Influence of developmental lead exposure on expression of DNA methyltransferases and methyl cytosine-binding proteins in hippocampus

Abstract

Developmental exposure to lead (Pb) has adverse effects on cognitive functioning and behavior that can persist into adulthood. Exposures that occur during fetal or early life periods may produce changes in brain related to physiological re-programming from an epigenetic influence such as altered DNA methylation status. Since DNA methylation is regulated by DNA methyltransferases and methyl cytosine binding proteins, this study assessed the extent to which developmental Pb exposure might affect expression of these proteins in the hippocampus. Long Evans dams were fed Pb-containing food with or without added Pb acetate (0, 150, 375, 750 ppm) prior to breeding and stayed on the same diet through weaning (perinatal exposure group). Other animals were exposed to the same doses of Pb but exposure started on postnatal day 1 and continued through weaning (early postnatal exposure group). All animals were euthanized on day 55 and hippocampi were removed. Western analyses showed significant effects on DNMT1, DNMT3a, and MeCP2 expression, with effects often seen at the lowest level of exposure and primarily modified by sex and developmental window of Pb exposure. These data suggest potential epigenetic effects of developmental Pb exposure on DNA methylation mediated at least in part through dysregulation of methyltransferases.

Seven-Year Neurodevelopmental Scores and Prenatal Exposure to Chlorpyrifos, a Common Agricultural Pesticide

“…In this study, there was a significant increase in Pb levels in patients with ASD compared with the control group, coupled with a correlation between Pb concentration and the severity of SRS and CARS scores. These observations support a recent study on patients with ASD by Schneider et al (2013) [24], who suggested potential epigenetic effects of developmental Pb exposure on DNA methylation. These effects were mediated at least partially through the dysregulation of methyltransferases as multiple forms of proteins, at least some of which are potentially involved in cognition [25], and the resulting abnormalities were recorded in patients with ASD [26].…”

Evaluation of passive avoidance learning and spatial memory in rats exposed to low levels of lead during specific periods of early brain development

“…Lead alters the expression of the NMDAR subunits resulting in the defective NMDAR structure affecting the hippocampal development and maturation [35,36,40]. Lead is believed to influence the expression of hippocampal DNA methyltransferases and methyl cytosine-binding proteins which are involved in early brain development process [41]. Lead exposure from the gestation day 0 to the postnatal day 21 in rats, enhances oxidative stress and alters the apoptosis process in developing hippocampal neurons [42].…”

Adverse Outcome Pathway on binding of agonists to ionotropic glutamate receptors in adult brain leading to excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment

“…In addition, aggregation of the amyloid peptide β was particularly enhanced in these monkeys after re-exposure to Pb 2+ . These epigenetic modifications may be due to DNA methylation mediated in part through lead-induced dysregulation of methyltransferases (Schneider et al, 2013). The particular sensitivity of cortical areas to heavy metal exposure together with the increase of amyloid peptide deposition suggest a link between heavy metal exposure and Alzheimer's pathology (Castoldi et al, 2008;.…”