内容来源：https://www.quantamagazine.org/how-dads-fitness-may-be-packaged-and-passed-down-in-sperm-rna-20251222/

内容总结：

父亲的生活方式或可通过精子RNA影响后代健康

传统观点认为，精子仅为携带父亲DNA的载体，胚胎发育的绝大部分物质与环境均来自母亲。然而，近二十年来，多项独立研究正在挑战这一认知。科学家发现，精子头部除DNA外，还可能携带反映父亲生活经历（如饮食、运动、压力水平）的RNA分子。这些非DNA信息在受精时进入卵子，可能调控胚胎基因表达，从而影响后代的发育与长期健康。

这一新兴领域的研究目前主要基于小鼠模型。美国犹他大学医学院的生殖发育生物学家齐陈指出，这意味着“我们此生所为可能影响下一代”。具体而言，父亲在受孕前数周至数月的饮食、运动、压力等经历，或能以分子形式“编码”并封装于精子中，传递给后代。研究人员重点关注RNA分子——它们是DNA的短暂副本，能反映特定时刻的基因活动状态。

尽管机制尚不明确，但证据不断积累。2025年11月发表于《细胞·代谢》的一项研究揭示，父鼠的运动锻炼能改变其精子中一类特定微小RNA（microRNA）的含量，这些RNA靶向调控胚胎中线粒体功能与代谢的关键基因。研究还发现，经常运动的男性精子中同样存在许多同类RNA的高表达。齐陈评论称，这显示“父亲运动可为后代带来增强的耐力和代谢健康益处”，并提示许多精子介导的表观遗传效应本质上是适应性的。

表观遗传学关注不改变DNA序列、但调控基因开关的分子过程。精子中携带的RNA等分子，被认为可能作为表观遗传载体影响后代。研究人员提出，男性身体可能通过附睾等器官，将环境信号转化为分子信息并打包进精子。例如，压力、高脂饮食或运动等经历可能改变血液中循环的细胞外囊泡（内含RNA等分子）的内容，这些囊泡可将信号传递至生殖细胞。

然而，从分子信号到后代可观测性状的转化机制尤为复杂。有实验表明，将来自经历特定环境父鼠的精子RNA注射入受精卵，后代小鼠会出现与父代经历相关的代谢或行为特征。2024年的一项研究证实，精子微小RNA可改变小鼠胚胎的基因表达。前述《细胞·代谢》研究进一步阐明，父源运动相关的微小RNA通过抑制胚胎中特定蛋白，激活了线粒体与代谢相关基因，最终使成年后代骨骼肌中线粒体增多、运动耐力增强。

尽管跨物种线索令人鼓舞（人类运动男性精子中也发现类似微小RNA变化），但研究人员态度审慎。美国宾夕法尼亚大学的表观遗传学家科林·科宁坦言，目前对RNA具体作用机制的理解仍“非常模糊”。苏黎世大学的伊莎贝尔·曼苏伊教授也指出，尚需明确RNA等因子在受精卵中如何精确调控发育过程中的基因组活动。

齐陈将当前研究比作“盲人摸象”，认为其背后机制很可能是“精子RNA密码与其他因素的协同交响”。要将小鼠研究成果转化为对人类健康的指导，仍需大量工作，包括长期多代人群追踪、解析精子携带分子与表型特征的关联等。

尽管前路漫漫，这些发现已促使我们重新审视遗传的内涵。正如马萨诸塞大学医学院表观遗传学家奥利弗·兰多所言，如果机制得到证实，这将是生命科学的一个新事实。作为两个男孩的父亲，他有时会想，在孩子出生前自己的哪些经历可能通过RNA影响了他们。“我们尚未掌握足够知识来给出具体建议，”他说，“但也许未来可以做到。”

