Sex- and brain region- specific effects of prenatal stress and lead exposure on permissive and repressive post-translational histone modifications from embryonic development through adulthood

Abstract

Developmental exposure to prenatal stress (PS) and lead (Pb) can affect brain development and adversely influence behavior and cognition. Epigenetic-based gene regulation is crucial for normal brain development and mis-regulation, in any form, can result in neurodevelopmental disorders. Post-translational histone modifications (PTHMs) are an integral and dynamic component of the epigenetic machinery involved in gene regulation. Exposures to Pb and/or PS may alter PTHM profiles, promoting lifelong alterations in brain function observed following Pb ± PS exposure. Here we examined the effects of Pb ± PS on global levels of activating marks H3K9Ac and H3K4Me3 and repressive marks H3K9Me2 and H3K27Me3 at different developmental stages: E18, PND0, PND6 and PND60. Dams were exposed to 0 or 100 ppm Pb beginning 2 months prior to breeding followed by no PS (NS) or PS resulting in 4 offspring treatment groups per sex: 0-NS (control), 0-PS, 100-NS and 100-PS. Global levels of PTHMs varied from E18 through adulthood even in control mice, and were influenced by sex and brain-region. The developmental trajectory of these PTHM levels was further modified by Pb ± PS in a sex-, brain region-and age-dependent manner. Females showed a preferential response to Pb alone in frontal cortex (FC) and differentially to PS alone and combined Pb + PS in hippocampus (HIPP). In males, PS-induced increases in PTHM levels in FC, whereas PS produced reductions in HIPP. Pb ± PS-based changes in PTHM levels continued to be observed in adulthood (PND60), demonstrating the la sting effect of these early life environmental events on these histone marks. These results indicate that epigenetic consequences of Pb ± PS and their contribution to mechanisms of toxicity are sex dependent. Additional studies will assist in understanding the functional significance of these changes in PTHM levels on expression of individual genes, functional pathways, and ultimately, their behavioral consequences.

Lead exposure and child maltreatment as models for how to conceptualize early‐in‐life risk factors for violence

“…One study has shown, for example, that prenatal exposure to lead was associated with hypermethylation of three regions in hippocampal tissue for female, but not male, adult mice (Sánchez-Martín et al, 2015). Another study has shown that prenatal exposure to lead was associated with histone modifications, some of which had sex-and tissue-dependent effects (Schneider, Anderson, Kidd, Sobolewski, & Cory-Slechta, 2016;Varma, Sobolewski, Cory-Slechta, & Schneider, 2017).…”

Developmental lead and/or prenatal stress exposures followed by different types of behavioral experience result in the divergence of brain epigenetic profiles in a sex, brain region, and time-dependent manner: Implications for neurotoxicology

“…Subsequent extension of these studies to a panel of 4 PTHMs (global levels of H3K9ac, H3K4Me3, H3K9Me2 and H3K27Me3) examined at embryonic day 18 and PND0, 6 and 60 in FC and HIPP further underscored these complexities [39]. Sex, brain region and time-dependent changes occurred in controls even in the absence of Pb±PS.…”

“…Results from these studies indicate that at any given time point, global PTHM profiles differ by context, i.e., developmental exposure conditions (control, Pb, PS or Pb+PS), sex and brain region , as summarized in Table 1 adapted from data taken at PND6 from a recently reported study from our laboratories [39]. It presents changes in the expression levels of the 4 PTHMs (H3K9Ac, H3K4Me3, HeK9Me2 and H3K27Me3) as a percent of control group expression levels (100%) for all treatment groups (rows) [39], with arrows indicating direction of change.…”

“…It presents changes in the expression levels of the 4 PTHMs (H3K9Ac, H3K4Me3, HeK9Me2 and H3K27Me3) as a percent of control group expression levels (100%) for all treatment groups (rows) [39], with arrows indicating direction of change. Table 1 shows that Pb alone produced almost no changes in FC or HIPP PTHM expression levels at this time point in males, whereas PS alone increased FC expression levels, but reduced levels in HIPP of all 4 PTHMs, while Pb+PS increased levels of all marks in both FC and HIPP.…”

“…In sum, brain epigenetic responses to such CNS stressors as Pb exposure and PS are not only sex-dependent, but also brain region dependent [37, 39]. Furthermore, these profiles change over time, meaning that conclusions or hypotheses generated from a single point in time, particularly during development, may not reflect trends though development or final adult epigenetic profiles, indicating the significant impact of environmental contexts in determination of these PTHM profiles.…”