Exposure to synthetic chemicals commonly found in insecticides and garden products adversely affects melatonin receptor signaling, creating a higher risk for metabolic diseases such as diabetes, University at Buffalo researchers have found.
The study combined a big data approach, using computer modeling on millions of chemicals, with standard wet-laboratory experiments. Margarita L. Dubocovich, PhD, senior author on the paper, said:
“This is the first report demonstrating how environmental chemicals found in household products interact with human melatonin receptors. No one was thinking that the melatonin system was affected by these compounds, but that’s what our research shows."
Dubocovich is 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.
Carbaryl And Carbofuran
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.
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.
Co-author Marina Popevska-Gorevski, now a scientist with Boehringer Ingelheim Pharmaceuticals, who worked in Dubocovich’s lab while earning her master’s degree at UB, said:
“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. 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 bio-assay that might be able to assess environmental chemicals for this kind of activity.
Melatonin Signaling Disruption
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.
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.
The research was funded by a grant from the National Institute of Environmental Health Sciences, part of the National Institutes of Health.
Marina Popovska-Gorevski, Margarita L. Dubocovich, Rajendram V. Rajnarayanan Carbamate Insecticides Target Human Melatonin Receptors Chemical Research in Toxicology, 2017; DOI: 10.1021/acs.chemrestox.6b00301
_Image: Melatonin (in yellow) and carbaryl, (in light turquoise), a commonly used insecticide, bind directly to the same binding region on the human melatonin receptor. _Credit: Raj Rajnarayanan, UB