中文翻译：

父亲的健康密码如何封装于精子RNA并传递给后代

传统观点认为，精子不过是裹着DNA的"运输载体"，其使命仅仅是向卵子输送父亲的基因。胚胎发育所需的细胞与环境成分几乎完全来自母亲，与父亲无关。

但近二十年来，多个独立实验室的研究正在改写这一认知。研究表明，精子头部除了DNA，还携带着反映父亲健康状况（如饮食、运动习惯、压力水平）的分子信息。这些非DNA物质可能在受精过程中影响基因组活动，调控胚胎发育，甚至塑造后代成年后的特征。

犹他大学医学院生殖发育生物学家齐晨指出："这暗示我们今生的行为会影响下一代。"父亲在受孕前数周至数月的饮食、压力等经历，可能以分子形式编码于精子细胞中传递给后代。目前研究焦点集中在RNA分子——这些反映特定时期基因活动的DNA短期副本。

尽管机制尚不明确，但证据不断累积。2025年11月《细胞·代谢》期刊发表的研究，追踪了父鼠运动如何改变精子中调控线粒体功能的关键microRNA，并在运动量充足的男性精子中发现了相同现象。齐晨评价："这项研究证明父亲运动能赋予后代更强的耐力和代谢健康，提示精子介导的表观遗传效应具有高度适应性。"

在大多数动物中，精子体积远小于卵子。人类卵子体积是精子的1000万倍，为受精卵提供绝大部分细胞成分。正因如此，母亲健康对后代的影响长期备受关注。但近15年来，父系经验通过非DNA方式遗传的证据也在不断增强。

马萨诸塞大学医学院表观遗传学家奥利弗·兰多指出："多个实验室通过饮食和压力实验发现，后代通常会出现代谢或行为改变。"例如，给雄鼠高脂饮食或幼年母子分离，其后代会继承线粒体功能改变等特征。这些特征未必有害——接触尼古丁的父鼠所生雄性后代，肝脏解毒能力反而增强。

兰多解释道："这存在生存逻辑。后代很可能经历与父辈相似的环境，提前做好生物准备有助于生存。"但逻辑需要机制验证。齐晨、兰多等科学家正致力于揭示父系表观遗传的运作机制。

表观遗传不改变DNA序列，而是调控基因表达程度。触发基因表达变化的信号既来自DNA预设程序，也来自环境因素。某些分子（如甲基或乙酰基）能直接作用于DNA，而RNA分子也能干预基因表达。虽然RNA寿命较短，但某些类型可存续数周甚至更久。

为证实精子传递表观遗传，需要解答三个核心问题：父体如何将生活经验编码为分子信号？这些信号如何进入精子？受精过程中如何影响后代特征？

齐晨团队2012年启动的研究发现，小鼠精子成熟过程中特定RNA浓度激增，且这类RNA在多种脊椎动物血清中含量丰富。更关键的是，高脂饮食雄鼠的精子RNA组成与正常饮食组差异显著，将这些RNA注入受精卵后，部分雄性后代出现了代谢异常。

2018年，兰多团队发现精子在附睾成熟期间，会通过名为"附睾体"的囊泡装载小RNA。兰多指出："附睾正在成为父系影响的关键枢纽，它可能是感知外界环境的潜在传感器。"

苏黎世联邦理工学院科学家伊莎贝尔·曼苏伊的研究则揭示了另一条途径：血液中循环的细胞外囊泡能将创伤应激的分子效应传递给精子。她发现，经历早期创伤的小鼠，其代谢变化甚至能延续五代。

2024年康宁实验室的研究证实，精子microRNA能改变小鼠胚胎基因表达。而《细胞·代谢》的最新研究进一步揭示了运动获益的传递机制：运动小鼠精子中特定microRNA通过抑制某种蛋白质，激活了线粒体相关基因，最终使后代获得更强运动耐力。值得注意的是，经常运动的男性精子中也发现了相同microRNA水平升高的现象。

尽管机制尚未完全阐明，但研究人员已能勾勒出大致图景。兰多假设："附睾感知环境变化后调整其产生的RNA，这些RNA在受精时传递给受精卵，调控早期基因表达从而塑造后代健康。"齐晨则比喻："我们如同盲人摸象，基本机制很可能是精子RNA密码与其他因素的合奏。"

