Altered metabolic and hormonal responses in male rats exposed to acute bright light-at-night associated with global DNA hypo-methylation
Introduction
In recent years, artificial light at night (ALAN) particularly that of short wavelength (SWL3) blue light, is increasingly being recognized as a new form of environmental pollutant that may impose a substantial burden on the metabolic homeostasis of human and non-human animals [1,2]. In mammals, natural changes in light interact with the master circadian clock located at the suprachiasmatic nucleus (SCN4) of the hypothalamus to modulate a wide array of metabolic responses [3]. The SCN vigorously controls the daily rhythm of the pineal hormone melatonin that oscillates in opposite phase with the natural light cycle [4]. Light stimuli are detected by intrinsically photosensitive retinal ganglion cells (ipRGCs5) and propagated to the SCN by the retino-hypothalamic tract (RHT6). The SCN-controlled melatonin signals modulate variant circadian rhythms linked to metabolic homeostasis, including satiety hormones (insulin and leptin), enzymes involved in metabolic function, oxygen consumption, and blood glucose levels [5].
In human, the increase in SWL-ALAN exposure is associated with increased obesity incidence and impaired metabolic functions, including glucose tolerance, insulin sensitivity, energy expenditure, and body mass (Wb7) [6,7]. In mice, chronic ALAN exposure induced both significant increase in Wb and decrease in glucose tolerance [1,8]. In the social vole (Microtus socialis), 1 × 30-min/night ALAN of different wavelengths, particularly SWL clearly decreased Wb and increased daily energy expenditure compared with unexposed controls [9]. In a recent rat study, it has been demonstrated that ALAN can instantly induce glucose intolerance in an intensity-and wavelength- dependent manner [10]. Taken together, the results of these studies evidently support the detrimental effects of circadian disruption by SWL-ALAN on metabolic functions, but the exact mechanism of action remains unclear. Nonetheless, a possible mechanism of action is proposed to be mediated by the pineal melatonin suppression in response to SWL-ALAN exposure [11].
In all diurnal and nocturnal mammals studied to date, pineal melatonin production and secretion is strictly regulated by the SCN in a light duration-, intensity-, and wavelength-dependent manner and consequently ALAN exposure particularly of SWL suppresses the nocturnal melatonin rhythm [12]. Hence, several adverse health effects (i.e.; energy metabolism) of circadian disruption on human and non-human animals have been recurrently linked to suppression of nocturnal melatonin levels [2,13]. In regards to metabolism, melatonin may regulate pancreatic α-cell insulin secretion, improve glucose homeostasis, and lower levels of the hormone, might result in type 2 diabetes [14,15]. The precise signaling pathway involving melatonin regulation of metabolic responses remains unclear.
Melatonin may influence metabolic processes by modulating gene expression via epigenetic modifications [16]. The relation between environmental changes and epigenetics has been reviewed previously [17]. In this review, a putative association between environmental exposures (e.g., ALAN) and gene expression was suggested to be modulated by a crosstalk between epigenetics and hormonal responses (e.g., melatonin rhythm). Epigenetics is a complex molecular mechanism that regulates gene activation and silencing without modifying the DNA sequence [18]. Epigenetic modifications include nucleosome positioning, histone posttranslational modifications, noncoding RNAs, and DNA methylation. In matured vertebrate cells, the primary epigenetic mechanism is DNA methylation of where a methyl group is covalently added to the C5 position of cytosine residues in CpG dinucleotide sequences [19]. Methylation levels at different CpG sites of some circadian clock genes have been correlated with both obesity and metabolic syndrome in obese women after weight reduction program [20]. Melatonin may regulate metabolic functions by controlling enzymatic activity of DNA meythyltransferases involved in DNA methylation [21]. While there is compiling evidence that melatonin is strongly associated with energy metabolism homeostasis, the role of epigenetic modifications in this association is not clear [22]. Most of the previous study, investigated the relationship between ALAN and metabolic responses using mainly dim and continuous exposures [23,24,25].
The aim of the current study was to test the association between acute polychromatic bright ALAN exposure and metabolic chrono-disruption in male laboratory rats (Rattus norvegicus). Additionally, the effects of acute ALAN exposure on daily melatonin rhythm and epigenetic modifications were also tested.
Section snippets
Animals
Twenty male rats (Rattus norvegicus; 345 ± 11 g, 4–5 weeks) obtained from Laboratories Harlan Ltd., (Jerusalem, Israel). We choose to study only male rats to avoid potential interference from fluctuations in circulating female sex hormone levels with circadian responses in physiology and behavior. All experiment procedures were conducted with approval from the Ethics and Animal Care Committee of the University of Haifa (Protocol number: 202.3069/17). The rats were housed in an environmentally
Statistical Analysis
All statistical tests were performed using IBM SPSS© 21.0 for windows (IBM Corp., Armonk, NY, USA). Results are presented as mean ± one standard error (S.E.M.) or 95% confidence interval mean. Split-plot ANOVA repeated measures (SPANOVA13) with treatment as between subject variable and time as within subject variable (2 treatment × 7 or 9 time) was used to evaluate mean differences in urine production, body temperature (9 time), serum glucose, and serum
Wb
Starting from initial mass at day 1, both control and ALAN rats significantly increased Wb over time (SPANOVA: F3,54 = 357, P = .0001), with significant treatment (SPANOVA: F1,18 = 37, P = .0001) and treatment x time interaction effects (SPANOVA: F3,54 = 107, P = .0001). However, the rate of increase in ALAN interfered rats was more pronounced in comparison with that for control rats (Fig. 1A). Mean Wb levels of ALAN rats were significantly (t-test, all P = .0001) higher than those of control
Discussion
Currently, the pervasive ALAN exposure is suggested to be a novel lifestyle risk factor that disrupts the circadian system and may trigger downstream influence on variant metabolic functions [2,6]. Accordingly, we discovered that two bright ALAN exposures virtually affected all studied metabolic variables in male rats. After 3 weeks of exposures to ALAN, rats had a higher energy efficiency indicating a substantial mass gained compared with untreated rats (Fig. 1C). Additionally, the
Conclusions
ALAN exposure is increasingly being recognized as a novel environmental polluter that may impair several health functions, including metabolic and hormonal disorders [2,13]. In this study we assessed the effect of bright 2 × 30-min/night ALAN exposures on metabolic and hormonal responses in healthy male laboratory rats. Significant mass gain in ALAN rats with decreased food intake suggests enhanced lipogenesis. Reduced water consumption and increased urine production in response to ALAN
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
None.
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