Health risks associated with genetic alterations in internal clock system by external factors

Introduction

Specific phases of the day-night cycle, are linked to an internal biological clock that influences behavioral and physiological responses through synchronization of internal processes. The circadian system (comprising a network of tissue clocks) is coordinated in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus by central pacemaker. Rhythmic transcriptional pathways are driven by molecular clock machinery in a tissue-specific manner. Proteins encoded by clock genes generate circadian rhythms in the SCN ¹. A circadian pacemaker is directly synchronized by light to the solar cycle (24-h). This synchronization (entrainment) process is an interplay between period of intrinsic pacemaker and daily light perception. The circadian pacemaker in SCN synchronizes sleep-wake cycle, hormone secretion, skin temperature and heart rate ².

Circadian clock regulates early and late chronotypes through synchronization of the internal body time with the external cycle of light and dark. Light is associated with the wake, and dark with sleep period. However, self-selected sleep and wake timing differences are possible that are linked to specific chronotypes. Opposite to the late chronotypes, early chronotypes wake up and fall asleep early in the morning and evening respectively ³. Irregular sleeping periods and altered light-dark cycles in shift-work and long distance travel are associated with altered environment cues, which further influence daily rhythms via central and peripheral clocks ⁴.

Adverse impacts of circadian dysrhythmia on body and mind are linked with lifestyle or routines such as frequently flying, working in repeatedly changing shifts and exposure to irregular light-dark conditions. Working around the clock and jetting around the globe are becoming necessary in our globalized world in some high-profile services. Crossing multiple time zones results in “jet lag,” a circadian rhythm disorder, that disturbs spatial cognition and hippocampal neurogenesis. Jet lag immediately causes fatigue and indigestion while chronic exposure to jet lag has strong impacts on spatial cognition and temporal lobe ⁵. Externally induced disruption in natural sleep-wake cycles ⁶ and circadian rhythms is associated with neuronal dysfunction ^7,8, increased risk for psychiatric, cardiovascular and metabolic diseases ³, and affects bone health ⁹.

Long-term exposure to irregular dark-light cycles increases the risk of sleep disorders, metabolic disorders, mental abnormalities, depressive disorders, and hormonal abnormalities, that further develop cancer, gastrointestinal, and reproductive disorders ¹⁰. Trans meridian travel may develop general malaise, headaches, insomnia, daytime sleepiness, impaired cognitive or physical performance and gastrointestinal disturbances. Impacts of shift-work on sleep duration quality can disrupt the physiological rhythms via desynchronization between hormonal rhythms, metabolic function and sleep cycle ⁴. Physiological clock alterations ¹¹ increase the risk of peptic ulcer and diabetes ^12-14.

Exposure to irregular light-dark cycles (shift-work) and jet lag experiences are unavoidable in order to fulfill the fast-growing needs. Environmental and other external factors impact circadian rhythms and sleep regulations. These problems need proper investigation and development of preventive or curing techniques. Genetic mechanisms associated with severe diseases and circadian system and sleep regulation disruptions promoted by shift work, jet lag and other environmental factors, need to be investigated.

Circadian System

Circadian system is regulated by clock genes with the effects of oscillators, endocrine, and neural signals. However, circadian rhythm is maintained by a circadian clock through appropriate physiological activities ¹⁵. Circadian clock organization at cellular level takes place through brain and muscle ARNT like protein 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK) (Figure, 1). Two different loops are formed for the complete organization and activation of the circadian clock ¹⁶. In the first loop, CLOCK and BMAL1, positive clock arm comprising elements, heterodimerize in the cytoplasm and enter the nucleus to regulate the expression of negative core clock arm comprising elements which are; PER1, PER2, and PER3 and CRY1, CRY2. Various Per and Cry protein combination in cytoplasm interact with each other and enter the nucleus to inactivate BMAL1/CLOCK complexes. The expression of secondary feedback loop elements “REV-ERBα and RORα” is driven by CLOCK/BMAL1 that regulates Bmal1's rhythmic expression ¹⁶. RORα and REV-ERBα activate and represses BMAL1 expression respectively.

In case of activation, BMAL1 protein forms heterodimers with CLOCK that enters the nucleus to initiate the next cycle of gene activation of both loops ^17,18. Hence, the BMAL1's circadian oscillation is regulated by RORs and REV-ERBs (positively and negatively). The auto regulatory feedback loops constitute a circadian molecular clock after completing a cycle in a 24-hour time-period. This timing of molecular clock is regulated by post-translational modification proteins, including kinases, phosphateases, and ubiquitin ligases that affect the heterodimerization and degradation of PER and CRY ¹⁹.

Altered light-dark cycles or environmental factors can dysregulate clock either inactivating or overexpressing genes of core Clock genes. Core Clock genes and related factors if mutated, can lead to several abnormalities. For instance, Bmal1 and Clock mutations can cause abnormal gluconeogenesis, behavioral sensitization to psychostimulants and lipogenesis, and altered sleep pattern. Per1 and Per2 can lead to developing cancer. Cry1, Cry2 and Rora mutations can develop altered sleep pattern and cerebellar ataxia respectively. Rorb dysfunctionality is related to locomotor difficulties and retinal degeneration ¹⁹. Moreover, Some important metabolic process controlling genes are present in rhythmic transcriptome which is an indication of the fact that alteration in circadian rhythm causes metabolic problems ^15,20-22. For instance, Clock, Bmal and Per-2 are associated with obesity ^23,24.

