The long-term objective of this proposal is to identify what developmental impact the aryl hydrocarbon receptor (AHR) has in the absence of xenobiotic ligands and what are the global regulatory changes of gene expression caused by ligand-dependent activation. A critical question to be address in this application is whether ligand exposure during a window of development may be critical for environmental disease susceptibility in the adult. As in past cycles of this grant, much of the research proposed will focus on the biological responses to dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin;TCDD), because TCDD is the prototypical dioxin congener and a model for many other organochlorinated compounds. However, recent work has shown that different ligands induce diverse AHR target genes, hence, given the potential diversity of biological responses depending on ligand, this research will address ligand- specific differential outcomes as well. Findings during the previous cycle of the grant have led to the hypothesis that the AHR possesses regulatory functions during development that are potential targets of environmental injury and may be critical for disease susceptibility in the adult. For the five-year renewal of this grant the following specific aims will be addressed: (1), to identify regulatory gene expression trajectories in mouse embryonic stem cells and characterize how they respond to AHR ligands by following the differentiation of ligand-exposed and unexposed mouse ES cells into different lineages using chromatin immunoprecipitation and global gene expression analyses. (2), to identify in vivo developmental targets of AHR activation using chromatin immunoprecipitation and global gene expression analyses to probe tissues from in utero ligand-exposed and unexposed newborn mice for the expression of target gene clusters, focusing on analysis of cardiovascular tissues. (3), to identify long- term effects in adult mice exposed in utero by examining adult mice that were exposed in utero for persistent changes in gene expression of the target genes and target tissues, with a specific focus on the heart. By undertaking the characterization of specific aspects of the complexity of AHR signaling during embryonic development, it will be possible to greatly expand our current understanding of the molecular mechanisms by which the AHR perturbs normal cellular homeostasis when activated by environmental toxicants.
The exposure of human populations to aryl hydrocarbon receptor ligands has been associated with a number of toxicological outcomes and diseases, including cancer, chloracne, cardiovascular disease, diabetes, endometriosis, neurocognitive deficits, immunotoxicity and developmental abnormalities. A central question to be addressed in this context is whether ligand exposure during development is critical for environmental disease susceptibility in the adult. By focusing this renewal application on the potential consequences of fetal exposure on adult disease, we will address this one most critical issue of environmental health research today.
| Ovesen, Jerald L; Fan, Yunxia; Chen, Jing et al. (2014) Long-term exposure to low-concentrations of Cr(VI) induce DNA damage and disrupt the transcriptional response to benzo[a]pyrene. Toxicology 316:14-24 |
| Ko, Chia-I; Wang, Qin; Fan, Yunxia et al. (2014) Pluripotency factors and Polycomb Group proteins repress aryl hydrocarbon receptor expression in murine embryonic stem cells. Stem Cell Res 12:296-308 |
| Wang, Jingcai; Chen, Liang; Ko, Chia-I et al. (2012) Distinct signaling properties of mitogen-activated protein kinase kinases 4 (MKK4) and 7 (MKK7) in embryonic stem cell (ESC) differentiation. J Biol Chem 287:2787-97 |
