Exposure to light at night accelerates aging and spontaneous uterine carcinogenesis in female 129/Sv mice

Popovich, Irina G.; Zabezhinski, Mark A.; Panchenko, Andrey; Piskunova, Tatiana S.; Semenchenko, Anna V.; Tyndyk, M L; Yurova, Maria N.; Anisimov, Vladimir N.

doi:10.4161/cc.24879

Cited by 15 publications

(7 citation statements)

References 35 publications

(46 reference statements)

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“…In EPT-treated mice, progesterone did not increase mammary cancer risk (Figure 1D), but its dose was insufficient to inhibit uterine stimulation during the luteal phase of the estrous cycle (Figure 7B). However, in MEPT mice, melatonin supplementation significantly decreased mammary cancer risk without overstimulating the uterus to further support the previous reports of melatonin's uterine protective effects (53, 93, 139). Therefore, combining melatonin with a progesterone-containing HT resulted in reduced uterine stimulation in addition to mammary cancer protection.…”

Section: Discussionsupporting

confidence: 87%

“…Melatonin binding analyses indicate that the uteri remain melatonin-sensitive through age 14 months (Figure 8A). Previous studies report that melatonin inhibits estrogen stimulation of the uterus since LAN accelerates spontaneous uterine carcinogenesis in mice (139) and co-administration of melatonin and estradiol in ovariectomized rats decreases endometrial thickness and prevents atypia compared to the estrogen-only group (93). In women, a higher risk of endometrial cancer is also associated with lower levels of melatonin and night shift work (53).…”

Section: Discussionmentioning

confidence: 99%

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Co-administering Melatonin With an Estradiol-Progesterone Menopausal Hormone Therapy Represses Mammary Cancer Development in a Mouse Model of HER2-Positive Breast Cancer

et al. 2019

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Melatonin has numerous anti-cancer properties reported to influence cancer initiation, promotion, and metastasis. With the need for effective hormone therapies (HT) to treat menopausal symptoms without increasing breast cancer risk, co-administration of nocturnal melatonin with a natural, low-dose HT was evaluated in mice that develop primary and metastatic mammary cancer. Individually, melatonin (MEL) and estradiol-progesterone therapy (EPT) did not significantly affect mammary cancer development through age 14 months, but, when combined, the melatonin-estradiol-progesterone therapy (MEPT) significantly repressed tumor formation. This repression was due to effects on tumor incidence, but not latency. These results demonstrate that melatonin and the HT cooperate to decrease the mammary cancer risk. Melatonin and EPT also cooperate to alter the balance of the progesterone receptor (PR) isoforms by significantly increasing PRA protein expression only in MEPT mammary glands. Melatonin significantly suppressed amphiregulin transcripts in MEL and MEPT mammary glands, suggesting that amphiregulin together with the higher PRA:PRB balance and other factors may contribute to reducing cancer development in MEPT mice. Melatonin supplementation influenced mammary morphology by increasing tertiary branching in the mouse mammary glands and differentiation in human mammary epithelial cell cultures. Uterine weight in the luteal phase was elevated after long-term exposure to EPT, but not to MEPT, indicating that melatonin supplementation may reduce estrogen-induced uterine stimulation. Melatonin supplementation significantly decreased the incidence of grossly-detected lung metastases in MEL mice, suggesting that melatonin delays the formation of metastatic lesions and/or decreases aggressiveness in this model of HER2 + breast cancer. Mammary tumor development was similar in EPT and MEPT mice until age 8.6 months, but after 8.6 months, only MEPT continued to suppress cancer development. These data suggest that melatonin supplementation has a negligible effect in young MEPT mice, but is required in older mice to inhibit tumor formation. Since melatonin binding was significantly decreased in older mammary glands, irrespective of treatment, melatonin supplementation may overcome reduced melatonin responsiveness in the aged MEPT mice. Since melatonin levels are known to decline near menopause, nocturnal melatonin supplementation may also be needed in aging women to cooperate with HT to decrease breast cancer risk.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Co-administering Melatonin With an Estradiol-Progesterone Menopausal Hormone Therapy Represses Mammary Cancer Development in a Mouse Model of HER2-Positive Breast Cancer

et al. 2019

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“…Body weight gain was reduced after prolonged exposure of female rats to CL conditions, consistent with results of Vinogradova et al (). However, some authors reported no change (Baldissera et al, ) or even increase in body weight gain (Fonken et al, ; Popovich et al, ; Coomans et al, ). This discrepancy may be due to differences between the studies, namely the duration of exposure to CL treatment, intensity of illumination, and/or different rats' age at the beginning of the treatment.…”

Section: Discussionmentioning

confidence: 99%

Morphological and functional changes in pituitary‐thyroid axis following prolonged exposure of female rats to constant light

