Perinatal Lead (PB) Exposure and Cortical Neuron-Specific DNA Methylation in male Mice

Abstract

Lead (Pb) exposure is associated with a wide range of neurological deficits. Environmental exposures may impact epigenetic changes, such as DNA methylation, and can affect neurodevelopmental outcomes over the life-course. Mating mice were obtained from a genetically invariant C57BL/6J background agouti viable yellow Avy strain. Virgin dams (a/a) were randomly assigned 0 ppm (control), 2.1 ppm (low), or 32 ppm (high) Pb-acetate water two weeks prior to mating with male mice (Avy/a), and this continued through weaning. At age 10 months, cortex neuronal nuclei were separated with NeuN+ antibodies in male mice to investigate neuron-specific genome-wide promoter DNA methylation using the Roche NimbleGen Mouse 3x720K CpG Island Promoter Array in nine pooled samples (three per dose). Several probes reached p-value < 10-5, all of which were hypomethylated: 12 for high Pb (minimum false discovery rate (FDR) = 0.16, largest intensity ratio difference = −2.1) and 7 for low Pb (minimum FDR = 0.56, largest intensity ratio difference = −2.2). Consistent with previous results in bulk tissue, we observed a weak association between early-life exposure to Pb and DNA hypomethylation, with some affected genes related to neurodevelopment or cognitive function. Although these analyses were limited to males, data indicate that non-dividing cells such as neurons can be carriers of long-term epigenetic changes induced in development.