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Article Title: Gene Regulation and Epigenetic Effects of Lead Exposure


Embryonic life is a time when organisms are most sensitive to environmental signals, responding to cues with extreme phenotypic plasticity. Developmental plasticity however, often gives rise to maladaptive pathophysiological consequences in the embryo or in later adult life, as is the case with the responses to lead exposure. Developmental exposure to lead (Pb), an ubiquitous environmental contaminant, causes deficits in cognitive functions and IQ, behavioral effects, and attention deficit hyperactivity disorder. Long-term effects observed after early life exposure include reduction of gray matter, alteration of myelin structure, and increment of criminal behavior in adults. Despite growing research interest, the molecular mechanisms responsible for the effects of lead in the central nervous system are still largely unknown. We have developed an embryonic stem cell model of Pb exposure during neural differentiation that promises to be useful to analyze mechanisms of neurotoxicity induced by Pb and other environmental agents. We also used DNA methylation analyses to determine whether perinatal exposure to lead acetate in mice was associated with persistent DNA methylation changes. We find a highly significant sex- and tissue-dependent change in DNA methylation in the brains of exposed mice, negatively correlated with gene expression levels. Females showing greater hypermethylation than males. Lead exposure during embryonic life appears to have a sex- and tissue-specific effect that may produce pathological or physiological deviations from the epigenetic plasticity of unexposed mice. Further analyses to correlate DNA methylation and regulatory gene expression changes will be crucial to understand the mechanisms of lead neurotoxicity.