| First Author | Nault R | Year | 2017 |
| Journal | PLoS One | Volume | 12 |
| Issue | 9 | Pages | e0184842 |
| PubMed ID | 28922406 | Mgi Jnum | J:246675 |
| Mgi Id | MGI:5920156 | Doi | 10.1371/journal.pone.0184842 |
| Citation | Nault R, et al. (2017) Loss of liver-specific and sexually dimorphic gene expression by aryl hydrocarbon receptor activation in C57BL/6 mice. PLoS One 12(9):e0184842 |
| abstractText | The aryl hydrocarbon receptor (AhR) is a highly conserved transcription factor that mediates a broad spectrum of species-, strain-, sex-, age-, tissue-, and cell-specific responses elicited by structurally diverse ligands including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Dose-dependent effects on liver-specific and sexually dimorphic gene expression were examined in male and female mice gavaged with TCDD every 4 days for 28 or 92 days. RNA-seq data revealed the coordinated repression of 181 genes predominately expressed in the liver including albumin (3.7-fold), alpha-fibrinogen (14.5-fold), and beta-fibrinogen (17.4-fold) in males with corresponding AhR enrichment at 2 hr. Liver-specific genes exhibiting sexually dimorphic expression also demonstrated diminished divergence between sexes. For example, male-biased Gstp1 was repressed 3.0-fold in males and induced 4.5-fold in females, which were confirmed at the protein level. Disrupted regulation is consistent with impaired GHR-JAK2-STAT5 signaling and inhibition of female specific CUX2-mediated transcription as well as the repression of other key transcriptional regulators including Ghr, Stat5b, Bcl6, Hnf4a, Hnf6, Foxa1/2/3, and Zhx2. Attenuated liver-specific and sexually dimorphic gene expression was concurrent with the induction of fetal genes such as alpha-fetoprotein. The results suggest AhR activation causes the loss of liver-specific and sexually dimorphic gene expression producing a functionally "de-differentiated" hepatic phenotype. |
