Manganese (Mn) is an essential trace element and an established neurotoxicant with complex pharmacology. In the parent grant, ?Motor and Cognitive Health Outcomes in a Manganese-Exposed African Community,? we are conducting a population-based epidemiology study of Mn-exposed adults living near a large Mn smelter in Meyerton, South Africa, to investigate the association between environmental Mn exposure, at ambient levels below current Environmental Protection Agency regulatory levels, and motor, cognitive control, and mood dysfunction. This ViCTER proposal expands the scope of the parent human epidemiology study by including exploratory biomarker development, and initiating a deeper mechanistic understanding of the negative impact of Mn exposure on neurocognitive functions using in vitro human neuronal cell culture models and in vivo Drosophila Mn exposure models. These new aims will investigate the hypothesis that Mn exposure can lead to poor phenotypic outcomes via epigenetic processes driven by the synthesis and secretion of small, non-coding RNAs, known as micro RNAs (miRNAs). Growing evidence suggests that Mn is directly involved in the synthesis of miRNAs, and that miRNAs play a significant role in the pathogenesis of many chronic diseases, by repressing translation and regulating degradation of their target mRNAs. In this proposal, we take the unique approach of using cellular and Drosophila models of Mn toxicity to identify specific miRNAs associated with Mn exposure in vivo in humans, which will be used to identify specific human miRNAs from across the entire genome that may serve as biomarkers of Mn exposure and related health outcomes. We will also explore and confirm gene targets of the identified miRNA biomarkers. Ultimately, this ViCTER will generate novel data that will link environmental Mn exposure to biomarkers that could be used to monitor exposed communities and may contribute to a better understanding of mechanisms of Mn-induced human neurotoxicity. The expanded scope of this proposal will provide unprecedented bidirectional data from humans and model systems to investigate this important and common neurotoxicant.
In this ViCTER application, we propose to develop biomarkers of environmental manganese (Mn) exposure and health outcomes in the ?Motor and Cognitive Health Outcomes in a Mn-Exposed African Community? study using a discovery process derived from in vitro and in vivo model systems of environmental Mn exposure. This bidirectional flow of data between model systems and human epidemiology will provide new insights into disease mechanisms and will further expand the public health implications of the parent study.
|Ben-Shahar, Yehuda (2017) Epigenetic switch turns on genetic behavioral variations. Proc Natl Acad Sci U S A 114:12365-12367|