Arsenic is often referred to as the “king of poisons” and the “poison of kings” because of its high toxicity levels and murderous use in the Middle Ages.
Arsenic is a major pollutant of groundwater in Asia and some areas of the United States and is still a big threat to human health today. It is a naturally occurring element found in soil and rock, but it can dissolve into groundwater and contaminate drinking water sources, particularly private wells. It can also be present in certain foods, especially rice, seafood and some fruit juices.
More than 140 million people in over 70 countries across the globe, including the United States, are chronically exposed to arsenic in the environment with harmful physiological effects, including neurotoxicity.
Scientists at the Clemson University Center for Human Genetics conducted a comprehensive study to gain novel insights into the toxic effects of arsenic exposure on the central nervous system. The study is part of the international PrecisionTox consortium funded by the European Union’s Horizon 2020 Research and Innovation program under Grant No. 965406.
Clemson is one of 15 international institutions — and one of only two in the United States – involved in the consortium, which is led by John Colbourne at the University of Birmingham in the United Kingdom. The consortium uses genetics, genomics, metabolomics and the study of evolution to investigate the toxicity of hundreds of chemicals and explore how they disrupt biological processes fundamental to health.
Chronic arsenic exposure understudied in humans
Most studies of arsenic poisoning using animal models use lethality as an endpoint for acute exposure to arsenic. But in humans, neurologic effects due to chronic arsenic exposure (smaller doses over a longer period) are more relevant— and understudied.
“To chronicle the effect of low doses of arsenic over time, you have to do it in a short-lived model system,” said Trudy Mackay, director of the Clemson University Center for Human Genetics. “The average fruit fly lives between 30 and 40 days.”
Geneticists at the Clemson University Center for Human Genetics exposed the common fruit fly, Drosophila melanogaster, to a dose of arsenic that does not cause lethality to determine whether physiological impairments are accompanied by changes in gene expression in the central nervous system, how widespread the changes are and whether the changes are the same in males and females.
Flies have a natural tendency to climb up against gravity, a behavior called negative geotaxis. The researchers used a climbing assay to assess decline in performance of the fruit flies upon chronic exposure to arsenic. They found that females had a reduction in climbing ability already after the first day of exposure. “Male fruit flies started showing a significant reduction of climbing ability after six days of chronic exposure,”, said Anurag Chaturvedi, a postdoctoral fellow at the Clemson University Center for Human Genetics and lead investigator of the study.
“It looks like males are more resistant, at least in terms of this one assay, than the females,” Mackay said.
To assess the effects of chronic arsenic exposure on gene expression in the brain, the research team dissected fly brains. Because the fly brain is small, scientists can analyze the whole brain in a single analysis at single cell resolution, something that can’t be done in rodents, the typical model for toxicological studies.
Males, females affected differently
The results of their study showed that in females, more genes were affected in the neurons, while in males, more genes were differentially expressed in the glia, cells in the nervous system that support and protect neurons. The scientists saw that cells associated with vision and locomotion were profoundly affected.
“Sex-specific effects, which are seen repeatedly with all toxicants, are not generally paid attention to by regulatory authorities,” said Robert Anholt, Provost Distinguished Professor of Genetics and Biochemistry and director of faculty excellence in the College of Science.
“Most fly genes have human counterparts, and a genetic analysis showed that human genes could be superimposed on arsenic-associated genetic networks in flies, giving us confidence that results obtained in the fly system are relevant to human populations,” Chaturvedi said.
Anholt added that such networks cannot be derived from studies on human populations, especially in the brain.
“In flies we can look at the entire brain. We have very controlled exposure and we can identify genetic interaction networks on which you can superimpose known human genes that can indicate fundamental biological processes, including neurodevelopmental processes, that would predispose to arsenic sensitivity upon chronic exposure in human populations,” Anholt said.The study could eventually help identify clinically relevant effects of chronic arsenic exposure.
“Arsenic is one of the major environmental pollutants globally. If you are in an area where arsenic is known to be a problem and you see a child with intellectual disability, one could surmise the problem could be due to arsenic rather than another neurological disorder. If you have particular neurological issues in these areas where arsenic exposure could be a problem, doctors could do blood tests for the presence of arsenic,” Anholt said.
Detailed findings of the study were published in the journal Frontiers in Toxicology in an article titled, “Arsenic toxicity in the Drosophila brain at single cell resolution.”
