Sevin = 1-naphthyl methylcarbamate
The nightly release of melatonin from the pineal gland is regulated by biological clocks in the suprachiasmatic nucleus (SCN) of the hypothalamus and transmits signals to the brain and peripheral target tissues through activation of the G-protein coupled melatonin receptors MT1 and/or MT2.1–3 Rhythmicity of pineal melatonin synthesis from serotonin is tightly orchestrated by N-acetyltransferase (AA-NAT) and hydroxyindole-o-methyltransferase (HIOMT) both of which have peak enzymatic activities during the night.4–6 Activation of melatonin receptors play a pivotal role in modulating the phase and amplitude of circadian rhythms phase and amplitude through the body.1,7,8 Circadian rhythm misalignment is implicated in various conditions such as jet lag, delayed sleep phase syndrome (DSPS), advanced sleep phase syndrome (ASPS), and seasonal affective disorders (SAD).9 Activation of melatonin receptors inhibit cyclic adenosine monophosphate (cAMP) formation,10–13 regulate phosphorylation of the cAMP responsive element-binding protein (CREB),14 protein kinase activities,15,16 and ion fluxes.12,17 In essence, the melatonin receptor system regulates a wide-array of cellular signaling events essential to maintain rhythmicity and homeostatic balance of various regulatory processes.3,18 Aberrant melatonin receptor activation, sensitivity, and trafficking are linked to pathological conditions including cancer,19 diabetes,2,20 and cardiovascular disease.21
Exposure to chemicals that are structurally similar to melatonin can significantly alter this balance and could result in alteration of melatonin mediated signaling3 and potentially other conditions that impact human health. In the present study, innovative combinations of computational tools for chemical clustering of large data sets of environmental chemicals were employed in tandem with predictive three-dimensional models in an attempt to identify new-class of environmental neuroendocrine disruptors targeting melatonin receptors. Briefly, environmental chemicals that could potentially interact with melatonin receptors based on their structural similarity were identified using an integrated pharmacoinformatics screen from a comprehensive Chem2Risk knowledge-base. Molecular docking of select environmental modulators established novel bimolecular interactions of carbamate insecticides carbaryl and carbofuran with the MT1 and MT2 melatonin receptors in silico. Furthermore, the current study investigated ligand affinity, selectivity, and apparent intrinsic efficacy of selected environmental disruptors on hMT1 and hMT2 melatonin receptors in vitro.
Agricultural use of carbamates as insecticides is due to their strong yet reversible inhibitory effect on acetylcholinesterase.22 Occupational exposure to carbamates has been reported to be associated with psychological distress and depression among agricultural workers.23,24 There is also a positive correlation between carbamate exposure and the risk of developing diabetes and metabolic syndrome.25 Carbaryl produces behavioral changes in rodents such as tremor26 and hypothermia.27 Furthermore, a recent study reports age-specific sensitivity to carbaryl in Brown-Norway rats indicative of age-related changes in metabolism. Even low-dose (3 mg/kg) carbaryl treatment exhibits these age-specific differences in both biochemical and behavioral experiments.28 While some of these effects were attributed to cholinesterase inhibition and neurotoxicity at higher doses, persistent exposure to lower doses of insecticides including carbamates in both occupational and nonoccupational environment was associated with increased risk of various disease conditions including diabetes, cancer, and depression.24,25 Center for Disease Control (CDC) reports that in addition to the dermal routes (the most common route of exposure), several classes of insecticides including the carbamates that are used in spray formulations can reach the brain and other target tissues via inhalation, circumventing liver metabolism (CDC ToxGuide, 2003) and repeated exposure to these chemicals (as in occupational exposure) tend to render higher concentrations of insecticides in target tissues. It is imperative to find alternative targets and mechanisms through which carbamates and other insecticides render such a wide range of biochemical and behavioral effects.