Dmac033 PDF
Dmac033 PDF
Dmac033 PDF
24–44, 2023
Advance Access Publication on September 6, 2022 https://doi.org/10.1093/humupd/dmac033
*Correspondence address. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskye Gory,
House 1, Building 40, Room 322, Moscow 119992, Russia. E-mail: [email protected] https://orcid.org/0000-0002-5745-3348
Submitted on October 4, 2021; resubmitted on August 5, 2022; editorial decision on August 10, 2022
TABLE OF CONTENTS
................................................................................................................................
• Introduction
Delayed parenthood and advanced paternal age
Age and natural fertility
Environment and lifestyle-induced changes in gametes
Assisted reproductive technologies prolong fertile age
• Germ cells’ fate and epigenetic mechanisms of the sperm
• Age and genetic events in gametes
• Age-associated epigenetic markers in sperm and fertility
• Age-dependent changes in the sperm epigenome: animal data
DNA methylation
Small non-coding RNAs
Histone modifications
Interaction between age and environmental factors
Lessons from animal studies
• Age-associated epigenetic changes and epigenetic clocks in human sperm
• Age-induced epigenetic sperm changes and their influence on fertilization, embryo development and offspring
health
• Age, ART procedures and additional epigenetic risks
• Discussion
Age-dependent changes in sperm epigenome: stochastic errors or program targeting offspring fitness
Future perspectives characteristics of sperm epigenetic markers: dynamic/stability and reversibility
• Conclusions
†
These authors contributed equally to this work.
C The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which
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Age-associated sperm epigenetic changes 25
GRAPHICAL ABSTRACT
BACKGROUND: Modern reproductive behavior in most developed countries is characterized by delayed parenthood. Older gametes
are generally less fertile, accumulating and compounding the effects of varied environmental exposures that are modified by lifestyle factors.
Clinicians are primarily concerned with advanced maternal age, while the influence of paternal age on fertility, early development and
offspring health remains underappreciated. There is a growing trend to use assisted reproductive technologies for couples of advanced
reproductive age. Thus, the number of children born from older gametes is increasing.
OBJECTIVE AND RATIONALE: We review studies reporting age-associated epigenetic changes in mammals and humans in sperm,
including DNA methylation, histone modifications and non-coding RNAs. The interplay between environment, fertility, ART and
age-related epigenetic signatures is explored. We focus on the association of sperm epigenetics on epigenetic and phenotype events in
embryos and offspring.
SEARCH METHODS: Peer-reviewed original and review articles over the last two decades were selected using PubMed and the Web of
Science for this narrative review. Searches were performed by adopting the two groups of main terms. The first group included ‘advanced
paternal age’, ‘paternal age’, ‘postponed fatherhood’, ‘late fatherhood’, ‘old fatherhood’ and the second group included ‘sperm epige-
netics’, ‘sperm’, ‘semen’, ’epigenetic’, ‘inheritance’, ‘DNA methylation’, ‘chromatin’, ‘non-coding RNA’, ‘assisted reproduction’, ‘epigenetic
clock’.
OUTCOMES: Age is a powerful factor in humans and rodent models associated with increased de novo mutations and a modified sperm
epigenome. Age affects all known epigenetic mechanisms, including DNA methylation, histone modifications and profiles of small
non-coding (snc)RNA. While DNA methylation is the most investigated, there is a controversy about the direction of age-dependent
changes in differentially hypo- or hypermethylated regions with advanced age. Successful development of the human sperm epigenetic clock
26 Ashapkin et al.
based on cross-sectional data and four different methods for DNA methylation analysis indicates that at least some CpG exhibit a linear
relationship between methylation levels and age. Rodent studies show a significant overlap between genes regulated through age-
dependent differentially methylated regions and genes targeted by age-dependent sncRNA. Both age-dependent epigenetic mechanisms
target gene networks enriched for embryo developmental, neurodevelopmental, growth and metabolic pathways. Thus, age-dependent
changes in the sperm epigenome cannot be described as a stochastic accumulation of random epimutations and may be linked with autism
spectrum disorders. Chemical and lifestyle exposures and ART techniques may affect the epigenetic aging of sperm. Although most epige-
netic modifications are erased in the early mammalian embryo, there is growing evidence that an altered offspring epigenome and pheno-
type is linked with advanced paternal age due to the father’s sperm accumulating epigenetic changes with time. It has been hypothesized
that age-induced changes in the sperm epigenome are profound, physiological and dynamic over years, yet stable over days and months,
and likely irreversible.
