Abstract:To explore the combined toxic effect of formaldehyde and DEHP on learning and memory of mice and the mechanism, Kunming mice were randomly divided into 14groups:(1) the control group; (2) FA (formaldehyde) group:0.5mg/m3, 1mg/m3, 3mg/m3; (3) DEHP group:5mg/kg, 50mg/kg, 500mg/kg; (4) the joint exposure:0.5mg/m3 +5mg/kg, 1mg/m3 +50mg/kg, 3mg/m3 +500mg/kg; (5) VE group:saline+VE (100mg/kg), FA3.0mg/m3 + VE, DEHP500mg/kg + VE, FA3.0mg/m3 + DEHP500mg/kg + VE. The mice of FA and joint exposure groups were exposed to gaseous formaldehyde for 8h everyday (continuous exposure for 5days, interval for two days), and the mice of DEHP and joint exposure groups were gavaged with DEHP solution. Besides, blocking groups were also gavaged VE solution (100mg/kg) everyday. Their behaviors of learning and memory were tested by Morris water maze experiment. Then the change of biological indicators including oxidative damage, ROS, MDA, TNF-α, IL-β, and 5-HT, etc, was detected in the cerebral tissue. Results showed that Morris water maze test in space training and learning indicated that escape latency significantly extended in 3.0mg/m3 of formaldehyde and 500mg/kg of DEHP treatment group, 1.0mg/m3 +50mg/kg and 3.0mg/m3 +500mg/kg of the combined treatment groups (P<0.05). Compared with single exposure groups, escape latency significantly extended in the moderate and high dose of combined treatment groups (P<0.05). In space exploration experiments, the proportion of time of the target quadrant in 1.0mg/m3 and 3.0mg/m3 of formaldehyde treatment groups, the 500mg/kg of DEHP treatment group, and 1.0mg/m3 +50mg/kg, 3.0mg/m3 +500mg/kg of the combined treatment groups were less than the control group (P<0.05). The proportion of time of the target quadrant in combined treatment groups were significantly decreased compared with single exposure (P<0.05). Compared with control group,the contents of ROS and MDA in 1.0mg/m3 and 3.0mg/m3 of formaldehyde, 50mg/kg and 500mg/kg of DEHP groups and all the joint exposure groups were increased, while the contents of GSH decreased in 3.0mg/m3 of formaldehyde, 500mg/kg of DEHP groups and all the joint exposure groups decreased. Compared with formaldehyde or DEHP exposure groups, the contents of GSH in joint exposure groups were significantly decreased (P<0.01). The expression level of inflammatory factor TNF-α and IL-β were also significantly increased, and Caspase-3 was activated. The content of 5-HT in 3.0mg/m3 +500mg/kg of joint exposure group was significantly decreased (P<0.01). 0.5mg/m3 of formaldehyde had little effect on mice and their behaviors of learning and memory didn't obviously change. This study shows that 1.0mg/m3 and 3.0mg/m3 of formaldehyde and 500mg/kg of DEHP treatment group and 1.0mg/m3 +50mg/kg, 3.0mg/m3 +500mg/kg of the combined treatment groups could cause Kunming mice oxidative damage and inflammation. The joint exposure of formaldehyde and DEHP has synergistic effect. And VE could protect brain tissue by reducing Oxidative stress, inflammation, the level of Caspase-3, and increasing the content of 5-HT.
陆林洁, 蔡洁, 安结然, 杜俊停, 丁书茂. 甲醛与DEHP联合染毒对小鼠学习记忆能力的影响[J]. 中国环境科学, 2017, 37(12): 4751-4762.
LU Lin-jie, CAI Jie, AN Jie-ran, DU Jun-ting, DING Shu-mao. Joint toxic effect of formaldehyde and DEHP on learning and memory of mice. CHINA ENVIRONMENTAL SCIENCECE, 2017, 37(12): 4751-4762.
Tang X, Bai Y, Duong A, et al. Formaldehyde in China:Production, consumption, exposure levels, and health effects[J]. Environment International, 2009,35(8):1210-1224.
