阻燃剂TCPP暴露对小鼠的神经毒理作用观察及相关机制研究
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摘要
目的探讨阻燃剂TCPP(tris(2-chloroisopropyl)phosphate)暴露对小鼠的神经毒理作用观察及相关机制研究。方法将30只成年KM小鼠随机分为正常对照组(0 mg/(kg·d))、低剂量(TCPP)组(10 mg/(kg·d))和高剂量TCPP组(100 mg/(kg·d)),持续灌胃染毒30 d。染毒结束后,观察其体质量及一般情况。采用水迷宫实验检测小鼠的学习记忆能力;采用化学发光免疫分析法测定小鼠血清总三碘甲腺原氨酸(TT3)、游离三碘甲腺原氨酸(FT3)、总四碘甲腺原氨酸(TT4)和游离四碘甲腺原氨酸(FT4)水平;采用比色法测定小鼠脑组织中谷胱甘肽转移酶(GST)和超氧化物歧化酶(SOD)、丙二醛(MDA)、过氧化氢酶(CAT)水平。结果与对照组小鼠相比,TCPP高剂量组小鼠饮水量显著下降(P<0.05),肝和脾脏器指数明显升高(P<0.05)。TCPP暴露组小鼠在水迷宫实验中逃避潜伏期均较正常组小鼠出现延长(P<0.05),高剂量组小鼠游泳总路程出现明显升高(P<0.05),同时在目标象限停留时间也明显缩短(P<0.05)。高剂量TCPP染毒组小鼠与对照组小鼠相比TT3、FT3出现明显增高(P<0.05)。与对照组小鼠相比,高剂量TCPP染毒组小鼠GST、SOD出现明显降低,MDA显著增高(P<0.05)。与对照组小鼠相比,低剂量TCPP染毒组小鼠仅GST出现降低,MDA增高(P<0.05)。结论 TCPP暴露具有明显的神经毒性作用,能造成小鼠学习记忆能力丧失,其毒性机制可能与脑组织氧化损伤及甲状腺激素增高有关。
Objective To observe the neurotoxic effects and mechanism of TCPP(tris(2-chloroisopropyl)phosphate) exposure on mice. Methods Thirty adult KM mice were randomly divided into normal control(0 mg/(kg·d)), low-(10 mg/(kg·d)) and high-dose TCPP groups(100 mg/(kg·d)), and were given oral gavage exposure once a day for consecutive 30 days. The body mass of mice was recorded. Morris water maze was used to examine the ability of learning and memory ability in mice. The serum levels of total-triiodothyronine(TT3), total-tetraiodothyronine(TT4), free tetraimethionine(FT4) and free triiodothyronine(FT3) were detected with electro-chemiluminescence. The levels of glutathione transferase(GST), superoxide dismutase(SOD), catalase(CAT), and malonaldehyde(MDA) in brain tissues were detected by chemical colorimetry. Results Compared with the control group, the water intake of the high-dose TCPP group was significantly reduced(P< 0.05), and the argan coefficients of the liver and spleen were significantly increased(P< 0.05). In addition, the escape latency of TCPP exposure mice was longer than that of control group in the water maze test(P< 0.05). Furthermore, the total swimming course of the high-dose TCPP group was increased(P< 0.05) and swimming time in the target quadrant was significantly reduced compared with the control group(P< 0.05). In the high-dose TCPP group, the serum levels of TT3 and FT3 were increased(P< 0.05), the activities of GST and SOD were decreased, and the content of MDA was increased(P < 0.05) compared with the control group. In the low-dose TCPP group, the activity of GST was decreased and the content of MDA was increased(P < 0.05) compared with the control group. Conclusions TCPP exposure is neurotoxic by increasing thyroid hormones and inducing oxidative damage in mice.
Objective To observe the neurotoxic effects and mechanism of TCPP(tris(2-chloroisopropyl)phosphate) exposure on mice. Methods Thirty adult KM mice were randomly divided into normal control(0 mg/(kg·d)), low-(10 mg/(kg·d)) and high-dose TCPP groups(100 mg/(kg·d)), and were given oral gavage exposure once a day for consecutive 30 days. The body mass of mice was recorded. Morris water maze was used to examine the ability of learning and memory ability in mice. The serum levels of total-triiodothyronine(TT3), total-tetraiodothyronine(TT4), free tetraimethionine(FT4) and free triiodothyronine(FT3) were detected with electro-chemiluminescence. The levels of glutathione transferase(GST), superoxide dismutase(SOD), catalase(CAT), and malonaldehyde(MDA) in brain tissues were detected by chemical colorimetry. Results Compared with the control group, the water intake of the high-dose TCPP group was significantly reduced(P< 0.05), and the argan coefficients of the liver and spleen were significantly increased(P< 0.05). In addition, the escape latency of TCPP exposure mice was longer than that of control group in the water maze test(P< 0.05). Furthermore, the total swimming course of the high-dose TCPP group was increased(P< 0.05) and swimming time in the target quadrant was significantly reduced compared with the control group(P< 0.05). In the high-dose TCPP group, the serum levels of TT3 and FT3 were increased(P< 0.05), the activities of GST and SOD were decreased, and the content of MDA was increased(P < 0.05) compared with the control group. In the low-dose TCPP group, the activity of GST was decreased and the content of MDA was increased(P < 0.05) compared with the control group. Conclusions TCPP exposure is neurotoxic by increasing thyroid hormones and inducing oxidative damage in mice.
