Sleep Deprivation Potentiates Silica Nanoparticle-Induced Circadian Disruption and Lacrimal Gland Dysfunction in Mice

Sleep deprivation and engineered nanomaterials, such as silica nanoparticles, have emerged as potential risk factors for ocular surface disorders, including dry eye disease. However, the mechanisms by which sleep deprivation exacerbates nanoparticle-induced lacrimal gland dysfunction remain unclear. In this study, the combined effects of sleep deprivation and silica nanoparticle exposure on circadian rhythms, oxidative stress, inflammation, and structural integrity of the extraorbital lacrimal gland were investigated in mice. Male C57BL/6J mice were divided into control, silica nanoparticle-treated, and combined exposure groups. Locomotor activity, core body temperature, tear production, and glandular morphology were assessed, while RNA sequencing was performed to examine circadian gene expression and inflammatory pathways. Oxidative stress was evaluated via reactive oxygen species accumulation and γ-H2AX expression, and inflammation was assessed by immune cell infiltration and NLRP3 inflammasome activation. Silica nanoparticle exposure dampened behavioral and temperature rhythms, and these effects were further exacerbated by sleep deprivation, which also abolished diurnal tear secretion. Histological and transcriptomic analyses revealed reduced gland size, phase shifts in core clock gene expression, elevated oxidative stress, DNA damage, and increased activation of NF-κB, IL-17, and JAK-STAT pathways. The NLRP3 inflammasome was markedly activated in the combined exposure group, linking oxidative stress to chronic inflammation and tissue dysfunction. These findings demonstrate that sleep deprivation aggravates silica nanoparticle-induced lacrimal gland injury by disrupting circadian homeostasis and promoting oxidative and inflammatory damage, highlighting the importance of addressing environmental and behavioral stressors in the prevention and treatment of sleep deprivation-associated dry eye disease.