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Early life lead (Pb) exposure is detrimental to neurobehavioral development. The quality of the environment can modify negative influences from Pb exposure, impacting the developmental trajectory following Pb exposure. Little is known about the molecular underpinnings in the brain of the interaction between Pb and the quality of the environment. We examined relationships between early life Pb exposure and living in an enriched versus a non-enriched postnatal environment on genome-wide transcription profiles in hippocampus CA1. RNA-seq identified differences in the transcriptome of enriched vs. non-enriched Pb-exposed animals. Most of the gene expression changes associated with Pb exposure were reversed by enrichment. This was also true for changes in upstream regulators, splicing events and long noncoding RNAs. Non-enriched rats also had memory impairments; enriched rats had no deficits. The results demonstrate that an enriched environment has a profound impact on behavior and the Pb-modified CA1 transcriptome. These findings show the potential for interactions between Pb exposure and the environment to result in significant transcriptional changes in the brain and, to the extent that this may occur in Pb-exposed children, could influence neuropsychological/educational outcomes, underscoring the importance for early intervention and environmental enrichment for Pb-exposed children.

Introduction Exposure to low levels of lead (Pb) impairs a variety of cognitive processes. Although children exposed to Pb developmentally present with a variety of cognitive impairments that include deficits in learning, memory, language, and executive functioning, experimental work on Pb toxicity in rats has focused mostly on learning and memory deficits and less on executive functions. However, detrimental effects on executive functioning could lead to or even underlie a variety of other cognitive problems attributed to Pb exposure. In this study, we examined the ability of Long Evans rats (control and Pb-exposed: 150ppm Pb-acetate in food given perinatally (gestation through weaning) or early postnatally (EPN, birth through weaning)) to acquire and perform an attention set shifting test (ASST) that requires animals to locate a food reward based on discriminating between digging materials and odors. The task consisted of simple (SD) and compound (CD) discriminations and reversals and intra-dimensional (ID) and extra-dimensional (ED) shifts followed by reversals.