Aging mouse sperm affects MicroRNA, increasing the risk of neurodevelopmental disorders
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RESEARCHERS HAVE DISCOVERED THAT THE THE AGE OF THE MICE IMPACTS MICRORNAS.
view moreCREDIT: TOHOKU UNIVERSITY
A recent study has reported that changes in mice sperm microRNAs brought about by aging may affect the growth and development of offspring. The finding adds to the growing literature on the effects of paternal aging on offspring.
Details of the study were published in the journal Scientific Reports on December 7, 2023.
Marriages and childbearing later in life are increasingly becoming the norm. Whilst the impacts of maternal age on offspring, such as a higher risk of miscarriage and Down syndrome, are widely understood, the impacts from the paternal side are less so.
Yet this is changing. Recent epidemiological studies have demonstrated that paternal aging exerts a more substantial influence on the heightened risk of neurodevelopmental disorders such as autism spectrum disorder.
A research team led by Professor Noriko Osumi from the Department of Developmental Neuroscience at the Tohoku University Graduate School of Medicine has previously revealed that epigenetic factors, including histone modifications in spermatogenesis and DNA methylation in mice sperm, undergo changes with age. These alterations might lead to transgenerational effects.
However, the impact of paternal aging on microRNAs (miRNAs), small, non-coding RNA molecules that play a crucial role in regulating gene expression, remains under explored.
To rectify this, the same research team has conducted a comprehensive analysis of age-related variations in microRNAs in mice sperm. They compared microRNAs in sperm from mice aged 3, 12, and 20 months and identified the microRNAs that had changed in quantity.
The researchers discovered significant age-associated differences in the microRNAs. Some changes were in microRNAs responsible for regulating the nervous system and genes related to autism spectrum disorder, and these altered microRNAs included those transferred to fertilized eggs.
"Our study reveals the potential association between alteration in sperm microRNAs caused by paternal aging, underscoring the significance of investigating the impact of sperm microRNAs on offspring, an aspect that has been relatively overlooked in previous research," states Osumi.
The anticipation is that further exploration of epigenetic factors, specifically microRNAs, will not only contribute to unraveling the pathogenic mechanisms underlying neurodevelopmental disorders but will also offer insights into promoting the health and disease prevention of successive generations.
Osumi points out that their study widens the net when it comes to exploring the link between paternal age and potential health complications in children. "While the age-related changes in oocytes are well-documented, the focus has predominantly centered on the fertility of sperm. Recognizing the myriad epigenetic transformations associated with sperm aging, as exemplified by the microRNAs examined in this study, becomes imperative."
The findings also gain relevance in the context of Japan's rapidly declining birthrate, which necessitates incorporating the perspective on sperm-related factors in advancing reproductive medicine.
Venn diagram showing the number of miRNAs expressed in sperm samples from mice aged 3 M, 12 M and 20 M. A total of 447 miRNAs were expressed, and about half of them are common.
The expression levels of miR-10a-5p (left) and miR-146a-5p (right), microRNAs reported to be transferred to the fertilized egg, changes with age.
The expression levels of miR-10a-5p (left) and miR-146a-5p (right), microRNAs reported to be transferred to the fertilized egg, changes with age.
CREDIT
Kazusa Miyahara et al.
Kazusa Miyahara et al.
JOURNAL
Scientific Reports
ARTICLE TITLE
Investigating the impact of paternal aging on murine sperm miRNA profiles and their potential link to autism spectrum disorder
Singapore study reveals impact of early life adversity on a child’s brain development
Leveraging neuroimaging data from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort, researchers from A*STAR’s Singapore Institute for Clinical Sciences (SICS) identified an association between early life adversity and the pace of brain development in childhood.
