Researchers from the Harvard T.H. Chan School of Public Health have elucidated the potential molecular mechanism by which lead, a pervasive environmental toxin, harms neural stem cells and neurodevelopment in children.
The results of this study by Quan Lu and his colleagues suggest that exposure to lead leads to oxidative stress, which perturbs cell behavior. However, Lu and his coworkers found that lead also seems to disrupt the function of certain proteins within neural stem cells.
This study resulted from a collaboration between the Departments of Environmental Health, Biostatistics, and Genetics and Complex Diseases and the T.H. Chan School of Public Health, and the Department of Environmental Health Sciences at Columbia University Mailman School of Public Health, and Department of Preventative Medicine, Mount Sinai School of Medicine.
Epidemiological studies that conclusively linked lead exposure to specific health problems. Lu used these valuable studies are married the epidemiological data with the molecular data from his own work. In fact, this paper by Lu and others, is one of the first to integrate genetic analysis in the lab with genomic data from participants in an epidemiological study.
Lead exposure affects the early stages of neurodevelopment, but the underlying molecular mechanisms by which lead affects early childhood development remain poorly understood.
Lu and others in his laboratory identified one key mechanism that might lead to new therapeutic approaches to treat the neurotoxicity associated with lead exposure.
Numerous studies have suggested that lead exposure can harm the cognitive, language, and psychomotor development of children. Lead exposure also increases the risk that children will later engage in antisocial and delinquent behavior.
Although regulatory limits on the use of lead have definitely reduced blood lead levels in U.S., half a million children aged 1-5 in the U.S. have lead blood levels that are twice those deemed safe by the U.S. Centers for Disease Control. Recent incidents of lead contamination in drinking water in Flint, Mich., and several U.S. cities highlight the continued threat.
Outside the U.S., environmental levels of lead remain high in many countries where lead has not, or has only recently, been phased out from gasoline, paint, and other materials.
Lu and his coworkers explored the molecular mechanisms through which exposure to lead may impact neural stem cells. Neural stem cells can differentiate into other kinds of cells in the central nervous system and play a key role in shaping the developing brain.
In this paper, scientists in Lu’s laboratory and his collaborators conducted a genome-wide screen in neural stem cells for genes whose expression is changed during lead exposure. 19 different genes were identified, and many of these 19 genes are known to be regulated by a protein called NRF2. This is a significant finding, since the NRF2 proteins is known to control the oxidative stress response in cells. This led Lu and others to hypothesize that lead exposure induces an oxidative stress response in cells. However, the Lu group and their collaborators identified a new target of NRF2; a gene designated as SPP1 (also known as osteopontin).
Others involved in this work also conducted genetic analyses on blood samples from a group of infants who were part of the Early Life Exposures in Mexico and NeuroToxicology (ELEMENT) prospective birth cohort. The ELEMENT study was designed to assess the roles of environmental and social factors in birth outcomes and in infant and child development.
Data from the ELEMENT study showed that genetic variants in SPP1 in some blood samples that were statistically linked to abnormal cognition development in those children, whose neurodevelopmental progress was followed through age two. This suggests that lead exerts its deleterious effects, in part, through SPP1. Therefore, drugs that target SPP1 might provide protection against lead exposure in at-risk children.
This paper appeared here: Peter Wagner et al., “In Vitro Effects of Lead on Gene Expression in Neural Stem Cells and Associations between Upregulated Genes and Cognitive Scores in Children,” Environmental Health Perspectives, 2016; DOI: 10.1289/EHP265.