WIDER IMPLICATIONS: This review raises a concern about delayed fatherhood and age-associated changes in the sperm epigenome
that may compromise reproductive health of fathers and transfer altered epigenetic information to subsequent generations. Prospective
studies using healthy males that consider confounders are recommended. We suggest a broader discussion focused on regulation of the
Key words: sperm / epigenetics / advanced paternal age / age / DNA methylation / non-coding RNA / epigenetic clock / assisted repro-
ductive technologies / delayed parenthood / pregnancy success
..
et al., 2021; Pilsner et al., 2021). As one ages, it is not surprising that .. sncRNA profiles. The interplay between environment, lifestyle and fer-
the potential adverse effects of environmental conditions on gametes .. tility and age-related epigenetic markers is explored.
..
are compounded. Men may be more sensitive to these accumulating ..
effects due to the fundamental differences in gametogenesis among ...
men and women. In particular, the mitotic divisions in spermatogonia, ..
.. Germ cells’ fate and epigenetic
the undifferentiated male germ cell, occur throughout the life span of ..
men (Rosenwaks and Wassarman, 2014). Spermatogonia are charac- ..
..
mechanisms of the sperm
terized by their inherent self-renewal, with around 23 divisions every .. The germline transmits genetic and epigenetic information to the sub-
year (Goriely, 2016), that results in sperm production throughout
..
.. sequent generation (Hackett et al., 2012; Seisenberger et al., 2012;
man’s life span. While appearing to be evolutionary beneficial for men, .. Kagiwada et al., 2013; Xavier et al., 2019). The mammalian germline
the self-renewal properties of male germ cells allow for the accumula-
..
.. generates critical epigenetic information for embryo development
tion of genetic and epigenetic errors throughout the life course. .. through gene imprinting (Kelsey and Feil, 2013; Li, 2013; Tucci et al.,
Sperm are essential vehicles with specific molecular and epigenetic
..
.. 2019) as well as through some RNAs (Sendler et al., 2013; Zhang
..
A hallmark of spermiogenesis is the widespread change in chromatin .. stabilization by the known cytosine RNA methyltransferase activity of
structure, including the exchange of most canonical histones for prot- .. Dnmt2 (Goll et al., 2006; Ashapkin et al., 2016).
..
amines (Hao et al., 2019). Protamines are small basic proteins that ..
bind DNA to form toroids, tightly packed structures that compact the ...
genome to approximately 1/13 the size occupied by a human oocyte ..
.. Age and genetic events in
(Martins and Krawetz, 2007), which is well beyond that attainable with ..
nucleosomes. The high level of compaction is an essential attribute for
..
..
gametes
genome transport in the mature sperm head. The histone to the prot- .. A meta-analysis has shown a direct correlation between age and
amine exchange process is incomplete, with a small percentage (10%
..
.. nuclear DNA damage (Soares et al., 2014). An increase in DNA frag-
and 1% of histones in humans and mice, respectively) of the genome .. mentation with age has been confirmed in sperm (Wyrobek et al.,
..
remaining bound to nucleosomes (Wykes and Krawetz, 2003; .. 2006). Genetic and epigenetic changes in somatic cells related to aging
Hammoud et al., 2009; Brykczynska et al., 2010). The replacement of .. have been extensively studied, including their connection with age-
..
somatic histones by protamines is important for nuclear chromatin .. related diseases (reviewed in Ashapkin et al., 2017, 2019; Booth and
..
fertility or infertility biomarkers and biomarkers of the efficacy of ART .. rats using thin-layer chromatography (Oakes et al., 2003). Using a dif-
procedures. Epigenetic markers are among the promising biomarkers .. ferent approach (restriction landmark genomic scanning), the authors
..
of fertility or infertility, particularly for idiopathic (“unexplained”) infer- .. identified age-dependent hypermethylation of repeated ribosomal
tility (Jenkins and Turek, 2020). ... DNA (rDNA) loci. Later studies used more sensitive methods of
Selected imprinted genes were investigated in some of the earliest .. DNA methylation analysis.