引文
[1] 季麟, 高宇, 田英. 有机磷阻燃剂生产使用及我国相关环境污染研究现况 [J]. 环境与职业医学, 2017, 34(3): 271-279.
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[6] 沈扬, 于畅, 孔东东, 等. 有机磷阻燃剂甲状腺干扰效应及其作用机制研究—以磷酸三(2-氯丙基)酯(TCPP)为例 [J]. 中国环境科学, 2018, 38(6): 2337-2344.
[7] 孔琪, 夏霞宇, 赵永坤. 美国实验动物品种资源现状分析 [J]. 中国实验动物学报, 2015, 23(5): 539-542.
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[9] 王俊艳, 刘皓, 刘金宝, 等. 碘过量对后代鼠脑NSE和GFAP表达的影响 [J]. 中国比较医学杂志, 2007, 17(1): 18-21.
[10] 皮天星, 蔡磊明, 蒋金花, 等. 新型阻燃剂TCPP对斑马鱼的毒性研究 [J]. 生态毒理学报, 2016, 11(2): 247-256.
[11] 徐天天. 有机磷阻燃剂对秀丽线虫的慢性毒性 [D]. 华东师范大学, 2017.
[12] Zhao F, Wang J, Fang Y, et al. Effects of tris(1,3-dichloro-2-propyl)phosphate on pathomorphology and gene/protein expression related to thyroid disruption in rats [J]. Toxicol Res, 2016, 5(3): 921-930.
[13] Moser VC, Phillips PM, Hedge JM, et al. Neurotoxicological and thyroid evaluations of rats developmentally exposed to tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) and tris(2-chloro-2-ethyl)phosphate (TCEP) [J]. Neurotoxicol Teratol, 2015, 52(Pt B): 236-247.
[14] Tilson HA, Veronesi B, Mclamb RL, et al. Acute exposure to tris(2-chloroethyl)phosphate produces hippocampal neuronal loss and impairs learning in rats [J]. Toxicol Appl Pharrmacol, 1990, 106(2): 254-269.
[15] Umezu T, Yonemoto J, Soma Y, et al. Tris(2-chloroethyl)phosphate increases ambulatory activity in mice: pharmacological analyses of its neurochemical mechanism [J]. Toxicol Appl Pharmacol, 1998, 148(1): 109-116.
[16] Yuan LL, Li JS, Zha JM, et al. Targeting neurotrophic factors and their receptors, but not cholinesterase or neurotransmitter, in the neurotoxicity of TDCPP in Chinese rare minnow adults (Gobiocypris rarus) [J]. Environ Pollut, 2016, 208(Pt B): 670-677.
[17] Li C, Li L, Lin B, et al. Tris(1,3-dichloro-2-propyl)phosphate induces toxicity by stimulating CaMK2 in PC12 cells [J]. Environ Toxicol, 2017, 32(6): 1-8.
[18] Meeker JD, Stapleton HM. House dust concentrations of organophosphate flame retardants in relation to hormone levels and semen quality parameters [J]. Environ Health Perspect, 2010, 118(3): 318-323.
[19] Wang Q, Liang K, Liu J, et al. Exposure of zebrafish embryos/larvae to TDCPP alters concentrations of thyroid hormones and transcriptions of genes involved in the hypothalamic-pituitary-thyroid axis [J]. Aquat Toxicol, 2013, 126(1): 207-213.
[20] Farhat A, Crump D, Chiu S, et al. In ovo effects of two organophosphate flame retardants — TCPP and TDCPP — on pipping success, development, mRNA expression, and thyroid hormone levels in chicken embryos [J]. Toxicol Sci, 2013, 134(1): 92-102.
[21] An J, Hu J, Shang Y, et al. The cytotoxicity of organophosphate flame retardants on HepG2, A549 and Caco-2 cells [J]. Environ Sci Health A Tox Hazard Subst Environ Eng, 2016, 51(11): 980-988.
[22] Li L, Jiang S, Li K, et al. Assessment of tris(1,3-dichloro-2-propyl)phosphate toxicology in PC12 cells by using digital gene expression profiling [J]. Chemosphere, 2017, 183: 353-360.
[23] Villanueva I, Alva-Sánchez C, Pacheco-Rosado J. The role of thyroid hormones as inductors of oxidative stress and neurodegeneration [J]. Oxid Med Cell Longev, 2013, 2013: 218145.
[2] Butt CM, Congleton J, Hoffman K, et al. Metabolites of organophosphate flame retardants and 2-ethylhexyl tetrabromobenzoate in urine from paired mothers and toddlers [J]. Environ Sci Technol, 2014, 48(17): 10432-10438.
