Jie Xie , Lu Ouyang , Jiajun Li , Shuo Yang , Qi Li , Yue Li , Lingyu Yan , Yihong Fu , Qijun Li , Yuting Xia , Xinling Chen , Ziyang Fu , Weipeng Sun , Guihua Du , Fankun Zhou , Chang Feng , Guangqin Fan
{"title":"Chronic low-level exposure to Pb, Hg, and Cd mixture triggers brain premature aging in rat","authors":"Jie Xie , Lu Ouyang , Jiajun Li , Shuo Yang , Qi Li , Yue Li , Lingyu Yan , Yihong Fu , Qijun Li , Yuting Xia , Xinling Chen , Ziyang Fu , Weipeng Sun , Guihua Du , Fankun Zhou , Chang Feng , Guangqin Fan","doi":"10.1016/j.tox.2025.154196","DOIUrl":null,"url":null,"abstract":"<div><div>Lead (Pb), mercury (Hg), and cadmium (Cd), prevalent neurotoxic heavy metals in the environment, are commonly detected at low concentrations in the blood of the general population. Our previous studies demonstrated that Pb, Hg, and Cd mixture induced neurodevelopmental toxicity even at very low levels. However, the long-term effects of low-level Pb, Hg, Cd exposure on brain aging remain unclear. In this study, female rats were exposed to a mixture of 10 mg/L Pb(CH<sub>3</sub>COO)<sub>2</sub>, 0.05 mg/L HgCl<sub>2</sub>, and 3.5 mg/L CdCl<sub>2</sub> via drinking water from mating until offspring weaning. Offspring continued to exposed to heavy metal mixture (3.5 mg/L Pb(CH<sub>3</sub>COO)<sub>2</sub>, 0.015 mg/L HgCl<sub>2</sub>, and 0.5 mg/L CdCl<sub>2</sub>) for 32 weeks. At 52 weeks of age, brain aging was comprehensively evaluated through behavioral testing, histopathological examination, and telomere assessment. The results revealed that prolonged low-level exposure to the Pb, Hg, and Cd mixture compromised telomeric function by shortening telomere length, inhibiting telomerase activity, and induced neuronal loss in the hippocampal CA1 and CA3 regions. Additionally, Golgi staining revealed disrupted dendritic spines in the hippocampus and altered spine-related signaling pathways (Snk-SPAR pathway). Furthermore, behavioral testing showed that exposure to this mixture impaired spatial memory and social cognition. In conclusion, prolonged exposure to low levels of Pb, Hg, and Cd accelerated brain aging by causing hippocampal telomere dysfunction, neuronal loss, dendritic degeneration, and cognitive decline in rats. These findings offer novel insights into the potential neurotoxic effects of chronic exposure to low-level of Pb, Hg, and Cd mixtures on neurological health.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"516 ","pages":"Article 154196"},"PeriodicalIF":4.8000,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Toxicology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0300483X25001556","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
Lead (Pb), mercury (Hg), and cadmium (Cd), prevalent neurotoxic heavy metals in the environment, are commonly detected at low concentrations in the blood of the general population. Our previous studies demonstrated that Pb, Hg, and Cd mixture induced neurodevelopmental toxicity even at very low levels. However, the long-term effects of low-level Pb, Hg, Cd exposure on brain aging remain unclear. In this study, female rats were exposed to a mixture of 10 mg/L Pb(CH3COO)2, 0.05 mg/L HgCl2, and 3.5 mg/L CdCl2 via drinking water from mating until offspring weaning. Offspring continued to exposed to heavy metal mixture (3.5 mg/L Pb(CH3COO)2, 0.015 mg/L HgCl2, and 0.5 mg/L CdCl2) for 32 weeks. At 52 weeks of age, brain aging was comprehensively evaluated through behavioral testing, histopathological examination, and telomere assessment. The results revealed that prolonged low-level exposure to the Pb, Hg, and Cd mixture compromised telomeric function by shortening telomere length, inhibiting telomerase activity, and induced neuronal loss in the hippocampal CA1 and CA3 regions. Additionally, Golgi staining revealed disrupted dendritic spines in the hippocampus and altered spine-related signaling pathways (Snk-SPAR pathway). Furthermore, behavioral testing showed that exposure to this mixture impaired spatial memory and social cognition. In conclusion, prolonged exposure to low levels of Pb, Hg, and Cd accelerated brain aging by causing hippocampal telomere dysfunction, neuronal loss, dendritic degeneration, and cognitive decline in rats. These findings offer novel insights into the potential neurotoxic effects of chronic exposure to low-level of Pb, Hg, and Cd mixtures on neurological health.
期刊介绍:
Toxicology is an international, peer-reviewed journal that publishes only the highest quality original scientific research and critical reviews describing hypothesis-based investigations into mechanisms of toxicity associated with exposures to xenobiotic chemicals, particularly as it relates to human health. In this respect "mechanisms" is defined on both the macro (e.g. physiological, biological, kinetic, species, sex, etc.) and molecular (genomic, transcriptomic, metabolic, etc.) scale. Emphasis is placed on findings that identify novel hazards and that can be extrapolated to exposures and mechanisms that are relevant to estimating human risk. Toxicology also publishes brief communications, personal commentaries and opinion articles, as well as concise expert reviews on contemporary topics. All research and review articles published in Toxicology are subject to rigorous peer review. Authors are asked to contact the Editor-in-Chief prior to submitting review articles or commentaries for consideration for publication in Toxicology.