Hunt Piper Reid, Olejnik Nicholas, Yourick Jeffrey, Sprando Robert L
Division of Toxicology, Human Foods Program, U.S. Food and Drug Administration, Laurel, MD 20708, United States.
Toxicol Rep. 2025 Sep 5;15:102124. doi: 10.1016/j.toxrep.2025.102124. eCollection 2025 Dec.
Developmental delay and spontaneous locomotor activity changes, as well as the reversibility of these adverse effects are apical endpoints used in chemical safety evaluations. These endpoints were assessed at sublethal concentrations in using 5-fluorouracil (5FU), hydroxyurea (HU), or ribavirin (RV), teratogens that are associated with reduced fetal growth in mammals. develop from egg to egg-laying adult in about three days. Synchronized cohorts were exposed either continuously, or for 24 h (early-only) from first-feeding after hatching. Developmental delays were dose-responsive for all three chemicals in both exposure schemes. For 5FU and HU, developmental delays and hypoactivity levels were similar in continuous and early-only exposure groups, consistent with irreversible developmental effects. The observed hypoactivity in developing may be related to reported 5FU-induced muscle impairment and HU-induced post-exposure effects on locomotion parameters in mammals. In contrast to 5FU- and HU-induced hypoactivity, RV was associated with a non-significant trend to slight hyperactivity in both exposure schemes. Continuous RV exposures induced delays to sequential developmental milestones that increased with exposure duration. RV-induced delays were significantly reduced but not eliminated in early-only exposure cohorts, consistent with cumulative RV effects on developmental progress. These findings suggest that may be a useful model for detecting chemicals with irreversible, reversible, and/or cumulative effects on organismal development.
发育迟缓与自发运动活动变化,以及这些不良反应的可逆性,是化学安全评估中使用的关键终点指标。在使用5-氟尿嘧啶(5FU)、羟基脲(HU)或利巴韦林(RV)(这些致畸剂与哺乳动物胎儿生长受限有关)的亚致死浓度下,对这些终点指标进行了评估。[某种生物]在大约三天内从卵发育为产卵成虫。同步的群体在孵化后首次进食时要么持续暴露,要么暴露24小时(仅早期)。在两种暴露方案中,所有三种化学物质的发育迟缓都呈剂量反应关系。对于5FU和HU,持续暴露组和仅早期暴露组的发育迟缓和活动减退水平相似,这与不可逆的发育效应一致。在发育中的[某种生物]中观察到的活动减退可能与报道的5FU诱导的肌肉损伤以及HU暴露后对哺乳动物运动参数的影响有关。与5FU和HU诱导的活动减退相反,在两种暴露方案中,RV都与轻微多动的非显著趋势相关。持续暴露于RV会导致连续发育里程碑的延迟,且这种延迟随暴露持续时间增加。在仅早期暴露的群体中,RV诱导的延迟显著减少但未消除,这与RV对发育进程的累积效应一致。这些发现表明,[某种生物]可能是一种用于检测对机体发育具有不可逆、可逆和/或累积效应的化学物质的有用模型。