Resveratrol attenuates prenatal X-ray-induced microcephaly and adult depression via SIRT1-mediated senescence suppression and TPH2/5-HT pathway restoration in mice

  • Phytomedicine. 2025 Jul 25:143:156845. doi: 10.1016/j.phymed.2025.156845.
Yu Feng Zhang  1 ,  Ze Lin Xu  1 ,  Chen Wang  1 ,  Jing Li  1 ,  Meng Ying Wu  1 ,  Yi Qi Yi  1 ,  Ting Wang  1 ,  Po Bian  2
Affiliations
  • 1. Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, China.
  • 2. Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, China. Electronic address: [email protected].
PMID: 40440905 DOI: 10.1016/j.phymed.2025.156845
Abstract

Background: 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.

Purpose: 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.

Study design: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords
Microcephaly; Radiation; Resveratrol; SIRT1; TPH2.
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