Early Life Environment Modifies Behavioral, Epigenetic, and Transcriptional Outcomes from Developmental Lead Exposure

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Various environmental/behavioral factors can influence brain development and subsequent cognitive and be- havioral functioning. Among factors contributing to optimal neurodevelopment are the richness of the postnatal environment and caregiving quality, both of which have been shown to affect brain, behavior, and social devel- opment of offspring. Environmental exposures however, have the ability to derail neural and cognitive/behav- ioral development, with lifelong negative consequences. Developmental exposure to lead (Pb), an important public health problem, can affect all populations, however, members of low socioeconomic status (SES) com- munities are at higher risk of exposure, sustain the highest blood Pb levels, and have adverse outcomes that are potentially more severe. The effects of low SES on cognitive and behavioral development are multifactorial but variations in parental care and quality of the home environment appear to play important roles. How these factors act individually and interact to modulate the brain’s epigenetic and transcriptional responses to Pb ex- posure and affect cognitive/behavioral outcomes has not been examined. Previous studies from our lab and new preliminary data show that DNA methylation in the hippocampus (HIPP) and frontal cortex (FC) and trans- criptional profiles in HIPP are modulated by the quality of the postnatal environment and by Pb exposure, as are associative learning and memory and executive functioning. However, the impact of quality of maternal care has not been examined as an effect modifier in experimental studies of Pb neurotoxicity nor have the combined influences of maternal care and the quality of the post-weaning social environment been studied. Preliminary data show for the first time that quality of maternal care is an important effect modifier of the toxic influences of Pb exposure. Data suggest that different early life experiences may modify the expression of cog- nitive and behavioral deficits produced by developmental Pb exposure and may do so through further altera- tions of methylation and transcriptional profiles initially modified by Pb exposure. The proposed studies will investigate this through the following specific aims: Aim 1: Examine the extent to which variations in social en- vironment and quality of maternal care independently or jointly modify cognitive/behavioral outcomes in males and females with developmental Pb exposure; Aim 2: Identify critical gene-level methylation changes in HIPP, FC, and AMYG (using Methylation Dependent ImmunoPrecipitation sequencing (MeDIP-seq) and Methylation- sensitive Restriction Enzyme digestion sequencing (MRE-seq)) and transcriptional/functional network changes (using RNA-seq) that are affected by developmental Pb exposure and the extent to which altered profiles can be modulated by quality of maternal care and/or environmental enrichment. These studies will provide new in- formation on how environmental/behavioral factors may interact to influence neurodevelopmental vulnerability and resiliency following Pb exposure and provide information relevant to understanding the biological bases of social/behavioral interventions that are translationally relevant for improving outcomes from Pb exposure.