2,3,7,8 Tetrachlorodibenzo-p-dioxin-induced RNA abundance changes identify Ackr3, Col18a1, Cyb5a and Glud1 as candidate mediators of toxicity

Abstract

2,3,7,8 Tetrachlorodibenzo-p-dioxin (TCDD) is an aromatic, long-lived environmental contaminant. While the pathogenesis of TCDD-induced toxicity is poorly understood, it has been shown that the aryl hydrocarbon receptor (AHR) is required. However, the specific transcriptomic changes that lead to toxic outcomes have not yet been identified. We previously identified a panel of 33 genes that respond to TCDD treatment in two TCDD-sensitive rodent species. To identify genes involved in the onset of hepatic toxicity, we explored 25 of these in-depth using liver from two rat strains: the TCDD-resistant Han/Wistar (H/W) and the TCDD-sensitive Long–Evans (L–E). Time course and dose–response analyses of mRNA abundance following TCDD insult indicate that eight genes are similarly regulated in livers of both strains of rat, suggesting that they are not central to the severe L–E-specific TCDD-induced toxicities. The remaining 17 genes exhibited various divergent mRNA abundances between L–E and H/W strains after TCDD treatment. Several genes displayed a biphasic response where the initial response to TCDD treatment was followed by a secondary response, usually of larger magnitude in L–E liver. This secondary response was most often an exaggeration of the original TCDD-induced response. Only cytochrome b5 type A (microsomal) (Cyb5a) had equivalent TCDD sensitivity to the prototypic AHR-responsive cytochrome P450, family 1, subfamily a, polypeptide 1 (Cyp1a1), while six genes were less sensitive. Four genes showed an early inter-strain difference that was sustained throughout most of the time course (atypical chemokine receptor 3 (Ackr3), collagen, type XVIII, alpha 1 (Col18a1), Cyb5a and glutamate dehydrogenase 1 (Glud1)), and of those genes examined in this study, are most likely to represent genes involved in the pathogenesis of TCDD-induced hepatotoxicity in L–E rats.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-016-1720-0) contains supplementary material, which is available to authorized users.

Transcriptomic Impact of IMA-08401, a Novel AHR Agonist Resembling Laquinimod, on Rat Liver

“…As the study of TCDD effects was performed using a different setting, and a considerable number of genes were not available on both platforms (only a 9534 gene overlap), a less stringent significance threshold of FDR < 0.05 was used to consider overlap across studies. Shortly after a single exposure to either C2 or TCDD, 11 genes demonstrated changes to RNA abundance in the same direction with similar magnitudes (Figure 4a); these include a number of ‘AHR-core’ genes ( Cyp1a1 , Cyp1a2 , Nqo1 , and Cyb5a [60]), as well as Glrx and RGD1310209 (a gene similar to EIG121 that is involved in regulation of autophagy). Similarly, 10 days after initial exposure to either C2 or TCDD, 12 genes showed changes to RNA abundance of similar size and direction, again including Cyp1a1 , Cyp1a2 , Nqo1 , Glrx , and RGD1310209 (Figure 4b).…”

Identification of proteome markers for drug-induced liver injury in zebrafish embryos

“…The protein Glud1b plays a key role in nitrogen and glutamate metabolism, and also in the energy homeostasis (https://zfin.org/ZDB-GENE -030828-1). The human ortholog GLUD1 is a serum marker for hepatotoxicity along with ALT and AST (Hu et al, 2014), and Glud1 was identified as a marker in TCDD-induced hepatotoxicity in rats (Watson et al, 2017). The Eno1a protein is involved in glycolysis and was previously reported to be differentially expressed in zebrafish embryo after exposure to CsA (Ponnudurai et al, 2012), supporting a role in hepatotoxicity.…”