New integrative approaches to discovery of pathophysiological mechanisms triggered by night shift work.

Synchronization to periodic cues such as food/water availability and light/dark cycles is crucial for living organisms' homeostasis. Both factors have been heavily influenced by human activity, with artificial light at night (ALAN) being an evolutionary challenge imposed over roughly the last century. Evidence from studies in humans and animal models shows that overt circadian misalignment, such as that imposed to about 20% of the workforce by night shift work (NSW), negatively impinges on the internal temporal order of endocrinology, physiology, metabolism, and behavior. Moreover, NSW is often associated to mistimed feeding, with both unnatural behaviors being known to increase the risk of chronic diseases, such as eating disorders, overweight, obesity, cardiovascular, metabolic (particularly type 2 diabetes mellitus) and gastrointestinal disorders, some types of cancer, as well as mental disease including sleep disturbances, cognitive disorders, and depression. Regarding deleterious effects of ALAN on reproduction, increased risk of miscarriage, preterm delivery and low birth weight have been reported in shift-worker women. These mounting lines of evidence prompt further efforts to advance our understanding of the effects of long-term NSW on health. Emerging data suggest that NSW with or without mistimed feeding modify gene expression and functional readouts in different tissues/organs, which seem to translate into persistent cardiometabolic and endocrine dysfunction. However, this research avenue still faces multiple challenges, such as functional characterization of new experimental models more closely resembling human long-term NSW and mistimed feeding in males versus females; studying further target organs; identifying molecular changes by means of deep multi-omics analyses; and exploring biomarkers of NSW with translational medicine potential. Using high-throughput and systems biology is a relatively new approach to study NSW, aimed to generate experiments addressing new biological factors, pathways, and mechanisms, going beyond the boundaries of the circadian clock molecular machinery.