Advanced paternal age exacerbates neuroinflammation in offspring via m6A modification-mediated intergenerational inheritance
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Updated: Jun 11, 2025
Induction of Maternal Immune Activation in Mice at Mid-gestation Stage with Viral Mimic PolyI:C
Published on: March 25, 2016
Yiting Mao1,2,3, Yicong Meng2,4, Kexin Zou2,5
1Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, 200011, China.
Insights
Advanced paternal age (APA) in mice leads to offspring cognitive impairment and autism-like behaviors. Epigenetic changes in sperm, specifically involving m6A modification of Nr4a2 and elevated Ythdc1, contribute to neuroinflammation and behavioral deficits.
Area of Science:
- Reproductive Biology
- Neuroscience
- Epigenetics
Background:
- Advanced paternal age (APA) is a global trend linked to adverse pregnancy outcomes and offspring health issues.
- The mechanisms by which paternal aging impacts offspring neuropsychiatric disorders remain largely unknown.
- This study investigates behavioral and epigenetic changes in offspring from aging sperm.
Purpose of the Study:
- To explore behavioral phenotypes in offspring of advanced paternal age (APA) mice.
- To identify pathological epigenetic alterations in APA offspring inherited from aging sperm.
- To elucidate the role of N6-methyladenosine (m6A) modifications in intergenerational neurodevelopmental effects.
Main Methods:
- Behavioral tests, ELISA, immunofluorescence, and western blotting were conducted on offspring mice.
- Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA immunoprecipitation sequencing (RIP-seq) analyzed m6A profiles in sperm and hippocampus.
- Gene expression was manipulated using viral vectors to assess therapeutic targets for neuroinflammation.
Main Results:
- APA offspring exhibited cognitive impairment and autism-like behaviors with increased neuroinflammation and microglial overactivation.
- Nr4a2 was hypermethylated with decreased expression in APA offspring, affecting synaptic plasticity and microglial function.
- Elevated Ythdc1 in aging sperm and offspring hippocampus recognized and suppressed Nr4a2, contributing to abnormal phenotypes; Ythdc1 suppression alleviated these deficits.
Conclusions:
- Advanced paternal age is associated with specific behavioral abnormalities in offspring.
- Epigenetic modifications, particularly m6A methylation and reader proteins like Ythdc1, play a role in intergenerational transmission of neurodevelopmental risks.
- Targeting Ythdc1 presents a potential therapeutic strategy for mitigating APA-associated offspring neuroinflammation and behavioral issues.
Background:
The trend of postponing childbearing age is prevalent worldwide. Advanced paternal age (APA) is associated with adverse pregnancy outcomes and offspring health. However, the underlying mechanism by which paternal aging affects the risk of offspring neuropsychiatric disorders is unclear. Our study aims to explore the behavioral phenotypes and the pathologic epigenetic alterations of APA offspring inherited from aging sperm.
Methods:
Behavioral tests, ELISA assay, immunofluorescence and western blotting were performed on offspring mice. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA immunoprecipitation sequencing (RIP-seq) were used to investigate the modified N6-methyladenosine (m6A) profiles of paternal sperm and offspring hippocampus. Intervention of gene expression by lentivirus and adeno-associated virus in both vivo and vitro examined the potential therapeutic targets of intergenerational inherited neuroinflammation.
Results:
In our study, APA offspring exhibit cognitive impairment and autism-like behavior. An increase in neuroinflammation in APA offspring is associated with microglial overactivation, which manifests as abnormal morphology and augmented engulfment. MeRIP-seq of F0 sperm and F1 hippocampus reveal that Nr4a2 is hypermethylated with decreased expression in APA offspring involving in synaptic plasticity and microglial function. In addition, Ythdc1, an m6A reader protein, is markedly elevated in aging sperm and remains elevated in adult hippocampus of APA group. Enhanced Ythdc1 recognizes and suppresses the hypermethylated Nr4a2, thereby contributing to the abnormal phenotype in offspring. The overexpression of Ythdc1 triggers microglial activation in vitro and its suppression in the hippocampus of APA progeny alleviates behavioral aberrations and attenuates neuroinflammation.
Conclusion:
Our study provides additional evidence of the abnormal behavioral phenotypes of APA offspring and reveals potential epigenetic inheritance signatures and targeted genes for future research.
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