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Matthew D. Rand, Ph.D.

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Neural developmental toxicity of methylmercury.

Dr. Rand's research focuses on the mechanisms of neural developmental toxicity of the persistent environmental toxin methylmercury (MeHg). Human exposure to MeHg through dietary intake of fish continues to be a major health concern. MeHg preferentially targets the developing nervous system leaving the fetus and young children at greatest risk from exposure. However, considerable uncertainty remains as to the risk of MeHg versus the benefit of essential nutrients in a fish diet. Further uncertainty stems from the wide range of inter-individual variability seen in neurological outcomes, both with MeHg-exposed laboratory animals and in human epidemiological studies of children in fish eating populations.

Our laboratory is engaged in several research projects elucidating molecular, cellular and genetic mechanisms of neural development responsible for variation in tolerance or susceptibility to MeHg toxicity. We are executing transcriptomic and genome wide association methods in the Drosophila model to elucidate fundamental genes that influence tolerance and susceptibility phenotypes in fruit flies developmentally exposed to MeHg. Assays are being conducted at the embryonic and larval/pupal developmental stages using functional assays that target transgenes to neural and non-neural tissues. Candidate genes from Phase I (Cytochrome p450), Phase II (Glutathione S-transferases, GCLm, GCLc) and Phase III (multidrug resistance like protein, MRP1, ABCC1) xenobiotic metabolism pathways have been identified, either through unbiased screens or prospective functional assays, as major effectors of MeHg tolerance and susceptibility. A role for these conventional metabolism genes, specifically in developing neurons, is being characterized. In addition, human homologs of these genes, carrying polymorphic variations known to associate with varied MeHg metabolism in people, are being functionally characterized in this Drosophila system. We are also investigating the role of dietary and nutritional supplements in modifying the MeHg effect in development. With this approach we have identified a protective function for caffeine, and are further investigating the potential protective mechanisms of vitamin E and selenium in MeHg toxicity.

Additional studies are exploiting a novel method developed in the lab to introduce acute doses of small molecules through the eggshell of viable Drosophila embryos. allow us to identify the most MeHg-sensitive window of neural development. These studies, together with studies investigating localization of MeHg in target organs of developing fruit fly larvae with X-Ray fluorescence imaging, are establishing the Drosophila model as a premier platform for basic research in toxicology. In addition, we are initiating studies to develop biomarkers and a protocol to determine MeHg metabolism rates in individual people. These latter studies are aimed at translating our functional studies of Phase I-III metabolism genes in MeHg toxicity to understanding the genetic basis of variation in MeHg susceptibility in populations and in individuals.



B.S. | University of New Hampshire

Ph.D. | University of Vermont, College of Medicine

Post-doctoral Training & Residency

1998 - 2000
Research Fellow. Harvard Medical School, Cancer Center, Massachusetts General Hospital, Charlestown, MA. Advisor: Spyros Artavanis-Tsakonas, Ph.D. Research interests: Mechanisms of signal transduction in neurogenesis. Biochemical characterization of Notch receptor interaction with the Delta ligand. The role of the ADAM metalloprotease Kuzbanian in the proteolytic processing of the Notch ligands.

1997 - 1998
Research Fellow. Howard Hughes Medical Institute, Department of Cell Biology, Yale University School of Medicine, New Haven, CT. Advisor: Spyros Artavanis- Tsakonas, Ph.D. Research Interests: Interaction of the Notch receptor with its ligand Delta at the cellular level. Proteolytic processing of the Notch receptor and the Delta ligand.

1995 - 1997
Postdoctoral Fellowship. Department of Clinical Chemistry, Lund University, University Hospital, Malmo, Sweden. Advisor: Johan Stenflo, MD., Ph.D. Research Interests: Expression and characterization of tandem calcium-binding epidermal growth factor-like (EGF) modules from the ligand binding region of the human Notch receptor.

1991 - 1995
Doctoral Training- Department of Biochemistry, College of Medicine, University of Vermont, Burlington, VT. Advisor: Kenneth G. Mann, Ph.D. Research Interests: Phosphorylation of the coagulation cofactor factor Va by platelet kinasis. Characterization and determination of clearance rates of baboon factor V/Va. Development of a novel assay system to simultaneously quantitate activation of coagulation factors, inhibitor-enzyme complex formation and platelet activation during extrinsic pathway initiated clotting in whole blood.

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UVM,"Inventor Hall of Fame"
Sponsor: For co-invention of a patent with successful commercialization
Location: Office of Technology Transfer, UVM- Burlington, VT.


Journal Articles

Rand MD, Tennessen JM, Mackay TFC, Anholt RRH. "Perspectives on the Drosophila melanogaster Model for Advances in Toxicological Science." Current protocols.. 2023 Aug; 3(8):e870.

Coe GL, Krout IN, Munro-Ehrlich M, Beamish CR, Vorojeikina D, Colman DR, Boyd EJ, Walk ST, Rand MD. "Assessing the role of the gut microbiome in methylmercury demethylation and elimination in humans and gnotobiotic mice." Archives of toxicology.. 2023 Jul 1; Epub 2023 Jul 01.

Krout IN, Scrimale T, Rand MD. "Targeted Intracellular Demethylation of Methylmercury Enhances Elimination Kinetics and Reduces Developmental Toxicity in Transgenic Drosophila." Toxicological sciences : an official journal of the Society of Toxicology.. 2022 Oct 6; Epub 2022 Oct 06.

Books & Chapters

Chapter Title: Methylmercury Effects on Neural Developmental Signaling Pathways.
Book Title: Developmental Neurotoxicology Research: Principles, Models, Techniques, Strategi
Author List: Wand, C, and Slikker, W. Eds.
Published By: John Wiley & Sons., 2011. 2011