砷暴露诱导小鼠空肠结构损伤和免疫紊乱
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摘要
以C57BL/6雄性小鼠为受试动物,研究慢性饮水型砷(As)暴露对肠道的损伤效应及作用机制.小鼠饮用含5 mg·L~(-1)或50 mg·L~(-1) As的亚砷酸钠(NaAsO_2)水溶液6个月后,检测空肠组织的氧化应激指标、病理学改变、免疫相关基因表达及黏膜杯状细胞数量.结果发现,As组小鼠空肠组织的超氧化物歧化酶活性和总抗氧化能力显著下降,脂质过氧化产物丙二醛含量显著升高;空肠黏膜受到侵蚀,上皮吸收细胞排列紊乱,部分肠绒毛脱落.氧化应激指标及病理学改变呈现剂量依赖性.5 mg·L~(-1) As组免疫相关基因TNF-α、IFN-γ、IL-4、IL-5和IL-13的mRNA水平显著升高,黏膜杯状细胞数量显著增加;50 mg·L~(-1)As组TNF-α、IFN-γ和IL-4显著下调表达,IL-5和IL-13的表达水平及黏膜杯状细胞数量无显著变化.结果表明,慢性饮水型As暴露诱导小鼠空肠氧化损伤及组织结构改变的同时可能诱发了肠道免疫紊乱.As暴露引起的黏膜损伤可能与As诱导空肠的氧化损伤相关.
Effects of arsenic intake on the structure and mucosal immunity were investigated in mouse jejunum. The oxidative stress indexes, histopathological structure, immune-related genes expression, and mucosa goblet cell counts were examined. Our results showed that arsenic intake via water increased malondialdehyde content, and decreased the total superoxide dismutase activity and total antioxidant capacity in mouse jejunum. Meanwhile, arsenic intake via water caused the eroded jejunal mucosa, disorganized absorptive cells, and exfoliated villi in the jejunum. The oxidative damage and the above mentioned pathological changes were more serious in 50 mg·L~(-1) arsenic group than those in 5 mg·L~(-1) arsenic group. Compared to the control group, the expression of immune-related genes TNF-α, IFN-γ, IL-4, IL-5, and IL-13 were all up-regulated significantly in 5 mg·L~(-1) arsenic treatment group, associated with a significant increase in the counts of mucosa goblet cells. However, the expression of TNF-α, IFN-γ, and IL-4 were decreased significantly, and no marked change was found in the mRNA levels of IL-5 and IL-13, as well as in the counts of mucosa goblet cells in 50 mg·L~(-1) arsenic group. These results indicated that chronic arsenic exposure from drinking water induced oxidative damage and histopathological changes in mouse jejunum. Mucosal damage caused by arsenic might be related to arsenic-mediated oxidative stress. The structural failure of mouse jejunum mucosal might disturb the intestinal mucosal immunity in mice.
Effects of arsenic intake on the structure and mucosal immunity were investigated in mouse jejunum. The oxidative stress indexes, histopathological structure, immune-related genes expression, and mucosa goblet cell counts were examined. Our results showed that arsenic intake via water increased malondialdehyde content, and decreased the total superoxide dismutase activity and total antioxidant capacity in mouse jejunum. Meanwhile, arsenic intake via water caused the eroded jejunal mucosa, disorganized absorptive cells, and exfoliated villi in the jejunum. The oxidative damage and the above mentioned pathological changes were more serious in 50 mg·L~(-1) arsenic group than those in 5 mg·L~(-1) arsenic group. Compared to the control group, the expression of immune-related genes TNF-α, IFN-γ, IL-4, IL-5, and IL-13 were all up-regulated significantly in 5 mg·L~(-1) arsenic treatment group, associated with a significant increase in the counts of mucosa goblet cells. However, the expression of TNF-α, IFN-γ, and IL-4 were decreased significantly, and no marked change was found in the mRNA levels of IL-5 and IL-13, as well as in the counts of mucosa goblet cells in 50 mg·L~(-1) arsenic group. These results indicated that chronic arsenic exposure from drinking water induced oxidative damage and histopathological changes in mouse jejunum. Mucosal damage caused by arsenic might be related to arsenic-mediated oxidative stress. The structural failure of mouse jejunum mucosal might disturb the intestinal mucosal immunity in mice.
