Years of research show that lead can harm early brain development, but scientists know surprisingly little about how this damage occurs at the cellular level. New findings suggest that lead triggers oxidative stress, or cellular imbalance, in neural stem cells, which could damage the cells at a pivotal point in development. The new study, by Quan Lu, Ph.D., and others at the NIEHS-supported Harvard Superfund Research Program (SRP) center, was published Aug. 26 in the journal Environmental Health Perspectives.
“We have decades of research showing that lead is harmful and we know that children continue to be exposed in their homes and schools,” said Danielle Carlin, Ph.D., NIEHS program officer for the SRP. “Yet scientists previously understood very little about the exact mechanism of effect, which these findings may help explain.”
Oxidative stress in neural stem cells
Neural stem cells help to shape the developing brain and nervous system. Proper development depends on minimal interferences, for example, from foreign chemicals. Previous studies have shown that lead targets neural stem cells, so the researchers at the Harvard T.H. Chan School of Public Health exposed these cells to lead in their lab and examined the changes in gene expression that followed.
They found that 19 genes were expressed differently in lead-exposed cells compared with controls, which indicated cellular changes due to lead exposure. Many of the genes were activated during an oxidative stress response, which is a cell’s distress call after damage.
In particular, many genes were associated with the NRF2 signaling pathway, an established cellular mechanism for oxidative stress response. “We know that NRF2 is activated when cells need protection against injury and inflammation, so it makes sense that lead might trigger this response,” Carlin said.
Relating gene activation with cognitive development
The authors also assessed whether the activated genes were related to children’s cognitive development, language development, and psychomotor development using data from the Early Life Exposures in Mexico and NeuroToxicology (ELEMENT) cohort study. One gene in particular, called SPP1, was related to cognitive development in children, and the authors reported that it may provide a mechanistic link between lead-induced gene expression in neural stem cells and neurodevelopment in children.
“It is known that lead particularly affects the early stages of neurodevelopment, but the underlying molecular mechanisms remain poorly understood. Our study identified one such key mechanism and has potential implications for therapeutics to treat the neurotoxicity associated with lead exposure,” Lu said in a Harvard press release. Lu is an associate professor of environmental genetics and pathophysiology at Harvard and senior author of the study.
Citation: Wagner PJ, Park H-R, Wang Z, Kirchner R, Wei Y, Su L, Stanfield K, Guilarte TR, Wright RO, Christiani DC, Lu Q. 2016. In vitro effects of lead on gene expression in neural stem cells and associations between upregulated genes and cognitive scores in children. Environ Health Perspect; doi:10.1289/ehp265 [Online 26 August 2016].
(Virginia Guidry, Ph.D., is a technical writer and public information specialist in the NIEHS Office of Communications and Public Liaison and a regular contributor to the Environmental Factor.)