Transcriptomic and epigenetic mechanisms of lead (Pb)-induced neurobehavioral disease in aged populations and subsequent generations

PROJECT SUMMARY
A single toxicant exposure during development can produce negative outcomes in adulthood and subsequent
generations, presenting a major hurdle in the prevention and treatment of disease. In addition, given the
susceptibility to toxicants amid degenerative biological and genetic processes, exposure during old age is a
critical sensitive window. Despite their significance, however, the mechanisms that mediate both processes are
poorly understood. Lead (Pb) remains one of ten World Health Organization-identified toxicants of major public
health concern, even though there have been decades-long efforts to manage the routes of environmental
exposure. Numerous studies have demonstrated potent neurotoxic effects of lead exposure on gene
expression and the epigenome, resulting in outcomes such as impaired I.Q., behavioral dysregulation, and
speech and learning deficits. Our long-term goal is to determine how environmental toxicants interfere with
neurobehavior during critical windows so that evidence-based strategies to prevent and treat adult-onset and
transgenerational disease can be developed. The overall objective for this NIEHS R01 Award (PA-20-185)
application is to determine genome function alterations and epigenetic regulation of environmentally-influenced
neurobehavioral phenotypes. The central hypothesis is that environmentally relevant Pb exposure during
critical sensitive windows (early development and old age) lead to genomic and epigenetic dysregulation that
alters neurogenesis pathway function in the exposed and subsequent generations. The rationale for the
proposed research is that investigation of the mechanisms underlying Pb-induced outcomes will advance
prevention, risk-assessment, diagnostic, and treatment strategies. Guided by strong preliminary data, this
hypothesis will be tested by pursuing three specific aims: 1) Determine life stage-specific transcriptomic
changes in neurogenesis pathways following developmental and geriatric exposure to environmentally relevant
Pb levels; 2) Determine emergent changes in the epigenome related to phenotypic and genetic endpoints; 3)
Determine multigenerational and transgenerational transcriptomic and epigenetic changes induced by
ancestral exposure. Ultimately, these results will identify critical windows for biomarkers of effect, and inform
the interplay among pathways mediating toxic endpoints.

Grant Number: 5R01ES034878-03
NIH Institute/Center: NIH
Principal Investigator: Tracie Baker