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Paternal early-life stress and diet influence female offspring behavior through sperm DNA methylation and transcriptomic alterations in the Amygdala [Sperm_methylation_F0]

ABSTRACT: Obesity is a global epidemic influenced by stress-related experiences during development, which can program behavioral traits, with the amygdala playing a central role in stress regulation. These programmed effects may be inherited through epigenetic mechanisms. Here, we examined the impact of paternal early-life stress (ELS), alone or combined with a high-fat diet (HFD), on offspring behavior and gene regulation. Male Wistar rats underwent maternal separation to induce ELS, followed by elevated plus maze (EPM) testing and exposure to either HFD or standard chow. These males were bred with naïve females, and F1 offspring were raised under standard conditions. Amygdala tissue and sperm were collected; RNA from paternal and offspring amygdalae was deep-sequenced, and sperm DNA was analyzed using Reduced Representation Bisulfite Deep Sequencing (RRBS. Paternal exposure to ELS and HFD independently and jointly altered physiology and behavior in F1 female offspring. Offspring of ELS fathers showed increased exploratory behavior and mobility in the EPM, while; paternal HFD increased time spent in open arms. In the paternal amygdala, ELS and HFD induced distinct gene expression changes. Sperm methylation analysis revealed hundreds of differentially methylated genes, many overlapping with transcriptional changes in the F1 female amygdala, supporting a role for epigenetic inheritance. Overlapping expression patterns in F0 and F1 included genes involved in dopamine signaling and epigenetic regulation. Notably, the imprinted gene GRB10 showed increased promoter methylation in sperm and reduced expression in both paternal and offspring amygdala, validated by immunostaining. These findings suggest that paternal ELS and HFD shape offspring phenotype through heritable epigenetic modifications.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE306044 | GEO | 2026/05/19

REPOSITORIES: GEO

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Project description:Purpose: Paternal life experiences impact offspring health via germline, and epigenetic inheritance provides a potential mechanism. However, global reprogramming during offspring embryogenesis and gametogenesis represents the largest hurdle to conceptualize it. Yet, detailed characterization of how sperm epigenetic alterations carrying “environmental memory” can evade offspring embryonic reprogramming remains elusive. Methods: we profiled the sperm DNA methylation patterns of three consecutive generations (F0, F1 and F2) in both control and stress groups by using whole-genome bisulfite sequencing (WGBS). A total of 18 sperm samples were analyzed, including three biological replicates for each generation under each treatment. In addition, small RNA sequencing was carried out on paternal sperm samples to investigate whether long-term psychological stress affected the enrichment of certain sncRNAs and to identify whether they participated in mediating the occurrence and paternal inheritance of the stress-induced DMRs Rsults: Using an optimized data analysis workflow, we obtained approximately 800 million clean reads per sample (build mm10) with strand-specific coverage ~21×, and the data covered ~96.00% of the total 21,867,837 reference CpG dinucleotides. A total of 24,427, 7,975, and 5,173 differentially methylated regions (DMRs) between control and stress groups were found in the F0, F1, and F2 generations, respectively. Inter- and transgenerational inheritance of paternal DMRs were at frequencies approximately 11.36% and 0.48%, respectively. These DMRs related to genes with functional implications for psychological stress response, and tissue inheritance of these DMRs passed paternal disorders epigenetically to offspring. More importantly, these DMRs evaded offspring embryonic reprogramming through erasure and subsequent reestablishment, but not via un-erasure way. Nonetheless, their reestablishment proportions in the primitive streak (E7.5) stage were altered. Furthermore, sncRNA-seq revealed that stress-induced tsRNA, miRNA and rsRNA dysregulation in paternal sperm might play important roles in DMRs occurrence and paternal inheritance.

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Paternal early-life stress and diet influence female offspring behavior through sperm DNA methylation and transcriptomic alterations in the Amygdala [Sperm_methylation_F0]

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