Abstract
Lead (Pb) exposure in early life affects brain development resulting in cognitive and behavioral deficits. Epidemiologic and experimental evidence of sex as an effect modifier of developmental Pb exposure is emerging. In the present study, we investigated Pb effects on behavior and mechanisms of neuroplasticity in the hippocampus and potential sex differences. To this aim, dams were exposed, from one month pre-mating to offspring weaning, to Pb via drinking water at 5 mg/kg body weight per day. In the offspring of both sexes, the longitudinal assessment of motor, emotional, and cognitive end points was performed. We also evaluated the expression and synaptic distribution of N-methyl-D-Aspartate receptor (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits at post-natal day (pnd) 23 and 70 in the hippocampus. Neonatal motor patterns and explorative behavior in offspring were affected in both sexes. Pb effects in emotional response and memory retention were observed in adult females only, preceded by increased levels of GluN2A and GluA1 subunits at the post-synapse at pnd 23. These data suggest that Pb exposure during development affects glutamatergic receptors distribution at the post-synaptic spine in females. These effects may contribute to alterations in selected behavioral domains.
Highlights
Early-life exposure to environmental chemicals interferes with developmental programming and induces subclinical alterations that may result in pathophysiology and behavioral deficits later in life, consistently with the Developmental Origins of Health and Disease (DOHaD) hypothesis [1,2,3]
Blood Pb level considered of concern for neurodevelopmental toxicity in US children decreased from 60 μg/dL in the 1960s to 10 μg/dL in 1991, and 5 μg/dL in 2012
Experimental studies based on low Pb concentrations mirroring human exposure scenarios, assessing simultaneously brain molecular and behavioral outcomes in the two sexes are surprisingly lacking. To address these knowledge gaps, in the present study we investigated the potential contribution of sex to Pb effects on behavior and neuroplasticity in the hippocampus, a brain region previously shown to be sensitive to developmental Pb exposure [37]
Summary
Early-life exposure to environmental chemicals interferes with developmental programming and induces subclinical alterations that may result in pathophysiology and behavioral deficits later in life, consistently with the Developmental Origins of Health and Disease (DOHaD) hypothesis [1,2,3].Lead (Pb) is a systemic toxicant primarily affecting the central nervous system (CNS). Biomonitoring studies show a marked decrease in blood levels as a result of control measures taken to regulate lead in paint, petrol, food cans, and pipes since the 1970s [10,11]. Blood Pb level considered of concern for neurodevelopmental toxicity in US children decreased from 60 μg/dL in the 1960s to 10 μg/dL in 1991, and 5 μg/dL in 2012. The European Food Safety Authority (EFSA) established a 95th percentile lower confidence limit of the benchmark dose of 1% extra risk (BMDL01) of 12 μg blood Pb/L (corresponding to a dietary intake value of 0.50 μg/kg body weight, b.w. per day) as the reference point for intellectual deficits in children measured by the Full Scale IQ score and concluded that there is concern at current levels of Pb exposure for effects on neurodevelopment [19]. In spite of all measures undertaken to reduce environmental sources of exposure, Pb continues to be a public health concern worldwide [20]
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