Elkafas Hoda, Badary Osama, Elmorsy Engy, Kamel Rehab, Yang Qiwei, Al-Hendy Ayman
Department of Pharmacology and Toxicology, Egyptian Drug Authority (EDA) formally, (NODCAR), Cairo 35521, Egypt.
Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL 60612, USA.
J Adv Pharm Res. 2021 Spring;5(2):260-275. doi: 10.21608/aprh.2021.66748.1124.
Uterine fibroids (UFs) are the most prevalent gynecologic neoplasm, affecting 70-80% of women over their lifespan. Although UFs are benign they can become life-threatening and require invasive surgeries such as myomectomy and hysterectomy. Notwithstanding the significant negative influence UFs have on female reproductive health, very little is known about early events that initiate tumor development. Several risk factors for UFs have been identified including vitamin D deficiency, inflammation, DNA repair deficiency, and environmental exposures to endocrine-disrupting chemicals (EDCs). EDCs have come under scrutiny recently due to their role in UF development. Epidemiologic studies have found an association between increased risk for early UF diagnosis and EDC exposure. Environmental exposure to EDCs during uterine development increases UF incidence in a UF animal model. Notably, several studies demonstrated that abnormal myometrial stem cells (MMSCs) are the cell origin for UFs development. Our recent studies demonstrated that early-life EDC exposure reprogrammed the MMSCs toward a pro-fibroid landscape and altered the DNA repair and inflammation pathways. Notably, Vitamin D3 (VITD3) as a natural compound shrank the UF growth concomitantly with the reversion of several abnormal biological pathways and ameliorated the developmental exposure-induced DNA damage and pro-inflammation pathway in primed MMSCs. This review highlights and emphasizes the importance of multiple pathway interactions in the context of hypovitaminosis D at the MMSCs level and provides proof-of-concept information that can help develop a safe, long-term, durable, and non-surgical therapeutic option for UFs.
子宫肌瘤（UFs）是最常见的妇科肿瘤，在女性一生中的发病率为70%-80%。尽管子宫肌瘤是良性的，但它们可能会危及生命，需要进行诸如肌瘤切除术和子宫切除术等侵入性手术。尽管子宫肌瘤对女性生殖健康有重大负面影响，但对于启动肿瘤发展的早期事件却知之甚少。已经确定了子宫肌瘤的几个风险因素，包括维生素D缺乏、炎症、DNA修复缺陷以及环境暴露于内分泌干扰化学物质（EDCs）。由于EDCs在子宫肌瘤发展中的作用，它们最近受到了密切关注。流行病学研究发现，早期子宫肌瘤诊断风险增加与EDC暴露之间存在关联。在子宫肌瘤动物模型中，子宫发育期间环境暴露于EDCs会增加子宫肌瘤的发病率。值得注意的是，多项研究表明，异常的子宫肌层干细胞（MMSCs）是子宫肌瘤发展的细胞起源。我们最近的研究表明，生命早期EDC暴露使MMSCs重编程为促肌瘤状态，并改变了DNA修复和炎症途径。值得注意的是，维生素D3（VITD3）作为一种天然化合物，在使几种异常生物学途径逆转的同时缩小了子宫肌瘤的生长，并改善了发育暴露诱导的DNA损伤以及启动的MMSCs中的促炎途径。本综述强调了在MMSCs水平维生素D缺乏背景下多途径相互作用的重要性，并提供了概念验证信息，有助于开发一种安全、长期、持久且非手术的子宫肌瘤治疗选择。
