Altered genome-wide hippocampal gene expression profiles following early life lead exposure and their potential for reversal by environmental enrichment

Abstract

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.

Neurotoxicity and Outcomes from Developmental Lead Exposure: Persistent or Permanent?

“…In a recent publication from our group, we described relationships between early life lead exposure and living in an enriched vs. a nonenriched postnatal environment on adult genome-wide transcription profiles in the CA1 region of the hippocampus of rats. 18 In this RNA-sequencing study, we found that expression of genes was differentially affected by early postnatal lead exposure and that environmental enrichment further modified the lead-altered transcriptome. “Minimal significant differential gene expression changes were observed as a consequence of living in the enriched environment in normal control animals and the transcriptome of lead-exposed enriched animals was indistinguishable from that of non–lead-exposed control enriched animals.” Remarkably, we also found that living in the enriched environment largely reversed the vast majority of lead-induced alterations to the hippocampal transcriptome.…”

“…“Minimal significant differential gene expression changes were observed as a consequence of living in the enriched environment in normal control animals and the transcriptome of lead-exposed enriched animals was indistinguishable from that of non–lead-exposed control enriched animals.” Remarkably, we also found that living in the enriched environment largely reversed the vast majority of lead-induced alterations to the hippocampal transcriptome. 18 Animals raised in the enriched environment also had no memory deficit, whereas animals raised in a nonenriched environment had a lead-induced memory deficit. Further, “the biological, cellular, or molecular processes that were downregulated due to lead exposure were upregulated by environmental enrichment and vice versa.” 18 The expression of a large number of genes involved in synaptic transmission, plasticity, cytoskeletal regulation, and transcriptional regulation, as well as epigenetic regulators and long noncoding RNAs, were altered by lead exposure, and environmental enrichment, for the most part, reversed these lead exposure-induced alterations in expression.…”

“…Further, “the biological, cellular, or molecular processes that were downregulated due to lead exposure were upregulated by environmental enrichment and vice versa.” 18 The expression of a large number of genes involved in synaptic transmission, plasticity, cytoskeletal regulation, and transcriptional regulation, as well as epigenetic regulators and long noncoding RNAs, were altered by lead exposure, and environmental enrichment, for the most part, reversed these lead exposure-induced alterations in expression. 18 Thus, at least in animal studies, there is evidence for a biological mechanism through which some adverse outcomes from the effects of lead on the brain may be reversible under appropriately stimulating, enriched conditions.…”

“…Molecular and cellular data from animal studies suggest a potential blunting of the capacity for structural and functional plasticity as a consequence of early life lead exposure that is persistent and potentially permanent, with far-reaching negative effects on cognition, behavior, and educational outcomes. However, data on animal models of lead toxicity from this author’s group 18 , 51 , 52 and others 53 , 54 have shown that environmental enrichment can mitigate negative effects of lead exposure on at least some cognitive functions and alter molecular processes in the brain to effectively reverse many lead-induced changes in gene expression. In our study published in 2001, 51 the first to apply environmental enrichment to lead-exposed animals, we found that rearing in nonenriched or enriched environments had no significant effect on learning curves but that being reared in an enriched environment did have a significant effect on spatial memory in the Morris water maze (MWM) in lead-exposed animals.…”

Invited Perspective: Challenging the Dogma of Lead Neurotoxicity

“…For example, preclinical studies on the benefits of these types of enriching interventions on reversing lead-induced learning deficits have uncovered neurobiological mechanism(s) by which they benefit the lead-exposed brain. 22 , 23 …”