[2]
Sul D, Kim H, Oh E, et al. Gene expression profiling in lung tissues from rats exposed to formaldehyde[J]. Archives of Toxicology, 2007,81(8):589-597.
Kerns W, Pavkov K, Donofrio D, et al. Carcinogenicity of formaldehyde in rats and mice after long-term inhalation exposure[J]. Cancer research, 1983,43(9):4382-4392.
[6]
Arts J, Rennen M, De Heer C. Inhaled formaldehyde:evaluation of sensory irritation in relation to carcinogenicity[J]. Regulatory Toxicology and Pharmacology, 2006,44(2):144-160.
Takashima K, Ito Y, Gonzalez F, et al. Different mechanisms of DEHP-induced hepatocellular adenoma tumorigenesis in wild-type and Pparα-null mice[J]. Journal of Occupational Health, 2008,50(2):169-180.
[10]
Manikkam M, Tracey R, Guerrero-Bosagna C, et al. Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations[J]. PloS One, 2013,8(1):583-587.
[11]
Lu X, Liu Q, Jin C, et al. Study on neurotoxicity and lipid peroxidation of brain after exposure to DEHP in rats] [J]. Journal of Shenyang Medical College, 2008,4(2):198-201.
[12]
Pitten F, Kramer A, Herrmann K, et al. Formaldehyde neurotoxicity in animal experiments[J]. Pathology-Research and Practice, 2000,196(3):193-198.
[13]
Malek F, Möritz K, Fanghänel J. Effects of a single inhalative exposure to formaldehyde on the open field behavior of mice[J]. International Journal of Hygiene and Environmental Health, 2004,207(2):151-158.
Halliwell B. Oxidative stress and neurodegeneration:where are we now?[J]. Journal of Neurochemistry, 2006,97(6):1634-1658.
[19]
Reviews of environmental contamination and toxicology[M]. Springer, 2012.
[20]
Irmak M, Fadillioglu E, Sogut S, et al. Effects of caffeic acid phenethyl ester and alpha tocopherol-on reperfusion injury in rat brain[J]. Cell Biochemistry and Function, 2003,21(3):283-289.
[21]
Das M, Babu K, Reddy N, et al. Oxidative damage of plasma proteins and lipids in epidemic dropsy patients:alterations in antioxidant status[J]. Biochimica et Biophysica Acta (BBA)-General Subjects, 2005,1722(2):209-217.
[22]
Ga?a?yn-Sidorczuk M, Brzóska M, Jurczuk M, et al. Oxidative damage to proteins and DNA in rats exposed to cadmium and/or ethanol[J]. Chemico-Biological Interactions, 2009,180(1):31-38.
[23]
Xiao G, Wang M, Li N, et al. Use of proteomics to demonstrate a hierarchical oxidative stress response to diesel exhaust particle chemicals in a macrophage cell line[J]. J. Biol. Chem., 2003, 278(50):50781-50790.
[24]
Brown D, Donaldson K, Borm P, et al. Calcium and ROSmediated activation of transcription factors and TNF-α cytokine gene expression in macrophages exposed to ultrafine particles[J]. American Journal of Physiology-Lung Cellular and Molecular Physiology, 2004,286(2):L344-L353.
[25]
Shankar E, Vykhovanets E, Vykhovanets O, et al. High fat diet-activates pro inflammatory-response in the prostate through association of Stat-3and NF-κB[J]. The Prostate, 2012,72(3):233-243.
[26]
Metz B, Kersten G, Hoogerhout P, et al. Identification of formaldehyde-induced modifications in proteins reactions with model peptides[J]. Journal of Biological Chemistry, 2004,279(8):6235-6243.
[27]
Gurel A, Coskun O, Armutcu F, et al. Vitamin E against oxidative damage caused by formaldehyde in frontal cortex and hippocampus:biochemical and histological studies[J]. Journal of Chemical Neuroanatomy, 2005,29(3):173-178.