[3] 阮伟, 谭晓欣, 罗孝俊, 等. 东江表层沉积物中的有机磷系阻燃剂 [J]. 中国环境科学, 2014, 34(9): 2394-2400.
[4] Dishaw LV, Powers CM, Ryde IT, et al. Is the PentaBDE replacement, tris(1,3-dichloro-2-propyl)phosphate (TDCPP), a developmental neurotoxicant? Studies in PC12 cells [J]. Toxicol Appl Pharmacol, 2011, 256(3): 281-289.
[5] Fernie KJ, Palace V, Peters LE, et al. Investigating endocrine and physiological parameters of captive American kestrels exposed by diet to selected organophosphate flame retardants [J]. Environ Sci Technol, 2015, 49(12): 7448-7455.
[6] 沈扬, 于畅, 孔东东, 等. 有机磷阻燃剂甲状腺干扰效应及其作用机制研究—以磷酸三(2-氯丙基)酯(TCPP)为例 [J]. 中国环境科学, 2018, 38(6): 2337-2344.
[7] 孔琪, 夏霞宇, 赵永坤. 美国实验动物品种资源现状分析 [J]. 中国实验动物学报, 2015, 23(5): 539-542.
[8] 龚梦鹃, 王立为, 刘新民. 大小鼠游泳实验方法的研究概况 [J]. 中国比较医学杂志, 2005, 15(5): 311-314.
[9] 王俊艳, 刘皓, 刘金宝, 等. 碘过量对后代鼠脑NSE和GFAP表达的影响 [J]. 中国比较医学杂志, 2007, 17(1): 18-21.
[10] 皮天星, 蔡磊明, 蒋金花, 等. 新型阻燃剂TCPP对斑马鱼的毒性研究 [J]. 生态毒理学报, 2016, 11(2): 247-256.
[11] 徐天天. 有机磷阻燃剂对秀丽线虫的慢性毒性 [D]. 华东师范大学, 2017.
[12] Zhao F, Wang J, Fang Y, et al. Effects of tris(1,3-dichloro-2-propyl)phosphate on pathomorphology and gene/protein expression related to thyroid disruption in rats [J]. Toxicol Res, 2016, 5(3): 921-930.
[13] Moser VC, Phillips PM, Hedge JM, et al. Neurotoxicological and thyroid evaluations of rats developmentally exposed to tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) and tris(2-chloro-2-ethyl)phosphate (TCEP) [J]. Neurotoxicol Teratol, 2015, 52(Pt B): 236-247.
[14] Tilson HA, Veronesi B, Mclamb RL, et al. Acute exposure to tris(2-chloroethyl)phosphate produces hippocampal neuronal loss and impairs learning in rats [J]. Toxicol Appl Pharrmacol, 1990, 106(2): 254-269.
[15] Umezu T, Yonemoto J, Soma Y, et al. Tris(2-chloroethyl)phosphate increases ambulatory activity in mice: pharmacological analyses of its neurochemical mechanism [J]. Toxicol Appl Pharmacol, 1998, 148(1): 109-116.
[16] Yuan LL, Li JS, Zha JM, et al. Targeting neurotrophic factors and their receptors, but not cholinesterase or neurotransmitter, in the neurotoxicity of TDCPP in Chinese rare minnow adults (Gobiocypris rarus) [J]. Environ Pollut, 2016, 208(Pt B): 670-677.
[17] Li C, Li L, Lin B, et al. Tris(1,3-dichloro-2-propyl)phosphate induces toxicity by stimulating CaMK2 in PC12 cells [J]. Environ Toxicol, 2017, 32(6): 1-8.
[18] Meeker JD, Stapleton HM. House dust concentrations of organophosphate flame retardants in relation to hormone levels and semen quality parameters [J]. Environ Health Perspect, 2010, 118(3): 318-323.
[19] Wang Q, Liang K, Liu J, et al. Exposure of zebrafish embryos/larvae to TDCPP alters concentrations of thyroid hormones and transcriptions of genes involved in the hypothalamic-pituitary-thyroid axis [J]. Aquat Toxicol, 2013, 126(1): 207-213.
[20] Farhat A, Crump D, Chiu S, et al. In ovo effects of two organophosphate flame retardants — TCPP and TDCPP — on pipping success, development, mRNA expression, and thyroid hormone levels in chicken embryos [J]. Toxicol Sci, 2013, 134(1): 92-102.
[21] An J, Hu J, Shang Y, et al. The cytotoxicity of organophosphate flame retardants on HepG2, A549 and Caco-2 cells [J]. Environ Sci Health A Tox Hazard Subst Environ Eng, 2016, 51(11): 980-988.
[22] Li L, Jiang S, Li K, et al. Assessment of tris(1,3-dichloro-2-propyl)phosphate toxicology in PC12 cells by using digital gene expression profiling [J]. Chemosphere, 2017, 183: 353-360.
[23] Villanueva I, Alva-Sánchez C, Pacheco-Rosado J. The role of thyroid hormones as inductors of oxidative stress and neurodegeneration [J]. Oxid Med Cell Longev, 2013, 2013: 218145.