University at Buffalo
Synthetic chemicals commonly found in insecticides and garden
products bind to the receptors that govern our biological clocks, University at
Buffalo researchers have found. The research suggests that exposure to these insecticides adversely affects melatonin receptor signaling, creating a higher risk for metabolic diseases such as diabetes.
Published online on Dec. 27 in Chemical Research in
Toxicology, the research combined a big data approach, using computer
modeling on millions of chemicals, with standard wet-laboratory experiments. It
was funded by a grant from the National Institute of Environmental Health
Sciences, part of the National Institutes of Health.
Disruptions in human circadian rhythms are known to put people at higher risk for diabetes and other metabolic diseases but the mechanism involved is not well-understood.
"This is the first report demonstrating how environmental
chemicals found in household products interact with human melatonin
receptors," said Margarita L. Dubocovich, PhD, senior author on the paper
and SUNY Distinguished Professor in the Department of Pharmacology and
Toxicology and senior associate dean for diversity and inclusion in the Jacobs
School of Medicine and Biomedical Sciences at UB.
"No one was thinking that the melatonin system was affected
by these compounds, but that's what our research shows," she said.
The current research focuses on two chemicals, carbaryl, the
third most widely used insecticide in the U.S. but which is illegal in several
countries, and carbofuran, the most toxic carbamate insecticide, which has been
banned for applications on food crops for human consumption since 2009. It is
still used in many countries, including Mexico and traces persist in food,
plants and wildlife.
"We found that both insecticides are structurally similar
to melatonin and that both showed affinity for the melatonin, MT2 receptors,
that can potentially affect glucose homeostasis and insulin secretion,"
said Marina Popevska-Gorevski, co-author, now a scientist with Boehringer
Ingelheim Pharmaceuticals, who worked in Dubocovich's lab while earning her
master's degree at UB. "That means that exposure to them could put people
at higher risk for diabetes and also affect sleeping patterns."
The results suggest that there is a need to assess environmental
chemicals for their ability to disrupt circadian activity, something which is
not currently being considered by federal regulators. The UB researchers are
developing a rapid bioassay that might be able to assess environmental
chemicals for this kind of activity.
The work is part of a larger effort by Dubocovich and her
colleagues at UB to develop their Chem2Risk pipeline, combining UB's expertise
in computational biology and melatonin receptor pharmacology.
"Our approach seamlessly integrates the screening of
environmental chemicals through computer simulation, in vitro and in vivo
techniques to gauge the risk these chemicals present for various disease end
points," explained Raj Rajnarayanan, PhD, lead author and assistant
professor of pharmacology and toxicology at UB.
The UB database contains about four million chemicals reported
to have some level of toxicity.
"From those, we identified hundreds of
thousands of compounds that had readily available chemical structures so that
we could study them," Rajnarayanan explained.
After grouping the chemicals
in clusters according to their similarity, they found several with functional
groups similar to melatonin.
Using predictive computational modeling and in vitro experiments
with cells that express human melatonin receptors, they found that carbamates
selectively interact with a melatonin receptor. That interaction can disrupt
melatonin signaling and alter important regulatory processes in the body.
"By directly interacting with melatonin receptors in the
brain and peripheral tissues, environmental chemicals, such as carbaryl, may
disrupt key physiological processes leading to misaligned circadian rhythms,
sleep patterns, and altered metabolic functions increasing the risk for chronic
diseases such as diabetes and metabolic disorders," said Dubocovich.
For example, she explained, there is a fine balance between the
release of insulin and glucose in the pancreas at very specific times of day,
but if that balance becomes disrupted over a long period of time, there is a
higher risk of developing diabetes.
Dubocovich is an internationally renowned authority on the brain
hormone melatonin and how melatonin receptors are regulated. Her work has
significantly boosted the scientific understanding of how melatonin impacts
circadian rhythms and human health in general, including sleep disorders,
metabolic disease and drug addiction.
Popovska-Gorevski presented preliminary findings on this work at
the 2014 Experimental Biology meeting in San Diego, receiving a Best Abstract
Award from the Toxicology Division of the American Society for Pharmaceutical
and Experimental Therapeutics and a Best Poster Award from the Upstate New York
Pharmacology Society.