SINGAPORE – A study led by researchers from A*STAR's Singapore Institute for Clinical Sciences (SICS) has found evidence suggesting that children exposed to elevatec levels of early life adversity (ELA) exhibit an accelerated pattern of brain development during the preschool years. When exposed to ELA, such as a mother's mental and physical health challenges during pregnancy, the child’s brain undergoes accelerated development in order to adapt to the adverse circumstances. This hastened pace of brain development could lead to a higher risk of adverse cognitive and mental health outcomes. The paper, “The influence of early-life adversity on the coupling of structural and functional brain connectivity across childhood” was published in Nature Mental Health on 4 January 2024.
Exposure to ELA is a recognised risk factor for poor health outcomes throughout life. This includes an increased risk of cognitive impairment as well as the development of mental health disorders such as major depressive disorders. Exposure to ELA in the prenatal period triggers changes in the pace of brain development across childhood, most prominent during the preschool period – a crucial time window whereby experience-dependent learning and adaptation set the stage for future brain function. Previous studies suggest that ‘accelerated brain development’ is an adaptive mechanism to early life challenges and may mediate the association between ELA and poor mental health and cognitive outcomes.
To effectively quantify the impact of ELA, the research team adopted a scoring framework created by Professor Patricia Silveira at McGill University, to produce a composite score of ELA which considered factors that extend across a population. These factors focused on exposures experienced before birth, encompassing the mother's mental and physical health during pregnancy as well as the family’s structure and financial circumstances. When we add up or combine different risk factors, it gives us a better prediction of child’s outcome. Using this composite score, the study team stratified the GUSTO cohort into different levels of cumulative ELA exposure. The pace of brain development was then examined across children exposed to different levels of ELA.
To model the pace of brain development across childhood, the study team utilised multi-modal MRI scans from the GUSTO birth cohort. These MRI brain scans were acquired from 549 children at three time-points, ages 4.5, 6.0 and 7.5 years, allowing the study team to examine the link between ELA and brain development in a longitudinal manner. As most mental health disorders have roots in childhood, the study of developmental trajectories in a longitudinal manner is strongly relevant. In this study, a measure which combines structural connectivity and functional connectivity of the brain was used to provide insights into the association between brain structure and function. This measure, known as structure-function coupling (SC-FC), reflects a child’s potential for neuroplasticity, the brain's ability to adapt and reorganise itself to learn, recover from injury, and adjust to new experiences. In early childhood, the brain is expected to be less specialised and more adaptable, matching a decreasing trajectory of SC-FC over childhood.
Led by Dr Tan Ai Peng, Principal Investigator with A*STAR’s SICS and clinician with National University Hospital, along with Dr Chan Shi Yu, a researcher at A*STAR’s SICS, the study found that exposure to high levels of ELA is linked to a faster decline in SC-FC between ages 4.5 and 6, indicating accelerated brain development. This accelerated pattern of brain development is likely an adaptive mechanism when exposed to environmental cues that requires ‘maturity’. Although this is meant to be a ‘protective mechanism’ against adversity, it does have negative implications in the long term as it results in a shorter window of neuroplasticity and adaptive-learning. Notably, results from this study pinpoint the period between ages 4.5 and 6 years as a potential window for early intervention to improve outcomes for children who were exposed to ELA.
“Our study provided evidence that exposure to early-life challenges affects the pace of brain development across childhood. This, in turn, has significant effects on future cognitive and mental health outcomes. If we can develop screening tools to detect accelerated brain development, we will be able to implement interventions earlier, and prevent cascading consequences of accelerated brain development for mental health.” said, Dr Tan Ai Peng
Already looking forward, the researchers have identified important areas for future investigation – determining whether ELA’s effects on accelerated brain development across childhood set the stage for premature brain ageing in later stages of life, and the effectiveness of intervention strategies that could mitigate the effects of ELA exposure such as the promotion of psychological resilience through cognitive behavioural therapy.
JOURNAL
Nature Mental Health
ARTICLE TITLE
The influence of early-life adversity on the coupling of structural and functional brain connectivity across childhood
ARTICLE PUBLICATION DATE
4-Jan-2024
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