Epigenetic changes in sperm are associated with paternal and child quantitative autistic traits in an autism-enriched cohort

Feinberg, Jason I.; Schrott, Rose; Ladd‐Acosta, Christine; Newschaffer, Craig J.; Hertz‐Picciotto, Irva; Croen, Lisa; Fallin, M. Daniele; Feinberg, Andrew P.; Volk, Heather E.

doi:10.1038/s41380-023-02046-7

Cited by 7 publications

(3 citation statements)

References 58 publications

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“…Hundreds of DNA methylation changes are evident in the spermatozoa of ageing males, many of which are present in the CpG regions that regulate the expression of key genes governing neurological, psychiatric and behavioural disorders, including conditions such as spontaneous schizophrenia, bipolar disease, mood disorders and autism, that are known to be increased in the offspring of ageing fathers ( Milekic et al , 2015 ; Yatsenko and Turek, 2018 ). Importantly, recent data have confirmed that epigenetic changes in spermatozoa are associated with the appearance of autism-spectrum changes in the offspring ( Feinberg et al , 2023 ) and could be a key mechanism by which paternal age impacts the health and wellbeing of children. The molecular mechanisms underpinning these epigenetic changes in the male germ line are unknown but could be yet another reflection of the oxidative stress that characterizes male reproductive ageing ( Menezo et al , 2016 ).…”

Section: Paternal Ageing and Epigenetic Changementioning

confidence: 96%

Male reproductive ageing: a radical road to ruin

Aitken

2023

Human Reproduction

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In modern post-transition societies, we are reproducing later and living longer. While the impact of age on female reproductive function has been well studied, much less is known about the intersection of age and male reproduction. Our current understanding is that advancing age brings forth a progressive decline in male fertility accompanied by a reduction in circulating testosterone levels and the appearance of age-dependent reproductive pathologies including benign prostatic hypertrophy and erectile dysfunction. Paternal ageing is also associated with a profound increase in sperm DNA damage, the appearance of multiple epigenetic changes in the germ line and an elevated mutational load in the offspring. The net result of such changes is an increase in the disease burden carried by the progeny of ageing males, including dominant genetic diseases such as Apert syndrome and achondroplasia, as well as neuropsychiatric conditions including autism and spontaneous schizophrenia. The genetic basis of these age-related effects appears to involve two fundamental mechanisms. The first is a positive selection mechanism whereby stem cells containing mutations in a mitogen-activated protein kinase pathway gain a selective advantage over their non-mutant counterparts and exhibit significant clonal expansion with the passage of time. The second is dependent on an age-dependent increase in oxidative stress which impairs the steroidogenic capacity of the Leydig cells, disrupts the ability of Sertoli cells to support the normal differentiation of germ cells, and disrupts the functional and genetic integrity of spermatozoa. Given the central importance of oxidative stress in defining the impact of chronological age on male reproduction, there may be a role for antioxidants in the clinical management of this process. While animal studies are supportive of this strategy, carefully designed clinical trials are now needed if we are to realize the therapeutic potential of this approach in a clinical context.

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Section: Paternal Ageing and Epigenetic Changementioning

confidence: 96%

Male reproductive ageing: a radical road to ruin

Aitken

2023

Human Reproduction

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“…Such disorders, with a higher incidence in children of older fathers, include spontaneous schizophrenia, bipolar disease, mood disorders, and autism [86,102]. Recent studies suggest that sperm cell epigenetic profile alterations are linked to autism-related changes in offspring, indicating a critical mechanism by which paternal age influences child health and well-being [103].…”

Section: Paternal Aging: Effects On Sperm Integrity Epigenetics and R...mentioning

confidence: 99%

Advanced Paternal Age in Focus: Unraveling Its Influence on Assisted Reproductive Technology Outcomes

Kaltsas,

Zikopoulos,

Vrachnis

et al. 2024

JCM

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As global demographics shift toward increasing paternal age, the realm of assisted reproductive technologies (ARTs), particularly in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), faces new challenges and opportunities. This study provides a comprehensive exploration of the implications of advanced paternal age on ART outcomes. Background research highlights the social, cultural, and economic factors driving men toward later fatherhood, with a focus on the impact of delayed paternity on reproductive outcomes. Methods involve a thorough review of existing literature, centering on changes in testicular function, semen quality, and genetic and epigenetic shifts associated with advancing age. Study results point to intricate associations between the father’s age and ART outcomes, with older age being linked to diminished semen quality, potential genetic risks, and varied impacts on embryo quality, implantation rates, and birth outcomes. The conclusions drawn from the current study suggest that while advanced paternal age presents certain risks and challenges, understanding and mitigating these through strategies such as sperm cryopreservation, lifestyle modifications, and preimplantation genetic testing can optimize ART outcomes. Future research directions are identified to further comprehend the epigenetic mechanisms and long-term effects of the older father on offspring health. This study underscores the need for a comprehensive approach in navigating the intricacies of delayed fatherhood within the context of ART, aiming for the best possible outcomes for couples and their children.

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“…Epigenetic modifications in sperm have emerged as another plausible mechanism underlying the effects of paternal aging on offspring [27][28][29][30][31] . We have previously revealed age-related modifications in DNA methylation in mouse sperm 4 and changes in histone modifications within the testis 32 , suggesting their potential influence on offspring development.…”

Section: Introductionmentioning

confidence: 99%

Investigating the impact of paternal aging on murine sperm miRNA profiles and their potential link to autism spectrum disorder

Miyahara

Tatehana

Kikkawa

et al. 2023

Preprint

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Background: Paternal aging has been consistently linked to an increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD), in offspring. While de novo mutations arising from paternal aging have been extensively studied, recent evidence has highlighted the role of epigenetic factors. We have previously revealed age-related DNA hypomethylation in mouse sperm and alterations in histone modifications during spermatogenesis. Objectives: This study aimed to investigate age-related alterations in the microRNA (miRNA) profile of mouse sperm and analyze the target genes regulated by differentially expressed miRNAs. Materials and Methods: Microarray analyses were conducted to identify differentially expressed miRNAs in sperm samples from mice at different ages: 3 months (3M), over 12M, and beyond 20M. The expression levels of genes potentially regulated by these miRNAs were also accessed. Comprehensive bioinformatic analyses were performed to unravel the intricate relationship between differentially expressed miRNAs and their target genes. Results: We identified 26 miRNAs exhibiting differential expression between the 3M and 20M, 34 miRNAs between the 12M and 20M, and 2 miRNAs between the 3M and 12M mice. Notably, the target genes regulated by these differentially expressed miRNAs were significantly associated with apoptosis and ferroptosis pathways. Some of these target genes were relevant to the nervous system and potentially involvement in ASD. Discussion: The findings suggest that aging induces alterations in the sperm miRNA profiles . Importantly, the target genes regulated by these differentially expressed miRNAs are associated with cell death and ASD, implying a potential link between paternal aging and an increased risk of neurodevelopmental disorders. Conclusion: The observed age-related changes in sperm miRNA profiles have the potential to impact sperm quality and subsequently affect offspring development. Further validation and through investigations are necessary to gain a comprehensive understanding of the precise effects of paternal aging on subsequent generations.

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Epigenetic changes in sperm are associated with paternal and child quantitative autistic traits in an autism-enriched cohort

Cited by 7 publications

References 58 publications

Male reproductive ageing: a radical road to ruin

Male reproductive ageing: a radical road to ruin

Advanced Paternal Age in Focus: Unraveling Its Influence on Assisted Reproductive Technology Outcomes

Investigating the impact of paternal aging on murine sperm miRNA profiles and their potential link to autism spectrum disorder

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