Study is First to Show Carbamates Upset Circadian Rhythms

“This is the first report demonstrating how environmental chemicals found in household products interact with human melatonin receptors,” says co-author Margarita L. Dubocovich, PhD, SUNY Distinguished Professor of pharmacology and toxicology.

The researchers suggest that exposure to the insecticides adversely affects melatonin receptor signaling. 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.

“No one was thinking that the melatonin system was affected by these compounds, but that’s what our research shows,” says Dubocovich.

The results suggest that there is a need to assess environmental chemicals for their ability to disrupt circadian activity, something that is not currently being considered by federal regulators. Dubocovich and her colleagues are developing a rapid bioassay that might be able to assess environmental chemicals for this kind of activity.

The research focuses on two chemicals: carbaryl and carbofuran.

Carbaryl is the third most widely used insecticide in the United States, but it is illegal in several countries. Carbofuran is the most toxic carbamate insecticide and 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.

The researchers found that both insecticides are structurally similar to melatonin and both showed affinity for the MT2 melatonin receptors that can potentially affect glucose homeostasis and insulin secretion. Therefore, exposure to the insecticides could put people at higher risk for diabetes and affect sleeping patterns.

The research combines a big data approach — using computer modeling on millions of chemicals — with standard wet-laboratory experiments.

The work is part of a larger effort by researchers in the laboratories of Rajendram Rajnarayanan, PhD, and Dubocovich 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,” explains Rajnarayanan, assistant professor of pharmacology and toxicology, who is the paper’s lead author. 

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 explains. 

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, the researchers 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. This increases the risk for chronic diseases such as diabetes and metabolic disorders,” says Dubocovich, who is an internationally known authority on melatonin.

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.

In addition to Rajnarayanan and Dubocovich, the paper was co-authored by Marina Popovska, a graduate of UB’s master’s program in pharmacology, who is now a scientist with Boehringer Ingelheim Pharmaceuticals.

Like many UB students, Popovska had the opportunity to present mentored research at a national meeting. She presented preliminary findings on this work at the 2014 Experimental Biology meeting, 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.

Popovska was mentored by Dubocovich, who 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. 

Additionally, Dubocovich is senior associate dean for diversity and inclusion in the Jacobs School of Medicine and Biomedical Sciences.

The research, “Carbamate Insecticides Target Human Melatonin Receptors,” was published in Chemical Research in Toxicology on Dec. 27, 2016.

The article has been ranked No. 1 among 986 articles published by the journal. 

It was also chosen as a paper of the month by the National Institute of Environmental Health Sciences, which funded the research.

Altmetric, a data science company that tracks where published research is mentioned online, ranks the paper in the top 5 percent of about 7.4 million research outputs it has tracked.