Chronodisruption and Loss of Female Reproductive Potential Due to Shift Work

Introduction

Movement of the earth brings predictable daily and seasonal environmental challenges. The mammalian physiology was evolutionarily programmed to a 24 hour light/dark cycle and the environmental photoperiod (being seasonal) is the absolute factor that governs it (Kennaway et al., 2012). The extra ordinarily rampant use of artificial light at night (ALAN) or light at night (LAN) truncates/manipulates the duration of darkness (as an exposure to artificial light after sunset or before sunrise) and also by interrupting the darkness at night. Thus, the natural entrainment of light/dark cycle is nowadays getting altered due to longer exposure to ALAN condition not only in corporate areas but also at home due to excessive usage of light emitting electronic devices. ALAN not only has widespread ecological effects like changing patterns of breeding seasons in wild, semi-wild and domestic animal species (Russart & Nelson, 2018)but also has increased the susceptibility of humans to a number of physiological and reproductive complications leading to disorders/diseases.

The 24-hr rhythms in mammalian physiology are orchestrated by a primary clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. This central circadian system is extremely sensitive and perceives the briefest exposure to light within the 24 hour cycle. Perception of light through lateral eyes, initiates an impulse at the retinal receptors that is transmitted via retino-hyothalamic tract to SCN- the master clock. This impulse alters the expression of a self-sustaining feedback loop of genes within the SCN that stimulates rhythmic production of a small indole-amine, melatonin from the pineal gland. The mammalian clock basically comprises of the interacting positive and negative transcriptional-/translational-feedback loops. This core clock loop involves commonly known clock genes viz. Clock, Bmal1, Per1, Per2, Per3, Cry1 and Cry2. The two transcription factors CLOCK (circadian locomotor output cycles kaput)(paralog to neuronal Per-Arnt-Sim (PAS) domain containing protein; NPAS2) and BMAL1 (brain and muscle arylhydrocarbon receptor nuclear transporter-like protein 1) (Ko& Takahashi, 2006) constitute the positive arm of the core clock loop.Protein products of the period genes, per1, per2 and per 3 (Per1,Per2 and Per3 respectively) and cryptochrome genes (cry1-CRY1 and cry2- CRY2) form the negative elements of the molecular circadian clock (Saha et al., 2019). The initiation of cellular clock function takes place with the hetero-dimerization of CLOCK and BMAL1, translocation of this heterodimer from the cytosol to the nucleus where it binds to the E-box cis-regulatory enhancer sequences in the promoters of per and cry genes, leading to the transcription of the elements of the negative arm of the loop (Husse et al., 2015). This increases the cytoplasmic level of PER1, PER2 and PER3, each protein reaching its peak level at different circadian time points (Jung et al., 2003). The PER and CRY proteins undergo post translational modifications like phosphorylation by Casein kinases, get accumulated in adequate amount and heterodimerize with each other. They get translocated to the nucleus and inhibit the transcription of their respective genes by blocking transcriptional activity of CLOCK/ BMAL enhancer complex (Tosini et al., 2008). As a result, the levels of PER (PER1, PER2, and PER3) and CRY (CRY1 and CRY2) proteins in the cytoplasm get depleted which then leads to removal of the inhibition of transcription of clock and bmal1 genes by the heterodimers of PER and CRY that cyclically causes CLOCK and BMAL-1 mediated stimulation of per and cry genes (Barnes et al., 2003). The entire process of nuclear translocation of the repressor complex, brought about by concomitant phosphorylation and protein degradation spans over approximately 24 hours, thus defining the period of the oscillator or a single oscillation (Sellix & Menaker, 2011). Additionally, a secondary loop of interlocking transcriptional regulators comprising of a repressor REV-ERBα and an enhancer- retinoic acid-like orphan receptor α(RORα) regulates BMAL1 expression (Sellix, 2015). The core clock genes also control output genes. Also known as clock-controlled genes, the clock output genes are the effector molecules of the clock that mediate temporal control of the core clock over cell-type–specific gene expression and physiology (Hamada et al., 2004; Kennaway et al., 2003).