..
sperm epigenetics and semen parameter studies among normozoo- .. In our recent study, we also used a rat model (Wistar rats) to ex-
spermic and oligozoospermic men. Abnormal methylation patterns at .. amine the effect of aging on DNA methylation in spermatozoa (Pilsner
..
both paternal (hypomethylated) and maternal (hypermethylated) .. et al., 2021). Profiles of DNA methylation were compared in 65- and
imprinted sites have been found in men with low sperm counts .. 120-day-old animals, corresponding approximately to young (20–
..
(Kobayashi et al., 2007; Marques et al., 2008; Boissonnas et al., 2010). .. 25 years old) and mature men (40–45 years old), respectively (Robb
High-throughput technologies for detecting DNA methylation across .. et al., 1978; Zanato et al., 1994). DNA methylation was assessed by
..
the genome allow the investigation of hundreds of DNA methylation .. reduced representation bisulfite sequencing (RRBS). In control animals,
targets. Houshdaran et al. (2007) were the first to find significant cor-
.. 5319 age-dependent differentially methylated regions (aDMRs) were
..
..
pathways. Contrary to the previous study, Xie et al. report overall loss .. targets. Interestingly, our results on age-dependent changes in miRNA
of methylation across Alu and LINE-1 repetitive elements in aged rela- .. and piRNA were concordant with changes in DNA methylation in the
..
tive to young sperm. .. same rat model (Pilsner et al., 2021). Genes associated with aDMRs
In a mouse model of autism spectrum disorder (ASD), the APA ef- ... were significantly enriched with gene targets of age-dependent miRNA
fect was manifested by vocal communication deficits in the offspring at .. and piRNA. In addition, genes (n ¼ 1052) overlapping as miRNA
..
infancy (Yoshizaki et al., 2021). Targeted sperm methylome analysis .. targets and as aDMR-associated genes were highly enriched for cate-
identified 16 hypermethylated and 96 hypomethylated DMRs in aged .. gories related to embryonic development.
..
(12 months old) compared to young (3 months old) mice. Binding .. Another recent study also reports age-dependent changes in
motifs for the neuron-restrictive silencer factor (NRSF) were detected
.. the distribution of fractions of sncRNA (Ma et al., 2020). The piRNA
..
in 19 out of 96 hypo-DMRs, while none were found in hyper-DMRs. .. fraction was significantly lower and the miRNA fraction was higher in
These changes in sperm DNA methylation appeared to lead to the
.. 12-month-old C57BL/6 mice than in 6–8-week-old animals. There
..
upregulation of NRSF target genes in the brain of the offspring em- .. were 162 miRNAs differentially expressed between age groups with
..
bryos at E14.5, the peak stage of neuronal production. .. 160 miRNA up-regulated in the sperm of older male mice. Gene tar-
..
respectively, in 4- and >21-month-old C57BL/6J mice. They identified .. affects the sperm epigenome; (ii) it is likely that pubertal life is associ-
a small region on chromosome 5 enriched with spermatogenesis- .. ated with more significant changes in the sperm epigenome than are
..
related genes (Speer), which contained 90% of the differential histone .. later stages; (iii) age-dependent changes of DNA methylation and
modifications (Xie et al., 2018). Tatehana et al. (2020) used a histo- ... sncRNA expression occur synchronously or are linked causatively and
chemical approach to analyze the patterns of histone modifications .. affect the same biological functions; (iv) age-dependent epigenetic
..
throughout spermatogenesis in young (3 months) and aged .. changes include changes in fractions of sncRNA subtypes; and
(12 months) mice. Among the transcription-repressive marks,
.. (v) genes associated with aDMRs or genes targets of age-dependent
..
