Perinatal Exposure to Metal Mixtures Disrupts Neuronal Function and Behavior

Abstract

BackgroundEnvironmental 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. ObjectiveTo 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. MethodsFemale 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. ResultsPerinatal 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. DiscussionOur 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. HighlightsO_LIPerinatal 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. C_LIO_LINeuronal excitability and synaptic transmission are altered in medial prefrontal cortex after PACC metal mixture exposure. C_LIO_LIPACC mixture exposure decreases short-term memory in both males and females, and increases anxiety in males C_LIO_LIPrincipal component and clustering analyses reveal that PACC mixture exposure and control mice form distinct, nonoverlapping populations in physiological-behavioral space. C_LIO_LIEnvironmentally relevant PACC metal mixtures exert stronger effects than individual metals alone. C_LI