Chandra Naveen, Karimi Benyamin, Bhobe Ankita, Pagadala Susmitha, Pandey Shekhar, Sanchez Sylvia S, Yeung-Luk Bonnie, Rivera Emily, Kohr Mark J, Riess Beth, Nachman Keeve E, Biswal Shyam, Sillé Fenna C M, Graves Austin R
bioRxiv. 2025 Sep 11:2025.09.05.673216. doi: 10.1101/2025.09.05.673216.
Environmental exposure to heavy metals such as lead (Pb), arsenic (As), hexavalent chromium [Cr(VI)], and cadmium (Cd), (PACC), is linked to neurodevelopmental disorders. These metals often co-occur in contaminated environments, but their combined effects on brain development remain poorly understood.
To test the hypothesis that perinatal exposure to a mixture of environmentally relevant levels of Pb, As, Cd, and Cr(VI), causes developmental defects in cognition, behavior, and neuronal function.
Female C57BL/6J mice were exposed to either a single metal or the PACC mixture in drinking water. Exposure began two weeks preconception and continued until weaning at postnatal day 21. Juvenile mice were tested at 4-5 weeks of age in open field (locomotion), novel object recognition (short-term memory), Y-maze (working memory), and elevated plus maze (anxiety-like behavior). A subset of animals underwent Whole-cell patch-clamp recordings in the medial prefrontal cortex (mPFC) and hippocampal CA1 neurons.
Perinatal exposure to PACC metal mixture increased anxiety-like behavior and impaired short-term memory but not locomotion or working memory. Pyramidal neurons in mPFC and hippocampal CA1 displayed increased intrinsic excitability, mPFC neurons also showed elevated amplitude in spontaneous excitatory postsynaptic currents.
Our findings suggest that perinatal exposure to the PACC metal mixture impairs cognition, increases anxiety-like behavior, and alters neuronal function in specific brain regions of juvenile mice, leading to disruption in neuronal function and behavior later in life. Further studies are needed to provide mechanistic insight into how perinatal heavy metal exposure affects neuronal development.
Perinatal exposure to a metal mixture including lead (Pb), arsenic (As), hexavalent chromium (Cr(VI)), and cadmium (Cd), collectively termed PACC metal mixture-impairs cognition and increases anxiety in mice.Neuronal excitability and synaptic transmission are altered in medial prefrontal cortex after PACC metal mixture exposure.PACC mixture exposure decreases short-term memory in both males and females, and increases anxiety in malesPrincipal component and clustering analyses reveal that PACC mixture exposure and control mice form distinct, nonoverlapping populations in physiological-behavioral space.Environmentally relevant PACC metal mixtures exert stronger effects than individual metals alone.
环境中暴露于铅（Pb）、砷（As）、六价铬[Cr(VI)]和镉（Cd）等重金属（PACC）与神经发育障碍有关。这些金属在受污染环境中常同时存在，但其对大脑发育的综合影响仍知之甚少。
验证围产期暴露于环境相关水平的Pb、As、Cd和Cr(VI)混合物会导致认知、行为和神经元功能发育缺陷这一假设。
将雌性C57BL/6J小鼠通过饮用水暴露于单一金属或PACC混合物中。暴露从受孕前两周开始，持续至出生后第21天断奶。在4 - 5周龄时对幼年小鼠进行旷场试验（运动能力）、新物体识别试验（短期记忆）、Y迷宫试验（工作记忆）和高架十字迷宫试验（焦虑样行为）。对一部分动物进行内侧前额叶皮质（mPFC）和海马CA1神经元的全细胞膜片钳记录。
围产期暴露于PACC金属混合物会增加焦虑样行为并损害短期记忆，但不影响运动能力或工作记忆。mPFC和海马CA1中的锥体神经元显示内在兴奋性增加，mPFC神经元的自发兴奋性突触后电流幅度也升高。
我们的研究结果表明，围产期暴露于PACC金属混合物会损害幼年小鼠的认知、增加焦虑样行为并改变特定脑区的神经元功能，导致后期生活中的神经元功能和行为紊乱。需要进一步研究以深入了解围产期重金属暴露如何影响神经元发育。
围产期暴露于包括铅（Pb）、砷（As）、六价铬（Cr(VI)）和镉（Cd）的金属混合物（统称为PACC金属混合物）会损害小鼠的认知并增加焦虑。PACC金属混合物暴露后内侧前额叶皮质的神经元兴奋性和突触传递发生改变。PACC混合物暴露会降低雄性和雌性小鼠的短期记忆，并增加雄性小鼠的焦虑。主成分分析和聚类分析表明，PACC混合物暴露小鼠和对照小鼠在生理 - 行为空间中形成不同的、不重叠的群体。与环境相关的PACC金属混合物比单独的单一金属具有更强的影响。
