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Of Fish and Fruit Flies

Recent grant funds research to discover how mercury harms the developing nervous system

By Jennifer Nachbur Article published August 30, 2007

Matthew Rand
Into the Notch: Neurobiologist Matthew Rand is using fruit flies to explore how mercury affects the Notch receptor protein, which is crucial to embryonic neural development. (Photo: UVM Medical Photography)

Mercury is a poison that can show up on dinner plates (lurking in seafood like swordfish), in air, water and soil (often from coal-burning power plants), and even in medicine cabinets (via old thermometers).

The news gets worse. In watersheds, mercury is converted to methylmercury, or MeHg, and becomes more biologically active and potentially harmful to humans and animals. Despite clear evidence of the neurotoxic effects of MeHg, scientists do not have a strong understanding of exactly how it harms the developing nervous system.

Neurobiologist Matthew Rand, research assistant professor of anatomy and neurobiology, wants to help change that. His team’s goal is to distinguish the primary means by which MeHg causes neurotoxicity in human neural development. Rand recently received a $1.4 million grant from the National Institute of Environmental Health Sciences to continue his research to identify the genes that respond to methylmercury, as well as those that are resistant to it. This effort may one day help direct future strategies of clinical treatment of MeHG toxicity.

Mercury is a real and growing problem. High-level exposure can cause damage to the brain, heart, kidneys, lungs and immune system according to the Environmental Protection Agency. “The bioaccumulation of MeHg in the aquatic food chain poses a significant risk to humans through dietary intake of fresh and saltwater fish and shellfish,” explains Rand.

Even more alarming is the risk that eating mercury-exposed fish poses to the developing fetus.

“Centers for Disease Control statistics show that six percent of women of childbearing age have more than the EPA-recommended level of blood mercury in their system,” says Rand. Based on recent studies that highlighted the susceptibility of the fetus to MeHg neurotoxicity, the EPA and Food and Drug Administration issued strict guidelines for fish and shellfish consumption for pregnant and nursing mothers.

Model MeHg
In order to uncover information about MeHg’s role in neurotoxicity, Rand and his colleagues are working with a well-established Drosophila (fruit fly) model system. Though this small insect looks nothing like a human, the fly genome includes “cousin” genes to about 60 percent of the 250 known human disease genes. Other scientists are studying MeHg neurotoxicity in rodent models, but Rand is the only investigator working with fruit flies.

“This model offers a powerful tool to identify and characterize fundamental genes that function in the environmental toxicity of compounds such as MeHg,” says Rand, who adds that this simple fruit fly model has provided some of the most fundamental genetic principles in neural development. “We’re capitalizing on a tried-and-true genetic model and seeking reasons and answering questions to help solve a vital human health issue,” explains Rand.

His current research focuses on MeHg activity at the molecular and cellular levels. MeHg is known to inhibit the function of key neurotransmitter receptors and calcium ion channels, as well as cause damage to mitochondria, which produce energy inside cells, and a host of other critical molecular processes. Rand and his team are looking closely at a receptor protein known as Notch, which operates in a highly conserved mechanism of cell-to-cell communication and is fundamental to embryonic neural development in species ranging from insects to humans.

“Once activated, the Notch receptor engages in signaling in several developmental contexts,” explains Rand. Of greatest note is its role in directing the fate of neuronal cells, influencing nerve structure and regulating the maturation of glial cells in the brain and spinal cord. “These processes are exquisitely sensitive to the levels of Notch signals,” says Rand.

Proteolysis, resistance and vulnerability
MeHg activates Notch receptor signaling and alters its function. In their fruit fly model, Rand and his team are analyzing the basic developmental defects that occur in the nervous system with exposure to MeHg. Of particular interest to the group is the proteolysis — or breakdown of proteins or peptides into amino acids — of Notch by ADAM proteases, which are proteins that reside on the cell surface known for their ability to cleave and release the extracellular component of receptor proteins.

“In one project in the lab, we are investigating the efficacy of each of the five Drosophila ADAM gene products in proteolysis and activity of Notch receptors to clarify the overall role that proteolysis plays in regulating the Notch signaling pathway,” says Rand.

Rand and his team discovered that MeHg causes degradation of Notch receptor proteins on developing neural cells and published their findings in the journal NeuroToxicology in April 2006. They believe that this degradation occurs through a mechanism that likely engages ADAM activity and are working to characterize the mechanism by which MeHg activates Notch, as well as explain the molecular basis for the cellular disruption seen in a MeHg-exposed nervous system.

“We are also identifying genes associated with tolerance, and alternatively, susceptibility to MeHg toxicity,” adds Rand. To accomplish this task, he is using the Drosophila model to identify wild type strains and create artificially selected populations in the laboratory that carry heritable MeHg resistance traits. Thanks to microarray technology, Rand and his colleagues have been able to begin to determine the specific changes in gene expression in the developing nervous system that occur in response to acute and long-term exposure to MeHg.

Outside the lab
Because of broad interest in the mercury toxicity issue, Rand has consulted and collaborated with a host of environmental scientists and champions of the issue. He keeps in touch with Neil Kamman, a water quality environmental scientist at the Vermont Department of Environmental Conservation, James Shanley of the water resources division of the U.S. Geological Survey office in Montpelier, David Evers of the Biodiversity Research Institute in Maine and David Duncan, a National Public Radio correspondent, San Francisco Chronicle syndicated columnist and author of an October 2006 National Geographic piece titled “The Pollution Within.”

Rand points out that Senator Patrick Leahy and former Senator Jim Jeffords were responsible for bringing the mercury toxicity issue to the forefront and that Congressman Peter Welch has also been supportive of efforts to increase awareness and research in this area.

A recent study by the Vermont Institute of Natural Science unexpectedly discovered higher than acceptable levels of mercury in songbirds and other animal species in nine “hot spots” in Northeastern United States, reinforcing the urgency of increasing our understanding of the considerable environmental and human health implications of MeHg exposure. Rand’s genetic research offers a starting point for studying the effects of this substance on the developing brain and provides important insight into how this toxin affects humans and other living things.