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

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.