Human activity has resulted in the environmental distribution of many toxic substances, among them the heavy metals that are spread throughout our biosphere. In addition to the acute toxic effects to humans exposed to lead (i.e. in lead paint or in contaminated drinking water) there are more insidious effects of chronic exposure on the development of all organisms. Children exposed to low levels of lead have altered developmental processes, and these children develop symptoms such as hyperactivity, changes in sensory function, and changes in cognitive abilities ("IQ"). We have made considerable progress during the first 5 years of this project in using Drosophila as a model organism to study the effects of lead exposure during development by using: (1) the sophisticated under-standing of its genetics, and the ease of manipulating its genome;(2) the availability of behavioral and morphological assays sensitive to small effects of very low doses of lead. There is a great deal of variability in the sensitivity of lead exposure, and both human and Drosophila cells are thought to induce expression of "protective genes" upon exposure to lead. Behavior is an especially sensitive end point of lead-induced neurotoxicity because it is a net result of sensory, motor, and cognitive functions in the nervous system. The hypothesis for this proposal is that one can identify some of the "protective genes" that make an organism resistant to the behavioral and developmental effects of lead toxicity using quantitative trait loci (QTL) mapping techniques combined with microarray and sophisticated genetic analyses. To test this hypothesis, we propose 3 Aims.
Aim 1 Identify the genes that affect locomotor activity and gene expression at marker loci 30AB and 50DF.
Aim 2 is to identify new QTLs that are involved in calcium conduction at the larval synapse.
Aim 3 is to translate our findings from flies to humans exposed to lead from the environment. In this aim, we will determine whether specific CpG site DNA methylation levels correlate with lead levels in blood collected from children in the Detroit metropolitan area. Results of these studies will identify candidates for the most important genes that are altered during lead exposure in humans, and could well lead to bioassays or treatments for heavy metal exposure in humans.
Over 120 million people in the world have blood lead levels of greater than 10 micrograms per deciliter, which is considered the 'safe level'by the Centers for Disease Control. We are continuing a project that uses sophisticated genetics and genomics techniques to understand why some strains of Drosophila are more sensitive to the neurotoxicological effects of lead. In the next 5 year period, we will begin studies to see how lead affects DNA methylation in children with high blood levels and determine the common regulatory mechanisms between Drosophila and humans.
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|Sen, Arko; Cingolani, Pablo; Senut, Marie-Claude et al. (2015) Lead exposure induces changes in 5-hydroxymethylcytosine clusters in CpG islands in human embryonic stem cells and umbilical cord blood. Epigenetics 10:607-21|
|Sen, Arko; Heredia, Nicole; Senut, Marie-Claude et al. (2015) Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren. Sci Rep 5:14466|
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|Senut, Marie-Claude; Sen, Arko; Cingolani, Pablo et al. (2014) Lead exposure disrupts global DNA methylation in human embryonic stem cells and alters their neuronal differentiation. Toxicol Sci 139:142-61|
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