Effects of Chlorpyrifos on Inflammatory Responses and T-Cell Polarization in Mouse Models of Colitis

Inflammatory bowel disease (IBD) is a relapsing and remitting disorder characterized by chronic inflammation of the gastrointestinal tract. Imbalances of CD4+ T-cell subsets contribute to the pathogenesis of IBD. CD4+ T cells can differentiate into T helper (Th) cells and regulatory T cells (Treg). Th cells are divided into distinct subsets, such as Th1, Th2, and Th17, characterized by distinct cytokine profiles and effector functions. Treg suppresses activation of Th cells, which is critical for modulating Th-cell immunity. The polarization of CD4+ T cells is regulated by acetylcholine (ACh) and acetylcholine receptors (AChRs). Activation of nicotinic AChRs promotes Th1 differentiation whereas activation of muscarinic AChRs leads to Th2 and Th17 polarization. Chlorpyrifos (CPF) is one of the most widely used organophosphate pesticides worldwide. CPF reduces ACh hydrolysis and affects the activation and expression of AChRs. Oral administration of CPF affects gut microbiome and increases gut permeability and bacterial translocation. However, the effects of CPF on ACh-AChRs signaling in CD4+ T-cell differentiation and immune function during gut inflammation is not clear. Therefore, we propose to carry out this study in 3 consecutive years to clarify the effects of dietary CPF exposure on inflammatory responses and CD4+ T-cell polarization during gut inflammation. In the first year, we plan to investigate whether CPF modulates circulating immune cells and mucosal inflammation in a murine model of acute colitis. In the second year, CD4+ T-cell subsets and immune function will be measured to evaluate the effects of CPF in a murine model of chronic colitis. In the third year, a murine model of chronic relapsing colitis will be used to investigate whether CPF modulates CD4+ T-cell polarization via ACh-AChRs signaling. This study may provide useful information of dietary CPF exposure in patients with IBD.