Carbamate Insecticide Carbaryl Targets Melatonin Receptors and Modulates Circadian Rhythms
Authors: Glatfelter Grant C. , Rajnarayanan Rajendram V. , Dubocovich Margarita L. 
Published: June 2021

Melatonin (MLT) binds to MT1 and MT2 G protein‐coupled receptors with high affinity to modulate physiological responses, most prominently those related to circadian rhythms. In‐silico molecular modeling and in‐vitro bioassays from our lab support that a common carbamate insecticide, carbaryl, and other carbamates (bendiocarb, fenobucarb, carbofuran) compete for MLT receptor binding at MT1 and MT2 with varying efficacies and potencies (Popovska‐Gorevski et al. 2017; Jones et al. 2017 EB Abstract; Glatfelter et al. 2017 EB Abstract). Due to the persistent and widespread use of carbaryl and other carbamates (insect control for agriculture & home gardening), humans are exposed daily to low levels of these compounds in household, food, and water products. Evidence indicates that environmental exposure to carbamate insecticides is linked to metabolic disorders and sleep apnea, though it is not clear which biological targets contribute to disease pathology (Montgomery et al. 2008; James‐Todd et al., 2016; Baumert et al. 2017). Therefore we hypothesize that carbamates, such as carbaryl, may produce alterations in circadian rhythms through interactions with MLT receptors that could contribute to the aforementioned disease symptomology, progression, or pathologies. Previous in‐vitro (1–100μM) and ex‐vivo (10mg/kg ip) experiments using tissue from C3H/HeN (C3H) mice demonstrated specificity of carbaryl for MLT receptors and the ability to reach target areas in the brain (suprachiasmatic nucleus: SCN, paraventricular nucleus of the thalamus: PVNT, pars tuberalis: PT; Ki=1.2, 4.5, 3.7μM in SCN, PVNT, PT respectively) responsible for the control of circadian rhythms and other physiological processes (Glatfelter et al. 2017 EB Abstract). This study tested the ability of carbaryl (10mg/kg ip) to phase shift circadian running wheel (RW) activity when injected at circadian time (CT) 10 (CT12 = onset of RW activity in constant darkness) for 3 days in male C3H mice. Our results indicate that carbaryl (0.81h ± 0.1; n=12; p<0.0001) and positive control MLT (3mg/kg sc; 0.97h ± 0.2; n=4; p<0.001; Benloucif & Dubocovich 1996) produce significant phase advances of RW activity compared to vehicle (0.03h ± 0.04; n=7) treated controls (F2,20=18.46; p<0.05; Dunnet's Post Test). We additionally tested the ability of carbaryl (10mg/kg ip) or vehicle at CT13 to influence phase delays of RW activity onset induced by a light pulse (300 lux for 15 min) given at CT14 in the presence and absence of exogenous MLT (3mg/kg sc; Benloucif et al. 1999). Mice receiving MLT (p<0.05, n=14) or carbaryl and MLT (p<0.01, n=13) exhibited significantly decreased phase shift by the light pulse compared to controls (n=12; One Way ANOVA [F3,50=4.78], p<0.05; Dunnet's post test). Further, carbaryl and MLT combined treatment produced fewer phase shifts (7/13) larger than 0.5h compared to MLT (12/14), carbaryl (13/15), or vehicle (12/12) supporting a possible combined effect of carbaryl on MLT‐mediated reduction of light‐induced phase shift. We conclude that carbaryl can target MLT receptors in‐vivo with the ability to modulate circadian rhythms similar to MLT possibly through interactions with MLT receptors in the SCN.Support or Funding InformationSupported by ES 023684 and JSMBS funds to MLD and RVR.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.