression between sensitive and resistant rat strains are strong candidates to mediate susceptibility to dioxin lethality. To test this hypothesis, we focused on genes that showed divergent responses between rat strains with differing TCDD-sensitivity.

We identified genes that were altered specifically in highly or moderately TCDD-sensitive L-E, F344, and Wis rats but not in resistant H/W rats (Fig. 4B). Here we see that although multiple genes showed the same directionality of change across all 6 strains, there are differences in the magnitude of response across the different strains, with some genes having a 4-fold difference in gene expression between strains. To examine whether genes identified from the above analysis belong to a specific pathway, perhaps leading to conserved strain-independent TCDD toxicity, we employed functional analysis for the 100 genes that showed the smallest adjusted p-values for each strain. We examined GO terms that have FDR of less than or equal to 0.