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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES012933-08
Application #
8490660
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Kirshner, Annette G
Project Start
2004-09-24
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
8
Fiscal Year
2013
Total Cost
$362,453
Indirect Cost
$72,764
Name
Wayne State University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
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
Niu, Qi; Wang, Wei; Li, Qian et al. (2014) Percutaneous Fine-Needle 5% Ethanol-Cisplatin Intratumoral Injection Combined with Second-Line Chemotherapy Improves On the Standard of Care in Patients with Platinum-Pretreated Stage IV Non-Small Cell Lung Cancer. Transl Oncol 7:303-8
Cingolani, Pablo; Cao, Xiaoyi; Khetani, Radhika S et al. (2013) Intronic non-CG DNA hydroxymethylation and alternative mRNA splicing in honey bees. BMC Genomics 14:666
Lu, Xiangyi; Xiao, Li; Wang, Luan et al. (2012) Hsp90 inhibitors and drug resistance in cancer: the potential benefits of combination therapies of Hsp90 inhibitors and other anti-cancer drugs. Biochem Pharmacol 83:995-1004
Padilla, Miguel A; Elobeid, Mai; Ruden, Douglas M et al. (2010) An examination of the association of selected toxic metals with total and central obesity indices: NHANES 99-02. Int J Environ Res Public Health 7:3332-47
Elobeid, Mai A; Padilla, Miguel A; Brock, David W et al. (2010) Endocrine disruptors and obesity: an examination of selected persistent organic pollutants in the NHANES 1999-2002 data. Int J Environ Res Public Health 7:2988-3005
Chen, Lang; Page, Grier P; Mehta, Tapan et al. (2009) Single nucleotide polymorphisms affect both cis- and trans-eQTLs. Genomics 93:501-8
Platts, Adrian E; Land, Susan J; Chen, Lang et al. (2009) Massively parallel resequencing of the isogenic Drosophila melanogaster strain w(1118);iso-2;iso-3 identifies hotspots for mutations in sensory perception genes. Fly (Austin) 3:192-203
He, T; Hirsch, H V B; Ruden, D M et al. (2009) Chronic lead exposure alters presynaptic calcium regulation and synaptic facilitation in Drosophila larvae. Neurotoxicology 30:777-84
Hirsch, Helmut V B; Possidente, Debra; Averill, Sarah et al. (2009) Variations at a quantitative trait locus (QTL) affect development of behavior in lead-exposed Drosophila melanogaster. Neurotoxicology 30:305-11

Showing the most recent 10 out of 15 publications