要将小鼠研究成果转化为人类健康指导，仍需大量工作。齐晨指出，这需要多代追踪研究，结合先进技术解码精子携带分子，并寻找分子数据与表型特征的强关联。

兰多作为两个男孩的父亲坦言，这些发现让他反思："年轻时哪些行为可能通过改变RNA影响了孩子？虽然现有知识还不足以给出具体指导，但或许未来我们能做到。"

英文来源：

How Dad’s Fitness May Be Packaged and Passed Down in Sperm RNA
Introduction
The standard sperm-meets-egg story posits that sperm cells are hardly more than bundles of shrink-wrapped DNA with tails. Their mission is simple: Deliver a father’s genes into a mother’s egg for sexual reproduction. Just about all other aspects of a developing embryo, including its cellular and environmental components, have nothing to do with dad. Those all come from mom.
But nearly two decades of studies from multiple independent labs threaten to rewrite that story. They suggest that dad’s gametes shuttle more than DNA: Within a sperm’s minuscule head are stowaway molecules, which enter the egg and convey information about the father’s fitness, such as diet, exercise habits and stress levels, to his offspring. These non-DNA transfers may influence genomic activity that boots up during and after fertilization, exerting some control over the embryo’s development and influencing the adult they will become.
The findings, so far largely described in mouse models, could end up changing the way we think about heredity. They suggest “that what we do in this life affects the next generation,” said Qi Chen, a reproductive and developmental biologist at the University of Utah Medical School who is among the pioneers of this research. In other words: What a father eats, drinks, inhales, is stressed by or otherwise experiences in the weeks and months before he conceives a child might be encoded in molecules, packaged into his sperm cells and transmitted to his future kid. The researchers have largely zeroed in on RNA molecules, those short-lived copies of DNA that reflect genetic activity at a given time.
It’s a tantalizing notion. But the mechanistic details — how experience is encoded, how it’s transferred from sperm to egg, and whether and how it affects a developing embryo — are not easy to unpack, especially given the challenges of conducting research in human subjects. For this reason, and because of the potentially textbook-rewriting implications of the findings, researchers, including those spearheading the work, are cautious about overselling their results.
“It’s still very hand-wavy,” said the epigeneticist Colin Conine of the University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia, who has been trying to uncover the mechanics of how sperm RNA can contribute nongenetic information to progeny. Some elements of the story are clear, he said: Researchers have significant evidence that the environment can regulate sperm RNAs, that these molecules transmit traits to offspring and that they can regulate embryonic development after fertilization. “We just don’t have really any understanding of how RNAs can do this, and that’s the hand-wavy part,” Conine said.
But evidence keeps piling up. Most recently, in November 2025, a comprehensive paper published in Cell Metabolism traced the downstream molecular effects of a father mouse’s exercise regimen on sperm microRNAs that target genes “critical for mitochondrial function and metabolic control” in a developing embryo. The researchers found many of those same RNAs overexpressed in the sperm of well-exercised human men.
“This study shows that paternal exercise can confer benefits — enhanced endurance and metabolic health — to offspring,” said Chen, who was not involved in the study. “It’s a powerful reminder that many sperm-mediated epigenetic effects are deeply adaptive in nature.”
The possibility that a previously undocumented avenue of inheritance is at play is too important to ignore. That’s why the researchers are now hunkering down in their labs to trace out the molecular processes that would have to operate for a father’s here-and-now experience to be transferred as developmental instructions to his partner’s egg.
Epigenetic Avenues
In most animals, a sperm cell is tiny compared to an egg cell. In humans, an egg contains 10 million times the volume of a sperm and contributes most cellular components — nutrition, cytoplasm, mitochondria and other organelles, the molecular machinery to make proteins, and more — to a zygote (a newly fertilized egg that hasn’t started dividing). Plus, a mother provides the environment within which an embryo and then fetus develops and grows. As a result, the effect of a mother’s health on her children has long been scrutinized, including at the molecular level. But over the past 15 years or so, the evidence for some kind of non-DNA inheritance of paternal experience has also been strengthening.
