Developmental Lead Exposure and Prenatal Stress Result in Sex-Specific Reprograming of Adult Stress Physiology and Epigenetic Profiles in Brain

Abstract

Developmental exposure to lead (Pb) and prenatal stress (PS) both impair cognition, which could derive from their joint targeting of the hypothalamic-pituitary-adrenal axis and the brain mesocorticolimbic (MESO) system, including frontal cortex (FC) and hippocampus (HIPP). Glucocorticoids modulate both FC and HIPP function and associated mediation of cognitive and other behavioral functions. This study sought to determine whether developmental Pb ± PS exposures altered glucocorticoid-related epigenetic profiles in brain MESO regions in offspring of female mice exposed to 0 or 100 ppm Pb acetate drinking water from 2 mos prior to breeding until weaning, with half further exposed to prenatal restraint stress from gestational day 11-18. Overall, changes in females occured in response to Pb exposure. In males, however, Pb-induced neurotoxicity was modulated by PS. Changes in serum corticosterone levels were seen in males, while glucocorticoid receptor changes were seen in both sexes. In contrast, both Pb and PS broadly impacted brain DNA methyltransferases and binding proteins, particularly DNMT1, DNMT3a and methyl-CpG-binding protein 2, with patterns that differed by sex and brain regions. Specifically, in males, effects on FC epigenetic modifiers were primarily influenced by Pb, whereas extensive changes in HIPP were produced by PS. In females, Pb exposure and not PS primarily altered epigenetic modifiers in both FC and HIPP. Collectively, these findings indicate that epigenetic mechanisms may underlie associated neurotoxicity of Pb and of PS, particularly associated cognitive deficits. However, mechanisms by which this may occur will be different in males versus females.

Lineage- and Sex-Dependent Behavioral and Biochemical Transgenerational Consequences of Developmental Exposure to Lead, Prenatal Stress, and Combined Lead and Prenatal Stress in Mice

“…Forty randomly chosen young adult females were assigned to receive distilled deionized drinking water or 100 ppm Pb acetate dissolved in distilled deionized drinking water beginning 2 months prior to mating to ensure a body burden of Pb (e.g., skeletal Pb accumulation) consistent with human Pb exposure. These exposure levels are consistent with our prior studies, allowing direct comparisons, and associated with blood Pb levels in mouse offspring at postnatal day 6-7 (PND6-7) of approximately 10-15 lg=dL (Sobolewski et al 2018b;Weston et al 2014), consistent with the Centers for Disease Control and Prevention definition of a level of concern of 10 lg=dL prior to 2012 (CDC 2019b) and within the range of human exposures (Pirkle et al 1994). Relative to the generational time represented in this study, blood leads of 24-36 lg=dL, with the highest exposed children at nearly 60 lg=dL in 1979, were reported in neurotoxicological studies (Needleman et al 1979).…”

“…These consequences can even persist across the life span (Needleman et al 1990;Schwabe et al 2012). Furthermore, in combination, Pb and PS can result in enhanced neurotoxicity as has been seen in both human studies (Tamayo y Ortiz et al 2017) and animal models (Rossi-George et al 2011;Sobolewski et al 2018aSobolewski et al , 2018bVirgolini et al 2006;Weston et al 2014), an outcome likely attributable to the shared biological targets of these two factors, that is, the hypothalamic-pituitary-adrenal (HPA) axis, as well as the brain mesocorticolimbic (MESO) system, a network that includes the frontal cortex, nucleus accumbens, and hippocampus (Barros et al 2004;Berger et al 2002;Jung et al 2019;Martínez-Telléz et al 2009;Rossi-George et al 2011;Virgolini et al 2008b). The potential for combined effects of Pb and PS may be further augmented by the fact that HPA axis and brain MESO neurotransmitter circuits have significant interactions critical to the mediation of executive functions and operant behaviors (Bahari et al 2018;Hernaus et al 2018).…”

“…The potential for combined effects of Pb and PS may be further augmented by the fact that HPA axis and brain MESO neurotransmitter circuits have significant interactions critical to the mediation of executive functions and operant behaviors (Bahari et al 2018;Hernaus et al 2018). Accordingly, a variety of outcomes along the MESO dopamine and stress pathways have been shown sensitive to Pb, PS, or combined Pb and PS during lifelong exposure and developmental exposures in F1 rat offspring (Barros et al 2004;Berger et al 2002;Cory-Slechta et al 1998, 1999Martínez-Telléz et al 2009;Rossi-George et al 2011;Virgolini et al 2008b), including alterations in HPA axis function in rats and mice [serum corticosterone and glucocorticoid receptor (GR) concentrations], in dopaminergic function [alterations in tyrosine hydroxylase (Th), the rate-limiting enzyme in dopamine synthesis], in brain-derived neurotrophic factor (BDNF) concentrations [critical to cognitive function and neuronal differentiation during development], and in behavior [learning of fixed-interval (FI) schedule-controlled behavior] (Sobolewski et al 2018b;Virgolini et al 2006Virgolini et al , 2008bWeston et al 2014). Recently, questions have arisen as to the potential for these phenotypic changes to span multiple generations, particularly questioning whether transgenerational inheritance of such developmental neural reprograming is possible.…”

Fetal and Infant Outcomes in the Offspring of Parents With Perinatal Mental Disorders: Earliest Influences

“…The most common studied epigenetic factor in human research is DNA methylation, which is sensitive to glucocorticoid signaling (166). Epigenetic changes due to cortisol provide a route by which the prenatal environment can impact fetal development, as epigenetic changes due to prenatal stress hormones can directly impact gene activity and functionality during development of the fetal brain and HPA axis (167, 168). Interestingly, not only maternal stress but also paternal prenatal stress has been studied in this context.…”

Are Blood Lead Levels in the United States Still Declining? The US National Health Nutrition and Examination Survey (NHANES) 1999-2016

“…Lead toxicity in children is particularly worrying as they suffer from more serious consequences. In children, high BLLs is a risk factor for cognitive deficits [10][11][12][13] and attention-deficit hyperactivity disorder [14,15]; and chelation therapy seems to be unable to correct the damage [16]. For this reason, efforts have been focusing on reducing environmental exposure to lead through monitoring and regulation.…”