Hunt Piper Reid, Ferguson Martine, Olejnik Nicholas, Yourick Jeffrey, Sprando Robert L
U.S. Food and Drug Administration, Human Foods Program, Office of Chemistry and Toxicology, Laurel, MD 20708, USA.
U.S. Food and Drug Administration, Human Foods Program, Office of Surveillance Strategy & Risk Prioritization, Division of Surveillance & Data Integration, College Park, MD 20740, USA.
Toxics. 2025 Jul 14;13(7):589. doi: 10.3390/toxics13070589.
Efficient new methods are needed to support initiatives to reduce, refine, and/or replace toxicity testing in vertebrates. 5-fluorouracil (5FU), hydroxyurea (HU), and ribavirin (RV) are mammalian teratogens. Skeletal, endocrine organ, and cardiac effects are often associated with teratogenesis, and a simple nematode like lacks these systems. However, many genetic pathways required for mammalian morphogenesis have at least some conserved elements in this small, invertebrate model. The lifecycle is 3 days. The effects of 5FU, HU, and RV on the morphology were evaluated on day 4 post-initiation of the feeding after hatching for continuous and 24 h (early-only) developmental exposures. Continuous exposures to 5FU and HU induced increases in the incidences of abnormal gonadal structures that were significantly reduced in early-only exposure groups. The incidence of prolapse increased with continuous 5FU and HU exposures and was further increased in early-only exposure groups. Intestinal prolapse through the vulval muscle in may be related to reported 5FU and HU effects on skeletal muscle and the gastrointestinal tract in mammals. Continuous RV exposures induced a phenotype lacking a uterus and gonad arms, as well as vulval anomalies that were largely, but not completely, reversed with early-only exposures, which is consistent with reported reversible reproductive tract anomalies after an RV exposure in mammals. These findings suggest that can be used to detect the hazard risk from chemicals that adversely affect conserved pathways involved in organismal morphogenesis, but to determine the fit-for-purpose use of this model in chemical safety evaluations, further studies using larger and more diverse chemical test panels are needed.
需要高效的新方法来支持减少、优化和/或替代脊椎动物毒性测试的倡议。5-氟尿嘧啶（5FU）、羟基脲（HU）和利巴韦林（RV）是哺乳动物致畸剂。骨骼、内分泌器官和心脏效应通常与致畸作用有关，而像秀丽隐杆线虫这样的简单线虫缺乏这些系统。然而，哺乳动物形态发生所需的许多遗传途径在这个小型无脊椎动物模型中至少有一些保守元件。秀丽隐杆线虫的生命周期为3天。在孵化后开始喂食后的第4天，评估5FU、HU和RV对秀丽隐杆线虫形态的影响，包括连续和24小时（仅早期）发育暴露。连续暴露于5FU和HU会导致异常性腺结构的发生率增加，而仅早期暴露组的发生率显著降低。脱垂的发生率随着5FU和HU的连续暴露而增加，并且在仅早期暴露组中进一步增加。秀丽隐杆线虫通过外阴肌肉的肠道脱垂可能与报道的5FU和HU对哺乳动物骨骼肌和胃肠道的影响有关。连续暴露于RV会导致一种缺乏子宫和性腺臂的表型，以及外阴异常，而仅早期暴露在很大程度上但并非完全逆转了这些异常，这与报道的哺乳动物暴露于RV后可逆的生殖道异常一致。这些发现表明，秀丽隐杆线虫可用于检测对参与生物体形态发生的保守途径产生不利影响的化学物质的危害风险，但为了确定该模型在化学安全评估中的适用性，需要使用更大和更多样化的化学测试组进行进一步研究。
