Zhang Yu Feng, Xu Ze Lin, Wang Chen, Li Jing, Wu Meng Ying, Yi Yi Qi, Wang Ting, Bian Po
Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, China.
Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, China.
Phytomedicine. 2025 Jul 25;143:156845. doi: 10.1016/j.phymed.2025.156845. Epub 2025 May 21.
With increasing use of medical imaging (e.g., CT scans) and environmental radiation sources, over 2 % of pregnancies worldwide are inadvertently exposed to low-dose ionizing radiation (IR), raising urgent concerns about fetal neuroprotection. While prenatal IR is implicated in microcephaly and lifelong neuropsychiatric risks, prior studies have not resolved whether sirtuin-mediated pathways, particularly SIRT1/TPH2 signaling, drive these deficits or whether dietary phytochemicals like resveratrol can mitigate them.
To determine (1) the role of SIRT1/TPH2 signaling in IR-induced neurodevelopmental and psychiatric impairments, and (2) the therapeutic potential of maternal resveratrol supplementation to counteract these effects-a strategy not previously explored in prenatal radiation models.
Mouse cohorts received prenatal X-ray irradiation (0, 1.0 Gy, 2 Gy gestational day 8) with/without resveratrol supplementation, followed by longitudinal cortical and behavioral analyses.
RNA sequencing/Western blotting quantified SIRT1, TPH2, BDNF, and senescence markers (P16, P21 and SA-β-gal). 5-HT levels were assessed by ELISA. Depression-like behaviors were tested via forced swim and tail suspension.
IR-exposed fetuses exhibited progressive microcephaly with reduced cortical thickness, accompanied by SIRT1 downregulation, BDNF suppression, and elevated cellular senescence. Adult offspring displayed depression-like behaviors, linked to TPH2 downregulation and diminished 5-HT levels. Resveratrol supplementation normalized SIRT1/TPH2 signaling, restored cortical neurotrophic factors, and attenuated both microcephaly and depressive phenotypes.
This study provides the first evidence that (1) SIRT1/TPH2 signaling is a central mediator of IR-induced neurodevelopmental and psychiatric impairments, and (2) maternal resveratrol supplementation prevents cortical damage and depression in offspring by rescuing this pathway. These findings position resveratrol as a novel, mechanism-driven intervention for fetal neuroprotection against environmental radiation.
随着医学成像（如CT扫描）和环境辐射源的使用增加，全球超过2%的孕妇在孕期无意中暴露于低剂量电离辐射（IR），这引发了对胎儿神经保护的迫切关注。虽然产前IR与小头畸形以及终身神经精神风险有关，但先前的研究尚未确定沉默调节蛋白介导的信号通路，特别是SIRT1/TPH2信号通路是否导致了这些缺陷，或者像白藜芦醇这样的膳食植物化学物质是否可以减轻这些缺陷。
确定（1）SIRT1/TPH2信号通路在IR诱导的神经发育和精神障碍中的作用，以及（2）母体补充白藜芦醇以抵消这些影响的治疗潜力——这是产前辐射模型中以前未探索过的策略。
小鼠队列在妊娠第8天接受产前X射线照射（0、1.0 Gy、2 Gy），同时有或没有补充白藜芦醇，随后进行纵向皮质和行为分析。
RNA测序/蛋白质印迹法对SIRT1、TPH2、脑源性神经营养因子（BDNF）和衰老标志物（P16、P21和衰老相关β-半乳糖苷酶）进行定量。通过酶联免疫吸附测定法评估5-羟色胺（5-HT）水平。通过强迫游泳和悬尾试验测试抑郁样行为。
暴露于IR的胎儿表现出渐进性小头畸形，皮质厚度减小，同时伴有SIRT1下调、BDNF抑制和细胞衰老增加。成年后代表现出抑郁样行为，这与TPH2下调和5-HT水平降低有关。补充白藜芦醇可使SIRT1/TPH2信号通路正常化，恢复皮质神经营养因子，并减轻小头畸形和抑郁表型。
本研究首次提供了以下证据：（1）SIRT1/TPH2信号通路是IR诱导的神经发育和精神障碍的核心介质，（2）母体补充白藜芦醇通过挽救该信号通路可预防后代的皮质损伤和抑郁。这些发现将白藜芦醇定位为一种新型的、基于机制的干预措施，用于保护胎儿神经免受环境辐射。
