Obesity and type II diabetes (T2D) have been increasing globally at epidemic proportions. Epidemiological studies indicate that air pollution is an environmental risk factor for development of insulin resistance (IR) and T2D. However, the mechanisms by which air pollution exposure causes progressive IR leading to T2D remain unclear. There is increasing evidence that IR, which often precedes the T2D by decades, may be modulated through epigenetic changes. Gestation and early childhood are periods of enhanced vulnerability to air pollution and also coincide with the stage at which epigenetic patterning is first established. We have previously established in mouse models that concentrated ambient pollution (CAP) exposure for >12 weeks potentiates the development of obesity, IR and T2D, and also induces a range of abnormalities that are prototypical for IR and T2D, including changes in immune function in systemic tissues (hypothalamus, circulation and adipose), reduced brown adipose tissue function, hepatic endoplasmic reticulum stress/steatosis and prototypical defects in insulin signaling in insulin response tissues such as liver, skeletal muscle and adipose. We have further demonstrated that early age is a period of vulnerability, as exposure to CAP during this period accelerates development of IR with overt changes in glycemic control developing in <10 weeks. Further, these defects are secondary to critical alterations in reactive oxygen species (ROS) pathways and inflammation in insulin responsive tissues. CAP exposure also results in genome-wide increases in in 5-mC. Hypothesis: Air pollution exposure results in global epigenetic alterations that result in metaboli re-programming in target tissues leading to obesity and insulin resistance. We posit that epigenetic programming during vulnerable periods of development (e.g. in utero or early childhood) is particularly prone to irreversible changes in the epigenome and the persistence of IR. This project will leverage access to state-of- the-art ambient exposure facilities, investigatie expertise in exposure science, disease pathways and epigenetics available at the University of Maryland and Johns Hopkins University to accomplish these specific aims. SA1: To characterize the epigenomic changes in response to air pollution that may either precede or overlap with the development of an insulin resistant phenotype. SA2: To define the IR and global epigenomic changes associated with early life CAP exposures. SA3: To determine whether cessation of air pollution exposure reverses insulin resistance and corresponding epigenomic changes. SA4: To integrate the epigenomic and transcriptomic perturbations that track with the development of the IR phenotype. These animal model studies with our well optimized controlled air pollution exposure that cause metabolic syndrome will reveal comprehensive epigenomic marks that precede the phenotype and are conserved between the target and surrogate tissues. The data will provide new leads for validation of mechanisms as well insight into interpretation of human studies.
Globally, 347 million people have diabetes mellitus, and this prevalence will continue to rise over the next few decades. Environmental factors, including air pollution, have been shown to play an important role in development of this disease, but the mechanisms underlying air pollution-induced insulin resistance and diabetes are unknown. This project will thoroughly determine how air pollution exposure during in utero and early life stages perturbs epigenomic patterning (DNA methylation, histone modifications, nucleosomal positioning) in target tissues and surrogate cells, leading to altered gene expression and phenotypes of insulin resistance, obesity, and diabetes.
Casin, Kevin M; Fallica, Jonathan; Mackowski, Nathan et al. (2018) S-Nitrosoglutathione Reductase Is Essential for Protecting the Female Heart From Ischemia-Reperfusion Injury. Circ Res 123:1232-1243 |
Gao, Lie; Zimmerman, Matthew C; Biswal, Shyam et al. (2017) Selective Nrf2 Gene Deletion in the Rostral Ventrolateral Medulla Evokes Hypertension and Sympathoexcitation in Mice. Hypertension 69:1198-1206 |
Sussan, Thomas E; Sudini, Kuladeep; Talbot Jr, C Conover et al. (2017) Nrf2 regulates gene-environment interactions in an animal model of intrauterine inflammation: Implications for preterm birth and prematurity. Sci Rep 7:40194 |
Ramanathan Jr, Murugappan; London Jr, Nyall R; Tharakan, Anuj et al. (2017) Airborne Particulate Matter Induces Nonallergic Eosinophilic Sinonasal Inflammation in Mice. Am J Respir Cell Mol Biol 57:59-65 |