Circadian rhythms are synchronized with the day time work and nighttime sleep, require a phase adjustment (as occur with exposure to bright light at night, experiencing jet lag or shift work) by central and peripheral oscillators. Because Per1 and Per2 shift faster than Cry1, the phase adjustment in certain cases causes internal desynchronization. Surprisingly, Per1 and Per2 behave differently during phase shifts (jet lag or shiftwork) ^6,25 that may ultimately cause the disruption in the circadian clock. Along with sleep regulation, circadian rhythms also direct normal physiological processes, including hormone secretion, body temperature, feeding behavior, cell-cycle progression and drug, glucose and xenobiotic metabolism ^10,22.

Disregulated Circadian Rhythm Disrupts Sleep

Sleep is a critical component of human health. This sleep health mainly depends on factors determining sleep quantity and quality. Several sleep and circadian rhythms related physiological functions including the sleep/wake cycle and metabolism are maintained by the SCN of the hypothalamus ²⁶. Insufficient and poor sleep is associated with increased risk of metabolic disorders and exacerbating metabolic outcomes ²⁷. Light exposure influences human physiology including sleep modulation. Its impacts on circadian physiology cause circadian misalignment that further alters sleeping energy expenditure and affects substrate oxidation. The alterations in 24 h energy expenditure increase the risk of obesity ²⁸.

Environmental stimuli (light at night) mediated sleep disruption is considered one of the potential risk factors for cardiovascular disease, dysregulation of immune function, stress, memory deficits and depression. Being the main environmental signal for circadian clock synchronization, light exposure in the early morning and late evening is associated with shifting of circadian phase ²⁹. Poor sleep develops endocrinal, psychiatric, cardiovascular and metabolic abnormalities. Its elevated affects are coronary artery calcifications, atherogenic lipid profiles, atherosclerosis, obesity, type 2 diabetes, and hypertension (Figure 2). Nocturnal environmental noise affects sleep architecture and quality in a similar way to that observed in endogenous sleep disorders. Being an important modulator sleep modulates cardiovascular function, hormonal release and glucose regulation. Both sleep restriction, and poor quality, reduces glucose tolerance and insulin sensitivity ³⁰.

Several aspects of human behavior and physiology are dominated by 24-h circadian rhythms including vigilance and sleep-wake cycle. An internal pacemaker generates rhythms spontaneously based on daily retinal light exposure. Such synchronization processes pose problems in the context of jet lag or working night shifts ³¹. Sleep is controlled genetically with the influence of environmental factors ³². Sleep and circadian rhythms influence physiologic processes which are critical to brain health ^33,34. Sleep consists of two repeated cyclic patterns “non-rapid eye movement (NREM) and rapid eye movement” and regulated by cyclic guanosine monophosphate (cGMP) kinase, regulatory subunit of Shaker, Sleepless (sss) gene and CLK and CYC proteins are the key players in sleep regulation ¹⁰.

Externally influencing factors may alter genetic expressions to develop sleep disorders. It can affect an SNP marker, MEIS1 locus and Neuronal nitric oxide synthase (NOS1) ^10,35-37. These factors can disrupt the normal functions of Per2, casein kinase Iδ and PRNP genes to develop Familial advanced sleep phase syndrome (FASPS) and fatal familial insomnia (FFI) respectively ¹⁰. They can also affect daytime activity increasing glucocorticoids and NSAIDs ³⁸, Protein NF-kB (up-regulated during sleep-deprivation) ³², TAK1 (TGF-b-activated kinase) and Sik3 (control sleep behaviors), Nalcn gene (involved in REMS) ³⁹. Furthermore, expression of Sur2 gene (play role in energy metabolism) ⁴⁰, daily patterns of human physiology, irregular energy patterns expenditure, hormones and lipids involved in energy metabolism ^41,42 can be affected (Figure, 2).

Major Health Problems

Genetic variation, environmental factors and jetlag increase the risks of a wide range of health abnormalities through altering circadian rhythms ¹. Desynchrony induced by external/environmental factors is linked with high risk of serious health issues, including depressive disorders, cardiovascular disorders, diabetes and cancer ^1,43. Social jet lag is associated with depressive and metabolic syndromes that further enhance the consumption of nicotine, caffeine and alcohol ³ while inappropriately timed sleep is associated with endocrine, metabolic, cardiovascular, and neurological disorders ⁹. Incompatibility between circadian rhythms and working periods causes sleep deprivation ⁴⁴ that further causes fatigue, vigilance and attention impairments ⁴⁵ (Figure 3).

Conclusions and benchmark prospects

Clock genes play a crucial role in maintenance of behavior and other body functions. Avoiding exposure to irregular dark-light cycles and environmental stresses is nearly impossible in today's world. These external factors have strong impacts on internal clock system, which make it necessary to be aware of complications related to them. Focusing on precautionary measurements is important to eliminate the chances of related health-risking disorders such as cancer, cardiac system disorders, sleep related disorders, depressive and other psychiatric disorders. Investigations related to changes in environmental conditions and associated disorders are needed to be carried which must focus on the genetic level alterations. Only in this way proper cure or precautions will become possible in future.