Increased Paternal Age at Conception Is Associated with Transcriptomic Changes Involved in Mitochondrial Function in...

Area of Science:

• Genetics
• Molecular Biology
• Aging Research

Background:

• Increased paternal age at conception (PAC) is linked to autism spectrum disorder, schizophrenia, and other neurodevelopmental disorders.
• Male germ cells undergo numerous cell divisions, increasing the risk of DNA point mutations with advanced paternal age.
• Replication errors and inefficient DNA repair in spermatogonia contribute to mutagenic load, potentially explaining paternal age effects.

Purpose of the Study:

• To investigate the association between paternal age at conception and gene expression profiles in offspring.
• To identify specific cellular processes and pathways affected by advanced paternal age.

Main Methods:

• Gene expression profiling using HumanHT-12 v4 Expression BeadChip on peripheral blood mononuclear cells from 38 nonagenarians.
• Spearman's rank correlation to assess associations between gene expression and PAC.
• Pathway analysis using GOrilla and IPA to identify enriched cellular processes.

Main Results:

• PAC was associated with the expression levels of 648 transcripts in nonagenarian subjects.
• These transcripts were enriched in mitochondrial translational termination and the canonical pathway of Mitochondrial dysfunction, specifically Oxidative phosphorylation.
• A systematic down-regulation of mitochondrial respiratory chain components was observed, suggesting compromised oxidative phosphorylation and energy production.

Conclusions:

• Advanced paternal age at conception is associated with molecular changes indicative of mitochondrial dysfunction in offspring.
• These findings suggest that impaired oxidative phosphorylation may be a mechanism underlying the health concerns linked to increased PAC.
• Further research is warranted to elucidate the full impact of paternal age on offspring health and development.