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.

Trimester-Specific Associations of Prenatal Lead Exposure With Infant Cord Blood DNA Methylation at Birth

“…Our study is one of a growing body of literature that shows associations between gestational Pb exposure and offspring DNA methylation in rodent models and humans. [17][18][19][20][71][72][73] While the DMPs and DMRs identified in this study by T1 and T3 maternal BLL and maternal bone Pb were not the same as those previously reported in other cohorts, collectively these studies show that Pb exposure and DNA methylation vary by timing of exposure, sex, and population. A rural Bangladesh birth cohort study with high environmental Pb exposure performed epigenome-wide DNA methylation profiling using the Infinium HumanMethylation450K BeadChip (450K) on UCB and assessed its association with prenatal Pb exposure measured in maternal urine at 8 weeks' gestation and in maternal erythrocytes at 14 weeks' gestation (n = 127).…”

Prenatal Lead (Pb) Exposure and Peripheral Blood DNA Methylation (5mC) and Hydroxymethylation (5hmC) in Mexican Adolescents from the ELEMENT Birth Cohort

“…Prenatal and early-life Pb exposures have been associated with altered DNA methylation patterns, which serve as potential mechanistic links for Pb-induced health effects ( Dou et al. 2019 ; Montrose et al.…”

Association Between miR-148a and DNA Methylation Profile in Individuals Exposed to Lead (Pb)

“…For example, Zhang et al (2019) observed alterations in DNA methylation profile of 356 significant CpG sites of blood cells, and these changes were related to the levels of exposure to the metal, in workers from car battery facilities, in China; Li et al (2013) demonstrated that individuals exposed to Pb levels similar to those found in our study (21 μg dl –1 ) had lower % of DNA methylation assessed by LINE-1 than the non-exposed ones (3.7 μg dl –1 ). Besides, associations between Pb exposure and DNA hypomethylation were also seen in animal laboratory models ( Dou et al, 2019 ; Nakayama et al, 2019 ).…”