Bodin Johanna, Groeng Else-Carin, Andreassen Monica, Dirven Hubert, Nygaard Unni Cecilie
Department of Toxicology and Risk Assessment, Norwegian Institute of Public Health, Oslo, Norway.
Toxicol Rep. 2016 Aug 29;3:664-672. doi: 10.1016/j.toxrep.2016.08.009. eCollection 2016.
Perfluoralkylated substances (PFAS) are classified as persistent, bioaccumulative and toxic substances and are widespread environmental contaminants. Humans are exposed through food, drinking water and air. We have previously reported that bisphenol A accelerates spontaneous diabetes development in non-obese diabetic (NOD) mice and observed in the present study that perfluoroundecanoic acid, PFUnDA, increased insulitis development, a prerequisite for diabetes development in NOD mice. We exposed NOD mice to PFUnDA in drinking water (3, 30 and 300 μg/l) at mating, during gestation and lactation and until 30 weeks of age. After 300 μg/l PFUnDA exposure, we report (i) increased pancreatic insulitis, (ii) increased number of apoptotic cells in pancreatic islets prior to insulitis and (iii) decreased phagocytosis in peritoneal macrophages. There was also a trend of decreased number of tissue resident macrophages in pancreatic islets prior to insulitis after exposure to 300 μg/l, and altered cytokine secretion in activated splenocytes after exposure to 3 μg/l PFUnDA. Although insulitis is a prerequisite for autoimmune diabetes, the accelerated insulitis was not associated with accelerated diabetes development. Instead, the incidence of diabetes tended to be reduced in the animals exposed to 3 and 30 μg/l PFUnDA, suggesting a non-monotonic dose response. The effects of PFUnDA exposure on increased apoptosis in pancreas and reduced macrophage function as well as accelerated insulitis development in NOD mice, may also be relevant for human insulitis. Further observational autoimmune diabetes clinical cohort studies and animal experiments for PFUnDA as well as other PFASs are therefore encouraged.
全氟烷基化物质(PFAS)被归类为持久性、生物累积性和有毒物质,是广泛存在的环境污染物。人类通过食物、饮用水和空气接触到这些物质。我们之前报道过双酚A会加速非肥胖糖尿病(NOD)小鼠的自发性糖尿病发展,并且在本研究中观察到全氟十一烷酸(PFUnDA)会增加胰岛炎的发展,而胰岛炎是NOD小鼠发生糖尿病的一个先决条件。我们在交配期、妊娠期和哺乳期以及直至30周龄时,将NOD小鼠暴露于饮用水中不同浓度(3、30和300μg/l)的PFUnDA中。在暴露于300μg/l PFUnDA后,我们发现:(i)胰腺胰岛炎增加;(ii)在胰岛炎发生之前,胰岛中凋亡细胞数量增加;(iii)腹膜巨噬细胞的吞噬作用降低。在暴露于300μg/l后,胰岛炎发生之前,胰岛中组织驻留巨噬细胞数量也有减少的趋势,并且在暴露于3μg/l PFUnDA后,活化脾细胞中的细胞因子分泌发生改变。尽管胰岛炎是自身免疫性糖尿病的一个先决条件,但加速的胰岛炎与糖尿病发展加速并无关联。相反,暴露于3和30μg/l PFUnDA的动物中糖尿病发病率有降低的趋势,这表明存在非单调剂量反应。PFUnDA暴露对NOD小鼠胰腺中凋亡增加、巨噬细胞功能降低以及胰岛炎发展加速的影响,可能也与人类胰岛炎相关。因此,鼓励进一步开展针对PFUnDA以及其他PFASs的自身免疫性糖尿病临床队列观察研究和动物实验。