H3K9me3 decreased, while H3K27me2/3 increased with age. The ac- .. sncRNA are enriched with metabolic pathways and major develop-
tivating mark H3K4me2 drastically decreased in the GCs of the aged
.. mental pathways, including nervous system-related signaling, Wnt,
..
males. .. Hippo, mTOR and Igf1.
..
Technical challenges in the assessment of nucleosome locations and ..
their histone modifications exist due to the structural constraints of ..
..
highly compact genome of mature sperm. Additional methodological .. Age-associated epigenetic
*
sncRNA, small non-coding RNA; DMRs, differentially methylated regions; RNA-seq, RNA sequencing; RRBS, reduced representation bisulfite sequencing.
#
ChIP-seq, chromatin immunoprecipitation sequencing.
**
SureSelect, SureSelect Methyl-Seq technique (Agilent).
***
EDMA, EmbryoGENE DNA methylation array.
##
EPIC, Infinium MethylationEPIC BeadChip (Illumina).
$
COBRA, combined bisulfite restriction analysis.
..
a gene-body CpG shore, in KCNA7, they were within a promoter .. mainly using samples from men of typical paternity ages (20–45 years).
CpG shore, while in NCOR2, they were within a distal CpG island. .. Of several design strategies tested, the model trained on a subset of
..
Single allele methylation profiles of FOXK1 (5 CpGs) and KCNA7 (12 .. 51 most robust aDMRs from Jenkins et al. (2014) was chosen. It per-
CpGs) were then studied in 13 sperm samples from young (25– .. formed well in the entire data set with an R2 ¼ 0.89 and a mean abso-
..
35 years) and 13 sperm samples from older (40–55 years) donors by .. lute error (MAE) of 2.04 years. Testing the model on independent
deep bisulfite sequencing. In sperm samples from younger donors, .. sperm samples (n ¼ 10) showed high accuracy of age prediction, with
..
both genes showed highly variable (0–100%) methylation levels, with .. an MAE of 2.37. When the epigenetic sperm ages were compared be-
most alleles exhibiting mixed methylation profiles (50–90% CpGs
.. tween individuals who had never smoked, smokers and long-term
..
methylated). In the sperm samples from older donors, methylation .. (>10 years) smokers of similar chronological ages, an increase of epi-
variation was much lower, and methylation profiles showed hypome-
.. genetic age was observed of around 1.5% in all smokers and 2.5% in
...
thylation (0–20% for FOXK1 and 10–40% for KCNA7) relative to young .. long-term smokers relative to never smokers. The authors suggested
sperm. Average methylation levels showed a significant negative corre- .. that their model is capable not only of correctly predicting age based
..
lation with paternal age (correlation coefficients 0.63 for FOXK1 and .. on sperm DNA methylation but also of predicting the aging-
0.77 for KCNA7). .. acceleration effects of smoking.
..
Sperm DNA methylation data obtained on the Illumina Infinium .. Another recent study used a customized methylC-capture sequenc-
HumanMethylation450 BeadChip microarray platform from three pre- .. ing approach to characterize DNA methylation in spermatozoa from
..
vious studies (Jenkins et al., 2014, 2017; Aston et al., 2015) were used .. 94 fertile and infertile men, who were categorized as young (48 men
to generate a DNA methylation sperm age prediction model (Jenkins
.. between 18 and 38 years) or old (46 men between 46 and 71 years)
..
et al., 2018). It should be noted that the model was constructed . (Cao et al., 2020). Among the 2.65 million CpGs covered, 21 971
Age-associated sperm epigenetic changes 33
..
were associated with aging, most of them (>99.5%) in regions not .. sequencing were used to derive an age predictor for sperm. Its valida-
reported previously. Interestingly, hypomethylation was less common .. tion in an independent set of sperm samples showed a good correla-
..