引文
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Smirnova M G,Guo L,Birchall J P,et al.2003.LPS up-regulates mucin and cytokine mRNA expression and stimulates mucin and cytokine secretion in goblet cells[J].Cellular Immunology,211:42-49
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Zeng Q,Yi H L,Huang L Q,et al.2019.Long-term arsenite exposure induces testicular toxicity by redox imbalance,G2/M cell arrest and apoptosis in mice[J].Toxicology,411:122-132
Zhao H J,Wang Y,Liu Z X,et al.2018.Subchronic arsenism disorders mRNA expression of cytokines and immunoglobulins in the intestinal tract of the cock[J].Biological Trace Element Research,182:111-118
Arnold L L,Eldan M,van Gemert M,et al.2003.Chronic studies evaluating the carcinogenicity of monomethylarsenic acid in rats and mice[J].Toxicology,190:197-219
Bradford M M.1976.A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding[J]. Analytical Biochemistry,72:248-254
Chakraborti D,Rahman M M,Das B,et al.2017.Groundwater arsenic contamination and its health effects in India[J].Hydrogeology Journal,25:1165-1181
Chiocchetti G M,Vélez D,Devesa V.2018.Effect of subchronic exposure to inorganic arsenic on the structure and function of the intestinal epithelium[J].Toxicology Letters,286:80-88
Di Gioacchino M,Verna N,Di Giampaolo L,et al.2007.Immunotoxicity and sensitizing capacity of metal compounds depend on speciation[J].International Journal of Immunopathology and Pharmacology,20:15-22
Evens A M,Tallman M S,Gartenhaus R B.2004.The potential of arsenic trioxide in the treatment of malignant disease:past,present,and future[J].Leukemia Research,28(9):891-900
Flora S J.2011.Arsenic-induced oxidative stress and its reversibility[J].Free Radical Biology and Medicine,51:257-281
Gonzalez M J,Aguilar M V,Martinez M C.1997.Mechanisms of absorption of As2O5 from rat small intestine:the effect of different parameters[J].Journal of Trace Elements in Medicine and Biology,11:239-247
Guha Mazumder D,Dasgupta U B.2011.Chronic arsenic toxicity:studies in west Bengal,India[J].Kaohsiung Journal of Medical Sciences,27:360-370
Guo Y,Zhao P P,Guo G Y,et al.2015.The role of oxidative stress in gastrointestinal tract tissues induced by arsenic toxicity in cocks[J].Biological Trace Element Research,168:490-499
Hei T K,Filipic M.2004.Role of oxidative damage in the genotoxicity of arsenic[J].Free Radical Biology and Medicine,37:574-581
Hong Y S,Song K H,Chung J Y.2014.Health effects of chronic arsenic exposure[J].Journal of Preventive Medicine and Public Health,47(5):245-252
Hughes M F.2002.Arsenic toxicity and potential mechanisms of action[J].Toxicology Letters,133:1-16
Jeong C H,Seok J S,Petriello M O,et al.2017.Arsenic downregulates tight junction claudin proteins through p38 and NF-κB in intestinal epithelial cell line,HT-29[J].Toxicology,379:31-39
Kim Y J,Kim J M.2015.Arsenic toxicity in male reproduction and development[J].Development & Reproduction,19(4):167-180
Li X J,Yi H L,Wang H.2018.Sulphur dioxide and arsenic affect male reproduction via interfering with spermatogenesis in mice[J].Ecotoxicology and Environmental Safety,165:164-173
Liu F F,Wang J P,Zheng Y J,et al.2013.Biomarkers for the evaluation of population health status 16 years after the intervention of arsenic-contaminated groundwater in Xinjiang,China[J].Journal of Hazardous Materials,262:1159-1166
Livak K J,Schmittgen T D.2001.Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method[J].Methods,25:402-408
Lu K,Abo R P,Schlieper K A,et al.2014.Arsenic exposure perturbs the gut microbiome and its metabolic profile in mice:an integrated metagenomics and metabolomics analysis[J].Environmental Health Perspectives,122:284-291
McDole J R,Wheeler L W,McDonald K G,et al.2012.Goblet cells deliver luminal antigen to CD103+ DCs in the small intestine[J].Nature,483(7389):345-349
Miller H,Zhang J B,KuoLee R,et al.2007.Intestinal M cells:the fallible sentinels?[J].World Journal of Gastroenterology,13(10):1477-1486
Rodríguez-Lado L,Sun G,Berg M,et al.2013.Groundwater arsenic contamination throughout China[J].Science,341(6148):866-868
Smirnova M G,Guo L,Birchall J P,et al.2003.LPS up-regulates mucin and cytokine mRNA expression and stimulates mucin and cytokine secretion in goblet cells[J].Cellular Immunology,211:42-49
Smith A H,Lopipero P A,Bates M N,et al.2002.Public health.Arsenic epidemiology and drinking water standards[J].Science,296:2145-2146
Watanabe C,Inaoka T,Matsui T,et al.2003.Effects of arsenic on younger generations[J].Journal of Environmental Science and Health (Part A),38(1):129-139
Wu L H,Yi H L,Yi M.2010.Assessment of arsenic toxicity using Allium/Vicia root tip micronucleus assays[J].Journal of Hazardous Materials,176:952-956
曾群,仪慧兰,黄立群,等.2018.砷暴露对小鼠葡萄糖稳态的影响[J].环境科学学报,38(8):3353-3360
Zeng Q,Yi H L,Huang L Q,et al.2019.Long-term arsenite exposure induces testicular toxicity by redox imbalance,G2/M cell arrest and apoptosis in mice[J].Toxicology,411:122-132
Zhao H J,Wang Y,Liu Z X,et al.2018.Subchronic arsenism disorders mRNA expression of cytokines and immunoglobulins in the intestinal tract of the cock[J].Biological Trace Element Research,182:111-118
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