Zhu Yu-Peng, Xi Shu-Hua, Li Ming-Yan, Ding Ting-Ting, Liu Nan, Cao Fu-Yuan, Zeng Yang, Liu Xiao-Jing, Tong Jun-Wang, Jiang Shou-Fang
Department of Occupational and Environmental Health, Hebei Province Key Laboratory of Occupational Health and Safety for Coal Industry, School of Public Health, North China University of Science and Technology, Tangshan, Hebei, PR China.
Department of Occupational and Environmental Health, Liaoning Provincial Key Lab of Arsenic Biological Effect and Poisoning, School of Public Health, China Medical University, Shenyang, Liaoning, PR China.
Neurotoxicology. 2017 Mar;59:56-64. doi: 10.1016/j.neuro.2017.01.006. Epub 2017 Jan 15.
Fluoride and arsenic are inorganic contaminants that occur in the natural environment. Chronic fluoride and/or arsenic exposure can induce developmental neurotoxicity and negatively influence intelligence in children, although the underlying molecular mechanisms are poorly understood. This study explored the effects of fluoride and arsenic exposure in drinking water on spatial learning, memory and key protein expression in the ERK/CREB signaling pathway in hippocampal and cerebral cortex tissue in rat offspring. Pregnant rats were divided into four groups. Control rats drank tap water, while rats in the three exposure groups drank water with sodium fluoride (100mg/L), sodium arsenite (75mg/L), and a sodium fluoride (100mg/L) and sodium arsenite (75mg/L) combination during gestation and lactation. After weaning, rat pups drank the same solution as their mothers. Spatial learning and memory ability of pups at postnatal day 21 (PND21) and postnatal day 42 (PND42) were measured using a Morris water maze. ERK, phospho-ERK (p-ERK), CREB and phospho-CREB (p-CREB) protein expression in the hippocampus and cerebral cortex was detected using Western blot. Compared with the control pups, escape latencies increased in PND42 pups exposed to arsenic and co-exposed to fluoride and arsenic, and the short-term and long-term spatial memory ability declined in pups exposed to fluoride and arsenic, both alone and in combination. Compared with controls, ERK and p-ERK levels decreased in the hippocampus and cerebral cortex in pups exposed to combined fluoride and arsenic. CREB protein expression in the cerebral cortex decreased in pups exposed to fluoride, arsenic, and the fluoride and arsenic combination. p-CREB protein expression in both the hippocampus and cerebral cortex was decreased in pups exposed to fluoride and arsenic in combination compared to the control group. There were negative correlation between the proteins expression and escape latency periods in pups. These data indicate that exposure to fluoride and arsenic in early life stage changes ERK, p-ERK, CREB and p-CREB protein expression in the hippocampus and cerebral cortex of rat offspring at PND21 and PND 42, which may contribute to impaired neurodevelopment following exposure.
氟化物和砷是自然环境中存在的无机污染物。长期接触氟化物和/或砷可诱发发育性神经毒性，并对儿童智力产生负面影响，尽管其潜在分子机制尚不清楚。本研究探讨了饮用水中氟化物和砷暴露对大鼠子代海马和大脑皮质组织中空间学习、记忆及ERK/CREB信号通路关键蛋白表达的影响。将怀孕大鼠分为四组。对照组大鼠饮用自来水，而三个暴露组的大鼠在妊娠和哺乳期饮用含氟化钠（100mg/L）、亚砷酸钠（75mg/L）以及氟化钠（100mg/L）与亚砷酸钠（75mg/L）混合物的水。断奶后，幼鼠饮用与母鼠相同的溶液。使用Morris水迷宫测量出生后第21天（PND21）和第42天（PND42）幼鼠的空间学习和记忆能力。采用蛋白质免疫印迹法检测海马和大脑皮质中ERK、磷酸化ERK（p-ERK）、CREB和磷酸化CREB（p-CREB）蛋白的表达。与对照幼鼠相比，暴露于砷以及同时暴露于氟化物和砷的PND42幼鼠逃避潜伏期延长，单独或联合暴露于氟化物和砷的幼鼠短期和长期空间记忆能力下降。与对照组相比，同时暴露于氟化物和砷的幼鼠海马和大脑皮质中ERK和p-ERK水平降低。暴露于氟化物、砷以及氟化物和砷混合物的幼鼠大脑皮质中CREB蛋白表达降低。与对照组相比，同时暴露于氟化物和砷的幼鼠海马和大脑皮质中p-CREB蛋白表达均降低。幼鼠中蛋白表达与逃避潜伏期之间存在负相关。这些数据表明，生命早期阶段暴露于氟化物和砷会改变大鼠子代在PND21和PND42时海马和大脑皮质中ERK、p-ERK、CREB和p-CREB蛋白的表达，这可能导致暴露后神经发育受损。