(38.3%; 8409 CpGs) than hypermethylation (61.7%; 13 562 CpGs) .. tion between calculated and chronological age with an MAE of
with age. The hypomethylated CpGs were frequently located near ... 9.8 years. The precision of this age predictor is lower than that of the
gene regions, whereas the hypermethylated CpGs were mostly in the .. sperm DNA methylation clock described above (Jenkins et al., 2018;
..
distal regions. Furthermore, 26% of age-associated CpGs were clus- .. Cao et al., 2020). While all clocks could be used in various experimen-
tered in DMRs where 5 CpGs in a 500-bp window were either .. tal settings, they should be confirmed by other studies, and a prospec-
..
hypomethylated (315 hypoDMRs) or hypermethylated (483 .. tive design using men from a healthy population is preferable.
hyperDMRs) with age. These aDMRs showed stronger associations .. Most recently, Pilsner et al. (2022) developed a novel sperm
..
with subgenomic regions. Clusters of hyperDMRs were found in chro- .. epigenetic clock utilizing a state-of-the-art ensemble machine learning al-
mosomes 4 and 16. The chr4 hyperDMR cluster overlaps the PGC-1a .. gorithm, Super Learner (van der Laan et al., 2007), to predict age from
..
locus, known to be involved in metabolic aging (Halling and Pilegaard, .. the sperm DNA methylation data from 379 semen samples from male
2020), and the chr16 hyperDMR cluster overlaps the RBFOX1 gene,
.. partners from male participants of the Longitudinal Investigation of
..
..
Only one study using a small sample size (n ¼ 3 for each age group) .. passed to the offspring (Milekic et al., 2015). The offspring of older
and semen samples that led to clinical pregnancy during in vitro fertiliza- .. fathers had reduced exploratory and startle behaviors and exhibited
..
tion procedures has been published with results of an age-related .. similar brain DNA methylation abnormalities as those observed in the
tsRNA profile in human sperm. Guo et al. found 34 up-regulated and ... paternal sperm. Offspring from old fathers also exhibited transcrip-
11 down-regulated tsRNA in older sperm (45–50 years old) compared .. tional dysregulation of developmental genes implicated in autism and
..
to young sperm (25–27 years old). Analysis of GO terms suggested .. schizophrenia.
that up-regulated tsRNA target genes were involved in neurogenesis
.. In addition, in a recent study of age-related changes in sperm
..
and nervous system development (Guo et al., 2021). For non-coding .. tsRNA, using the injection of sperm tsRNAs from aged and young
RNA in seminal plasma, one study of 40 older men (50–81 years) and
.. male mice into zygotes, Guo et al. investigated behavioral traits of F1
..
40 younger men (20–40 years) demonstrated lower expression of .. progeny and transcriptome of the cerebral cortex and hippocampus of
.. male mice and the embryo at two-cell and blastocyst stage (Guo
three selected miRNAs, miR-371, miR-122 and miR-146a, of 756 ana- ..
lyzed miRNA (Paoli et al., 2019) in older men. .. et al., 2021). They found that injection of sperm tsRNAs from aged
.. male mice into zygotes induced anxiety-like behaviors in F1 males and
Some discrepancies in results discussed in this section may be due ..
..
fathers and their offspring (Atsem et al., 2016). Collectively, these .. Assisted Reproductive Technology, 2017) due to a significant decrease
results suggest that paternal epigenome reprogramming in early em- .. in age-related female fertility for a couple and the slightly decreased
..
bryogenesis is incomplete, and some features of the sperm epigenome .. male fertility, and because ART is considered generally safe. A father’s
can persist in the offspring’s differentiated somatic cells. .. age for ART is rarely regulated in guidelines, except in Germany,
..
Recently, the possibility of aberrant DNA methylation being inher- .. where the age limit for ART is 50 years (Belaisch-Allart et al., 2016;
ited via aged sperm was approached by analyses of global methylomes .. Couture et al., 2021). ART spans the periconception period from ga-
..
in sperm of younger (30 years) and older (>50 years) fathers and .. metogenesis, fertilization and early embryonic development, coinciding
blastocysts donated from young fertile donor oocyte IVF cycles
.. with an intense epigenetic reprogramming in germ cells. ART-induced
..