“There are many different labs that have done diet and stress studies, and typically the readouts of those in the next generation are either metabolism or behavioral changes,” Conine said. Feed a male mouse a high-fat or low-protein diet, or take him away from his mom when he is young, and his offspring will inherit traits, such as changes in mitochondrial function, related to those environmental conditions. These traits aren’t necessarily detrimental. For instance, mouse fathers exposed to nicotine sire male pups with livers that are good at disarming not just nicotine but cocaine and other toxins as well.
There is a survival logic here, said Oliver Rando, an epigeneticist at the University of Massachusetts Chan Medical School who led the nicotine study. It’s reasonable to expect that offspring will experience an environmental context similar to that of their parents. Biologically priming them for those conditions could therefore help them survive.
“You might think of this as a way to tell your kids something useful for them so that they can be better at dealing with the world they inherit,” said Rando, a father of two boys.
But logic does not make the story true. That’s why Chen, Rando, Conine and other researchers have been working to uncover the mechanistic components of dad-based epigenetic heredity to add to what is already known about these processes in mothers. “Epigenetics” refers to heredity processes that do not change the DNA sequences of genes, but rather involve when and to what degree genes are expressed and made into functional proteins. Epigeneticists focus on the molecular biology that unfolds around genomic and chromosomal frameworks that can switch genes on and off in response to internal and external cues.
This kind of differential gene expression is central to some of biology’s greatest wonders — for example, the fact that all cells in the human body have the same DNA, and yet brain cells differ dramatically from liver, skin and blood cells. Some cues that trigger changes in gene expression are programmed into DNA, while others come from the environment — for example, a dearth of calories or nutrients due to food deprivation, or rising cortisol levels due to stressors such as the absence of parental care. These conditions affect the kinds of metabolites and other molecules circulating in our bodies, which influences what kinds of reactions and genomic processes cells can carry out.
Some molecules involved in epigenetic processes, such as methyl or acetyl groups, interface directly with DNA or bind to proteins attached to DNA. These actions loosen up or batten down portions of the genome and are akin to opening or closing doors to specific genes.
RNA molecules — flexible, ephemeral versions of DNA sequences — can also intervene in gene expression. But because they are relatively short-lived, sometimes surviving mere minutes or hours before degrading, they have been overlooked as epigenetic regulators. Since the 1990s, their roles have been clarified, as has their longevity: Certain RNAs can survive for weeks or longer. Some RNAs (such as long noncoding RNAs, or lncRNAs) regulate gene expression by modifying DNA or its proteins. Others, known as microRNAs, alter or repress other RNAs, including those that would otherwise be translated into proteins; this discovery was awarded the 2024 Nobel Prize in Physiology or Medicine.
Could sperm carry RNA or other molecules that then participate in epigenetic processes in the embryo? It seemed plausible to some researchers, but it would take a whole lot of experimental work to put the pieces together.
A Package of RNA
There are three core questions that biologists need to resolve to confirm that sperm cells transmit epigenetic inheritance. The first is how a father’s body physically encodes lived experience, such as stress, diet, exercise or nicotine use, in the form of molecules — for example, as RNAs circulating in blood that reflect gene expression in tissues. The next centers on how molecularly encoded experience could make its way into sperm cells. The third traces how those signals in sperm could become epigenetic vectors during and after fertilization to specify observable traits, known as phenotypes, in offspring.
In a series of studies beginning in 2012, Qi Chen started answering all three questions. In what he describes as one of the most serendipitous discoveries of his career, his team at the Chinese Academy of Sciences in Beijing used sequencing techniques to inventory the short RNA molecules present in mice sperm cells.
They were shocked to see a subset of the RNAs drastically increasing in concentration as sperm cells matured, and then crowding into the sperm heads with DNA. This same class of RNAs was abundant in the blood serum of various vertebrates, ranging from fish to humans, they found. All of this pointed to the possibility that information-carrying molecules were being transferred into the reproductive cells.