Miler

Šošić‐Jurjević

Nestorović

et al. 2014

Journal of Morphology

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Light regulates numerous physiological functions and synchronizes them with the environment, in part by adjusting secretion of different hormones. We hypothesized that constant light (CL) would disturb pituitary-thyroid axis. Our aim was to determine morphological and functional changes in this endocrine system in such extreme conditions and, based on the obtained results, to propose the underlying mechanism(s). Starting from the thirtieth postnatal day, female Wistar rats were exposed to CL (600 lx) for the following 95 days. The controls were maintained under the regular laboratory lighting conditions. After decapitation, pituitaries and thyroids were prepared for further histomorphometric, immunohistochemical, and immunofluorescence examinations. Concentration of thyroid stimulating hormone (TSH), total T4 and T3 (TH) were determined. Thyroid tissue of light-treated rats was characterized by microfollicular structure. We detected no change in total thyroid volume, localization and accumulation of thyroglobulin, thyroid peroxidase, and sodium-iodide symporter in the follicular epithelium of CL rats. The volume of follicular epithelium and activation index were increased, while volume of the colloid and serum levels of TH decreased. In the pituitary, the relative intensity of TSH β-immunofluorescence signal within the cytoplasm of thyrotrophs increased, but their average cell volume and the relative volume density decreased. Serum TSH was unaltered. We conclude that exposure of female rats to CL induced alterations in pituitary-thyroid axis. Thyroid tissue was characterized by microfollicular structure. Serum TH levels were reduced without accompanying increase in serum TSH. We hypothesize that increased secretion and clearance of TH together with unchanged or even decreased hormonal synthesis, resulted in decreased serum TH levels in CL group. We assume this decrease consequently led to increased synthesis and/or accumulation of pituitary TSH. However, decreased average TSH cell volume and relative volume density, together with unchanged serum TSH, point to additional, negative regulation of thyrotrophs.

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“…By phenotyping transgenic mice with mutant and/or deleted clock genes, a direct link was made between the circadian clock and the metabolic disorders. Moreover, disrupting the circadian system -either by repetitive jet lag [45] or by light exposure at night [46,47] -has been shown to increase mortality in ageing mice.…”

Section: Disruption Of the Light-dark Cycle And The Effect On Metabolismmentioning

confidence: 99%

Plasticity of circadian clocks and consequences for metabolism

Coomans

Lucassen

Kooijman

et al. 2015

Diabetes Obesity Metabolism

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The increased prevalence of metabolic disorders and obesity in modern society, together with the widespread use of artificial light at night, have led researchers to investigate whether altered patterns of light exposure contribute to metabolic disorders. This article discusses the experimental evidence that perturbed environmental cycles induce rhythm disorders in the circadian system, thus leading to metabolic disorders. This notion is generally supported by animal studies. Distorted environmental cycles, including continuous exposure to light, affect the neuronal organization of the central circadian pacemaker in the suprachiasmatic nucleus (SCN), its waveform and amplitude of the rhythm in electrical activity. Moreover, repeated exposure to a shifted light cycle or the application of dim light at night are environmental cues that cause a change in SCN function. The effects on the SCN waveform are the result of changes in synchronization among the SCN's neuronal cell population, which lead consistently to metabolic disturbances. Furthermore, we discuss the effects of sleep deprivation and the time of feeding on metabolism, as these factors are associated with exposure to disturbed environmental cycles. Finally, we suggest that these experimental studies reveal a causal relationship between the rhythm disorders and the metabolic disorders observed in epidemiological studies performed in humans. Keywords: circadian, desynchronization, suprachiasmatic nucleus, metabolic disorders, light Date submitted 11 April 2015; date of final acceptance 17 May 2015 Environmental Effects on the Rhythm of the SCNPerturbations in the circadian rhythm can develop under a variety of conditions, including ageing, neurodegenerative diseases and metabolic disorders. In order to effectively treat these diseases, it is important to elucidate the causal relationships behind these associations. Towards that end, several animal models have been used to specifically address the relationship between circadian disorders and metabolic disturbances. These models include transgenic mouse models with specific mutations in clock genes, as well as animals in which the function of the suprachiasmatic nucleus (SCN) has been altered by manipulating environmental cues. Transgenic models have been particularly valuable for elucidating the signalling pathways involved in the pathogenesis of metabolic disorders such as diabetes and obesity [1]. Moreover, performing complementary studies in wild-type animals and studying the effect of the environment on SCN functions are valuable as well, given the growing body of evidence suggesting that improper circadian timing interferes with health. For example, sleep disruption in humans is correlated with an increased risk of developing diabetes, and shift work has been associated with increased body mass index (BMI), altered plasma lipids and impaired insulin sensitivity [2][3][4] (Table 1). These studies indicate a potentially large influence of stable, robust environmental light-dark cycles on the maintenance o...

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Exposure to light at night accelerates aging and spontaneous uterine carcinogenesis in female 129/Sv mice

Cited by 15 publications

References 35 publications

Co-administering Melatonin With an Estradiol-Progesterone Menopausal Hormone Therapy Represses Mammary Cancer Development in a Mouse Model of HER2-Positive Breast Cancer

Co-administering Melatonin With an Estradiol-Progesterone Menopausal Hormone Therapy Represses Mammary Cancer Development in a Mouse Model of HER2-Positive Breast Cancer

Morphological and functional changes in pituitary‐thyroid axis following prolonged exposure of female rats to constant light

Plasticity of circadian clocks and consequences for metabolism

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