AIMS/HYPOTHESIS Exposure to environmental pollution has been consistently linked to diabetes incidence in humans, but the potential causative mechanisms remain unclear. Given the critical role of regulated insulin secretion in maintaining glucose homeostasis, environmental chemicals that reach the endocrine pancreas and cause beta cell injury are of particular concern. We propose that cytochrome P450 (CYP) enzymes, which are involved in metabolising xenobiotics, could serve as a useful biomarker for direct exposure of islets to pollutants. Moreover, functional CYP enzymes in islets could also impact beta cell physiology. The aim of this study was to determine whether CYP1A enzymes are activated in islets following direct or systemic exposure to environmental pollutants. METHODS Immortalised liver (HepG2) and rodent pancreatic endocrine cell lines (MIN6, βTC-6, INS1, α-TC1, α-TC3), as well as human islets, were treated in vitro with known CYP1A inducers 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene (3-MC). In addition, mice were injected with either a single high dose of TCDD or multiple low doses of TCDD in vivo, and islets were isolated 1, 7 or 14 days later. RESULTS CYP1A enzymes were not activated in any of the immortalised beta or alpha cell lines tested. However, both 3-MC and TCDD potently induced CYP1A1 gene expression and modestly increased CYP1A1 enzyme activity in human islets after 48 h. The induction of CYP1A1 in human islets by TCDD was prevented by cotreatment with a cytokine mixture. After a systemic single high-dose TCDD injection, CYP1A1 enzyme activity was induced in mouse islets ~2-fold, ~40-fold and ~80-fold compared with controls after 1, 7 and 14 days, respectively, in vivo. Multiple low-dose TCDD exposure in vivo also caused significant upregulation of Cyp1a1 in mouse islets. Direct TCDD exposure to human and mouse islets in vitro resulted in suppressed glucose-induced insulin secretion. A single high-dose TCDD injection resulted in lower plasma insulin levels, as well as a pronounced increase in beta cell death. CONCLUSIONS/INTERPRETATION Transient exposure to TCDD results in long-term upregulation of CYP1A1 enzyme activity in islets. This provides evidence for direct exposure of islets to lipophilic pollutants in vivo and may have implications for islet physiology.

中文翻译：

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污染物暴露后，在小鼠和人的胰岛中诱导功能性细胞色素P450 1A酶。

目的/假说暴露于环境污染一直与人类糖尿病的发病率相关，但是潜在的病因机制仍不清楚。考虑到调节胰岛素分泌在维持葡萄糖稳态中的关键作用，到达内分泌胰腺并引起β细胞损伤的环境化学物质尤其令人关注。我们建议，参与代谢异源生物的细胞色素P450（CYP）酶可作为将胰岛直接暴露于污染物的有用生物标记。此外，胰岛中的功能性CYP酶也可能影响β细胞的生理。这项研究的目的是确定在直接或全身暴露于环境污染物后，胰岛中的CYP1A酶是否被激活。方法用已知的CYP1A诱导剂2,3,7，体外对永生化肝（HepG2）和啮齿动物胰腺内分泌细胞系（MIN6，βTC-6，INS1，α-TC1，α-TC3）以及人胰岛进行体外处理8-四氯二苯并-对二恶英（TCDD）和3-甲基胆蒽（3-MC）。另外，在体内给小鼠注射单次高剂量的TCDD或多次低剂量的TCDD，并在1、7或14天后分离出胰岛。结果CYP1A酶在任何测试的永生化β或α细胞系中均未激活。然而，3-MC和TCDD都可有效诱导CYP1A1基因表达，并在48小时后适度增加人胰岛中CYP1A1酶的活性。与细胞因子混合物共同处理可防止TCDD对人胰岛中CYP1A1的诱导。全身性单次大剂量TCDD注射后，在小鼠胰岛中，CYP1A1酶活性在体内1、7和14天后分别比对照组诱导了约2倍，约40倍和约80倍。体内多次低剂量TCDD暴露也引起小鼠胰岛中Cyp1a1的显着上调。TCDD直接暴露于人和小鼠胰岛在体外导致抑制葡萄糖诱导的胰岛素分泌。单次大剂量TCDD注射可降低血浆胰岛素水平，并显着增加β细胞死亡。结论/解释短暂暴露于TCDD会导致胰岛中CYP1A1酶活性的长期上调。这为胰岛在体内直接暴露于亲脂性污染物提供了证据，并且可能对胰岛生理有影响。体内。体内多次低剂量TCDD暴露也引起小鼠胰岛中Cyp1a1的显着上调。TCDD直接暴露于人和小鼠的胰岛在体外导致葡萄糖诱导的胰岛素分泌受到抑制。单次大剂量TCDD注射可降低血浆胰岛素水平，并显着增加β细胞死亡。结论/解释短暂暴露于TCDD会导致胰岛中CYP1A1酶活性的长期上调。这为胰岛在体内直接暴露于亲脂性污染物提供了证据，并且可能对胰岛生理有影响。体内。体内多次低剂量TCDD暴露也引起小鼠胰岛中Cyp1a1的显着上调。TCDD直接暴露于人和小鼠胰岛在体外导致抑制葡萄糖诱导的胰岛素分泌。单次大剂量TCDD注射可降低血浆胰岛素水平，并显着增加β细胞死亡。结论/解释短暂暴露于TCDD会导致胰岛中CYP1A1酶活性的长期上调。这为胰岛在体内直接暴露于亲脂性污染物提供了证据，并且可能对胰岛生理有影响。单次大剂量TCDD注射可降低血浆胰岛素水平，并显着增加β细胞死亡。结论/解释短暂暴露于TCDD会导致胰岛中CYP1A1酶活性的长期上调。这为胰岛在体内直接暴露于亲脂性污染物提供了证据，并且可能对胰岛生理有影响。单次大剂量TCDD注射可降低血浆胰岛素水平，并显着增加β细胞死亡。结论/解释短暂暴露于TCDD会导致胰岛中CYP1A1酶活性的长期上调。这为胰岛在体内直接暴露于亲脂性污染物提供了证据，并且可能对胰岛生理有影响。