Journal of Steroid Biochemistry and Molecular Biology 213 (2021) 105957 Available online 27 July 2021 0960-0760/© 2021 Elsevier Ltd. All rights reserved. Vitamin D-independent benefts of safe sunlight exposure Anna S. Erem a , Mohammed S. Razzaque b, * a Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA b Department of Pathology, Lake Erie College of Osteopathic Medicine, Erie, PA, USA A R T I C L E INFO Keywords: Sunlight exposure Ultraviolet radiation Vitamin D Multiple sclerosis Diabetes Cancer COVID-19 ABSTRACT This review examines the benefcial effects of ultraviolet radiation on systemic autoimmune diseases, including multiple sclerosis and type I diabetes, where the epidemiological evidence for the vitamin D-independent effects of sunlight is most apparent. Ultraviolet radiation, in addition to its role in the synthesis of vitamin D, stimulates anti-infammatory pathways, alters the composition of dendritic cells, T cells, and T regulatory cells, and induces nitric oxide synthase and heme oxygenase metabolic pathways, which may directly or indirectly mitigate disease progression and susceptibility. Recent work has also explored how the immune-modulating functions of ultra- violet radiation affect type II diabetes, cancer, and the current global pandemic caused by SARS-CoV-2. These diseases are particularly important amidst global changes in lifestyle that result in unhealthy eating, increased sedentary habits, and alcohol and tobacco consumption. Compelling epidemiological data shows increased ul- traviolet radiation associated with reduced rates of certain cancers, such as colorectal cancer, breast cancer, non- Hodgkins lymphoma, and ultraviolet radiation exposure correlated with susceptibility and mortality rates of COVID-19. Therefore, understanding the effects of ultraviolet radiation on both vitamin D-dependent and -in- dependent pathways is necessary to understand how they infuence the course of many human diseases. 1. Introduction Sunlight includes more than just the light we can see. Infrared ra- diation (wavelengths greater than 700 nm) and ultraviolet radiation (wavelengths <400 nm) at opposite ends of the visible spectrum (approximately 400–700 nm), and ultraviolet radiation can be further subdivided into UVA (320–400 nm), UVB (290–320 nm), and UVC (100–290 nm). Most UV rays that reach the earth’s surface are UVA because shorter wavelengths are scattered by the ozone layer and the atmosphere [1]. This same principle of absorbance applies to human skin [2] – longer wavelengths (e.g., red or infrared light) penetrate deeper than shorter wavelengths (e.g., blue or ultraviolet light). Unlike UVB radiation, UVA can pass through glass windows, is partially transmitted through clothing [3], and indirectly causes DNA damage through activation of reactive oxygen species [4]. In addition, the amount of UV exposure depends on various factors such as latitude, altitude, climate, local weather, and pollution. Many studies use some of these factors as proxies for the amount of sunlight exposure [5]. UV radiation has a well-established role in producing vitamin D in the skin (Fig. 1). UVB radiation stimulates the production of pre-vitamin D from 7- dehydroxycholesterol. Vitamin D synthesis is not only affected by the amount of UV radiation but also by an individual’s physiological and metabolic properties, such as melanin synthesis and distribution, skin color, and genetics [6,7]. Vitamin D is an important fat-soluble prohormone involved in various functions, including maintaining cal- cium and phosphate homeostasis, by facilitating the body’s absorption of calcium and phosphate from food [8]. Vitamin D is transported in blood serum by vitamin D binding protein and is converted in the liver to the hydroxylated form 25-hydroxyvitamin D (25(OH)D) by the enzyme CYP2R1 [9]. This compound is converted into the active metabolite 1, 25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 , calcitriol) mainly in the kidneys by hydroxylation of serum 25(OH)D via the enzyme CYP27B1 (also known as 1 alpha-hydroxylase). After vitamin D is converted to 1,25 (OH) 2 D 3, it binds to the vitamin D receptor (VDR), which activates signaling pathways, such as nuclear factor kappa-B, and triggers the transcription of genes. Mutations in CYP27B1 can result in vitamin D defciencies, and vitamin D defciency results in osteopenia and osteo- porosis and increases the risk of bone fractures [10]. Clinically, a serum 25(OH)D level of 30–100 ng/mL (75–250 nmol/L) is considered suff- cient, 20–29 ng/mL (50–74 nmol/L) insuffcient, and <20 ng/mL (<50 nmol/L) defcient according to the Endocrine Society’s Practice Guide- lines on vitamin D [11]. Relevant to this, according to the Institute of * Corresponding author at: Department of Pathology, Lake Erie College of Osteopathic Medicine, 2000 West Grandview Boulevard, Erie, PA 16509, USA. E-mail addresses: mrazzaque@lecom.edu, msr.nagasaki@gmail.com (M.S. Razzaque). Contents lists available at ScienceDirect Journal of Steroid Biochemistry and Molecular Biology journal homepage: www.elsevier.com/locate/jsbmb https://doi.org/10.1016/j.jsbmb.2021.105957 Received 8 March 2021; Received in revised form 15 July 2021; Accepted 25 July 2021