It got even more interesting when Chen, who moved to the U.S. academic circuit in 2015, and his team collected sperm RNAs from male mice fed different diets. The RNA assemblages in mice reared on high-fat foods differed dramatically from those in mice that were fed normal diets. And when the researchers injected the RNAs from the sperm of the fat-eating mice into a zygote, some of the male offspring showed metabolic issues associated with a high-fat diet.
The experiments hinted at a seemingly heretical possibility, Chen said: that “certain acquired traits during paternal exposure can be ‘memorized’ in the sperm and inherited by the offspring.” After characterizing a pathway that regulates sperm RNAs, in 2019 Chen dubbed this channel of heredity the “sperm RNA code,” which he suggested “programs the metabolic health of offspring.”
He wasn’t the only one to become fixated on this idea. Around the same time, in an article published in Developmental Cell in 2018, Rando’s team reported the use of biochemical techniques to characterize where and when RNAs are packaged into sperm cells and how those RNAs might change during this process. They were trying to answer the question: “What tissue could be responsible for choosing what to tell sperm to tell kids?” he said. One logical place to start looking was the epididymis. Within this tubular organ attached to the back of the testicle, sperm cells undergo a maturation process, taking about one to two weeks in most mammalian species, before they become ready for fertilization.
Rando’s data showed that sperm cells gain almost all their small RNAs when they are in the epididymis. Using techniques for tracking specific RNA molecules, the scientists observed RNAs getting packaged into virus-size capsules, called epididymosomes, which shuttled the molecules into sperm.
“This shows how small RNAs can get trafficked between the body’s nonreproductive cells, like those in the epididymis, and germline cells,” such as sperm, Rando said. “The epididymis has been emerging as a key location for paternal effects. Certainly the epididymis has to be taken seriously as a potential sensor of the world.”
A Molecular Snapshot
By “sensor of the world,” Rando is referring to the first stage of a presumed paternal-effects mechanism — when a male’s body translates a lived condition, such as a high-fat diet, rigorous exercise or toxin exposure, into molecular signals. The epididymis then provides a route for the second step, packaging those signals for the next generation.
This is also where investigations by Isabelle Mansuy come in. At the University of Zurich and the Swiss Federal Institute of Technology Zurich, she studies the molecular and cellular mechanisms of epigenetic inheritance in mammals.
© Philippe Rossier / Ringier Media Switzerland
In one line of her research, she focuses on processes that transmit the molecular effects of traumatic stress to subsequent generations by focusing on extracellular vesicles (EVs) that circulate in blood. Shed by almost every type of cell in the body, including in the epididymis (the epididymosomes are EVs), they carry a diversity of molecular cargo, such as RNAs, proteins, lipids and metabolites. Because EVs circulate in blood just about anywhere in the body and can cross cell membranes, they provide a potential means to transfer molecules and the biological cues they carry between bodily tissues and reproductive cells. Notably, RNAs tend to survive longer when packaged in EVs.
Mansuy creates trauma in mice by subjecting the animals to conditions such as restraint or maternal separation when they are young. Then she searches for molecular changes in reproductive cells that could cause similar consequences of trauma to manifest in the children or even grandchildren of the animals who directly endure it.
She’s shown that traumatic stress alters metabolic pathways, especially those that involve lipids, in exposed male mice and their offspring. She has also found a similar metabolic profile in humans who experienced high stress in childhood. In mice, some of the metabolic changes remained discernible through five generations — a rare data-backed finding for epigenetic inheritance cascading through generations.
Dennis Kunkel Microscopy/Science Source
In March 2025, in a preprint uploaded to biorxiv.org, Mansuy and colleagues reported that EVs in mice can transport certain RNAs, metabolites and lipids linked to early-life stress from circulating blood to sperm, with consequences for offspring. The offspring produced by these sperm cells had stress-related metabolic dysfunction as adults and bore the stress signatures in their own sperm RNA. “These changes imply a mechanistic link between sperm RNA modifications and phenotypic features in the offspring,” Mansuy’s team concluded in their paper, which has not yet been peer-reviewed.
Phenotypic Translation
