Mechanisms underlying the regulation of beta cell function by environmental pollutants

持久性有机污染物（POPs）是高度稳定的环境污染物，可在食物来源中生物积累，导致人体慢性接触和细胞/组织特异性毒性。我的研究计划的长期目标是研究持久性有机污染物影响特定内分泌细胞的分子机制，以分泌胰岛素的胰腺β细胞为模型系统。胰腺作为环境污染物的靶器官很少被研究，但我们的初步数据表明，人类胰腺组织可能是持久性有机污染物的主要储存库。我们的初步研究重点是典型的二恶英，TCDD（2,3,7,8-四氯二苯并-对二恶英），一种持久性污染物和细胞色素P450氧化酶（CYP） 1A酶的有效诱导剂。CYP酶负责解毒外来化学物质，如处方药和环境污染物，但它们也可以产生剧毒的中间代谢物。传统的研究是在肝脏中进行的，而肝脏是大部分药物代谢发生的地方，但我们的研究表明TCDD激活胰腺内分泌细胞中的CYP1A酶。我们也有令人信服的证据表明，急性TCDD暴露会导致胰岛素分泌的长期抑制。因此，我们的短期目标是：1)通过TCDD表征胰腺内分泌细胞中CYP1A的激活动力学，并评估CYP1A酶在调节胰岛素分泌中的潜在参与；2)确定CYP1A酶的诱导和/或敲低是否会影响β细胞对环境化学物质的敏感性；3)评估选择性过表达CYP1A1特异性在β细胞中的影响。******我们的工作将为广泛了解二恶英和二恶英样持久性有机污染物如何影响专门的内分泌细胞提供基础。我们将在多个生物学水平上研究内分泌细胞，使用细胞系，原代组织培养和完整的哺乳动物模型。此外，这些研究将描述胰腺内分泌细胞中基本酶途径的基本生物学特征，而以前并未被认为是外源代谢的局部位点。如果我们发现局部CYP1A酶参与调节胰岛素分泌，这将具有广泛的意义，因为CYP1A酶受各种环境污染物、药物和饮食因素的诱导。这也提出了CYP酶是否可以被诱导，从而调节其他特殊细胞类型（如神经内分泌细胞或肠内分泌细胞）的激素分泌的问题。如果胰岛素分泌不依赖于CYP1A酶，我们将探索其对其他途径的影响，如细胞存活、增殖和氧化应激。了解环境化学物质对内分泌细胞的直接影响，对于向包括第一民族社区在内的暴露人群提出建议将是有价值的。

Persistent organic pollutants (POPs) are highly stable environmental contaminants that bioaccumulate in food sources, resulting in chronic human exposure and cell/tissue-specific toxicity. The long-term goal of my research program is to investigate the molecular mechanisms by which POPs impact specialized endocrine cells, using insulin-secreting pancreatic beta cells as a model system. The pancreas has rarely been studied as a target organ for environmental pollutants, yet our preliminary data suggest that human pancreas tissue may be a major reservoir for POPs. Our preliminary studies focused on the prototypical dioxin, TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), a persistent pollutant and potent inducer of cytochrome P450 oxidase (CYP) 1A enzymes. CYP enzymes are responsible for detoxifying foreign chemicals, such as prescription drugs and environmental pollutants, but they can also generate highly toxic intermediate metabolites. They are classically studied in the liver where the majority of drug metabolism occurs, but our research indicates that TCDD activates CYP1A enzymes in pancreatic endocrine cells. We also have compelling evidence that acute TCDD exposure leads to long-term suppression of insulin secretion. Therefore, our short-term goals are to: 1) characterize the dynamics of CYP1A activation in pancreatic endocrine cells by TCDD and assess the potential involvement of CYP1A enzymes in regulating insulin secretion; 2) determine if induction and/or knockdown of CYP1A enzymes impacts the susceptibility of beta cells to environmental chemicals; and 3) assess the impact of selectively overexpressing CYP1A1 specifically in beta cells.******Our work will provide a foundation for broadly understanding how dioxins and dioxin-like POPs impact specialized endocrine cells. We will study endocrine cells at multiple biological levels, using cell lines, primary tissue culture, and intact mammalian animal models. Furthermore, these studies will characterize the basic biology of a fundamental enzyme pathway in pancreatic endocrine cells, not previously considered as a local site of xenobiotic metabolism. If we find that local CYP1A enzymes are involved in regulating insulin secretion, there would be broad implications, since CYP1A enzymes are induced by a wide variety of environmental pollutants, drugs, and dietary factors. This would also raise the question of whether CYP enzymes can be induced and consequently regulate hormone secretion in other specialized cell types, such neuroendocrine or enteroendocrine cells. If insulin secretion does not depend on CYP1A enzymes, we will explore their impact on other pathways, such as cell survival, proliferation, and oxidative stress. Understanding the direct impact of environmental chemicals on endocrine cells will be valuable for making recommendations for exposed populations, including First Nations communities.