(Denomme et al., 2020). More than 3000 sperm aDMRs and nearly .. epigenetic changes may provide additional epigenetic changes and risks
4000 blastocyst aDMRs were detected. A statistical comparison of
.. for the next generation (Vrooman and Bartolomei, 2017; Chen et al.,
..
genes associated with aDMRs in the sperm and blastocysts revealed .. 2020). ART-related epigenetic changes (disruption of DNA methyla-
.. tion in imprinted control regions in mouse models were mainly investi-
218 common genes: 167 were hypomethylated and 61 were hyperme- ..
thylated in samples from older aged individuals. Ten genes contained .. gated) occur during the following ART procedures: ovarian stimulation
..
..
Discussion .. Similarly, natural selection may shape epigenetic programs transferred
.. to the new generation by fathers of different ages.
..
Age-dependent changes in sperm .. The alternative explanation of clear patterns in age-dependent
.. changes of sperm epigenome refers to the chromatin structure in
epigenome: stochastic errors or program ..
targeting offspring fitness .. spermatozoa. One can assume that open areas of chromatin accumu-
.. late stochastic epigenetic errors faster than densely packed sites.
Today, age-dependent changes in the sperm epigenome and changes
..
.. Several animal studies have demonstrated that genes encoding most
induced by different environmental or lifestyle stressors are usually .. key embryonic developmental and morphogenesis genes are associ-
..
explained by the accumulation of random epigenetic errors: epimuta- .. ated with modified nucleosomes in mature sperm (Arpanahi et al.,
tions. Indeed both extended periods of time and unfavorable condi- .. 2009; Hammoud et al., 2009; Brykczynska et al., 2010). Interestingly,
..
tions are likely factors that can increase rates of such stochastic errors. .. the majority of regions in fertile human males corresponding to regions
However, this hypothesis contradicts the patterns of enriched biologi- .. coincident with sperm RNAs genes were H3K4me3 and H3K27me3
..
cal functions usually identified when sperm epigenome changes are an- .. enriched within hypomethylated DNA regions (Sendler et al., 2013). In
.. one study, most hypomethylated aDMRs were found within 1 kb of
Figure 1. Proposed future research on age, environment and lifestyle and ART-associated sperm epigenetic changes in humans
and mice over their life span. The use of prospective design for human studies and animal models for investigation of age, epigenetic changes and
consequent events in offspring among the next generation(s) looks promising and is recommended to be implemented. (A) Although longitudinal hu-
man studies over life span stages (childhood, puberty, young adulthood, adulthood, APA, elderly age) are time intensive, expensive and difficult to do,
they are more conclusive and, therefore, this needs to be proposed. Animal models have an invaluable advantage of removing the environmental and
lifestyle factors from the design and they can be conducted much faster. (B) Involvement of healthy population including twins (human), prospective
follow up, controls and use of environmental and lifestyle factors, fertility status and method of fertilization in designs are recommended to distinguish
(1) age-associated changes; (2) environment and lifestyle changes; (3) fertility-associated changes; and (4) ART-induced changes of the sperm epige-
nome. *Equivalency of mouse reproductive ages to these of humans was determined based on previously published data (Flurkey et al., 2007; Brust
et al., 2015; Bell, 2018) as well as information from Charles River Laboratories that male mice breeders are usually retired by 9 months of age (270
days) due to the decline of their reproductive efficiency. ART, assisted reproductive technologies.
38 Ashapkin et al.
..
millions of spermatozoa produced, is selected to fertilize an oocyte ei- .. prepared the first draft. V.A., S.A.K., J.R.P., O.S. and A.S. revised the
ther from natural sperm competition, or in vitro, with the selection of .. article critically. All authors approved the final version of the article.
..
what appears to be the best sperm. Increasing evidence indicates that ..
delayed fatherhood is associated with the accumulation of changes in ...
male gametes induced by various factors, including aging, environmen- ..
.. Funding
tal exposures, lifestyle factors and in some cases, ART. Age-associated .. Russian Science Foundation (18-15-00202) (https://rscf.ru/en/proj
genetic and epigenetic changes affect the developmental trajectories of ..
.. ect/18-15-00202/).
offspring and may result in adverse health outcomes, including psychi- ..
atric and neurodevelopmental disorders. Yet, paternal age is rarely ..
..
considered an important factor for the fertility of couples’ fertility and ..
.. Conflict of interest
the health of offspring. ..
.. The authors declare that there is no conflict of interest.
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