Perhaps the trickiest step to understand is how sperm-borne molecules could influence an adult’s observable traits. In one form of experiment, researchers extract all the sperm RNA from mice that have been raised under stressful or health-altering conditions. Those isolated RNAs are then injected into a zygote. Pups that emerge usually “get the dad’s phenotypes,” Conine said, suggesting that the RNAs alone confer traits from dad to offspring.
But how? During early development, epigenetic processes reign. As one fertilized cell divides into two, and those cells divide again, and so on, one set of DNA instructions is dynamically and repeatedly reprogrammed. The growing body specializes into different cell types and is sculpted into a sequence of increasingly complex forms. It’s possible, then, that early epigenetic alterations to the genome could have significant downstream effects on an adult.
Research out of Conine’s lab, published in 2024, showed that sperm microRNAs alter gene expression in mouse embryos. Experiments like these, he said, support the idea that offspring can inherit paternal traits via the transfer of non-DNA molecular stowaways in sperm.
The recent Cell Metabolism paper took this idea a step further by tracing a mechanism by which this can happen. A team of more than two dozen Chinese researchers focused on the epigenetic transmission of exercise benefits, homing in on a set of microRNAs that reprogram gene expression in the early embryo. These changes ultimately result in skeletal muscle adaptations in adult offspring that enhance exercise endurance. The researchers found that well-exercised mice had more of these microRNAs in their sperm than sedentary mice did. When these microRNAs were transferred into zygotes, the adults they grew into were more physically fit, with more mitochondria in skeletal muscle and higher endurance.
But how did the molecules generate the exercise-positive phenotype? In experiments, the researchers found that the microRNAs suppressed a particular protein, which had the effect of boosting genes related to mitochondrial activity and metabolism.
Intriguingly, the sperm of physically trained male humans also hosted higher levels of many of the same microRNAs than those of untrained cohorts. “This cross-species conservation suggests a potential role for these sperm mi[cro]RNAs in intergenerational exercise adaptations in humans,” the researchers wrote.
The First Draft
The notion that a father’s lived experience can become recorded by his body, transmitted to his gametes and relayed to his offspring is no longer as outlandish as it once seemed. Many researchers in the field are willing to float speculative visions of what could be going on, even as they acknowledge that gaps remain.
“Our hypothesis is that the epididymis ‘sees’ the world and alters the small RNAs it produces in response,” Rando said. “These RNAs are then delivered to the zygote upon fertilization and control early gene regulation and development to shape offspring health and disease.”
Conine speculates that once certain RNAs make their way into the egg, they trigger “a cascade of changes in developmental gene expression that then leads to these phenotypes” of the father showing up in the next generation. Remarkably, this unfolds even though the sheer volume of the sperm’s contents is so much less than an egg’s contents, including the relative amounts of RNA.
The full picture of how paternal experience and behavior might epigenetically influence offspring is not nearly in hand. Researchers are currently piecing the story together, one experiment at a time, rather than proving out every step sequentially in the same set of organisms. One of the gaps is in the characterization of what RNA and perhaps other epigenetic factors do in the zygote to modify genomic activity as it unfolds during development, Mansuy said.
“We are still blind men describing for the first time different parts of the same elephant,” Chen said. “The underlying mechanism is almost certainly an orchestra of a sperm RNA code and factors beyond that.”
Confirming the findings in humans would take enormous effort, but it would be key to turning these findings in mice into “informed medical advice,” Chen said. This would require well-controlled experiments following multiple generations, tracking diet, exercise, aging and environmental exposures, while also using advanced tools to decode sperm-packaged molecules — and then looking for strong correlations between the molecular and phenotypic data.
Even amid the uncertainties, researchers are cautiously moving forward as they learn to believe the results of their own experiments. If they’re right, they will have discovered a new fact of life, Rando said. When he thinks about his two boys, he wonders what he might have done differently when he was younger, before they were born, that might have tweaked his RNA profile in ways that would affect them today.
“We don’t know enough yet to develop guidance like that,” Rando said. “Maybe we will get there.”