PCOS is one of the most common endocrine disorders affecting reproductive-age women. It is associated with excessive androgen activity, disrupted ovulation, infertility and changes in glucose and lipid metabolism. Although the syndrome is diagnosed in women, children born to mothers with PCOS can display altered growth, metabolic regulation and reproductive development, and some studies have raised the possibility that these effects may extend beyond a single generation. Scientists often study such questions in animals because they can control the timing of exposure, breeding and treatment, then follow descendants under standardized conditions. In this work, the researchers created a mouse model of PCOS by exposing developing animals before birth to anti-Müllerian hormone, a reproductive hormone involved in ovarian biology. The resulting animals were then used to examine whether treatment before conception could reshape outcomes in their descendants.

The intervention was Bu-Shen-Tian-Jing Formula, or BSTJF, a complex traditional Chinese medicine preparation. The researchers describe it as a patented formula previously shown to improve fertility in women with PCOS and to support pubertal neurobehavioral development in female offspring in earlier work. Its ingredients include several medicinal materials used in traditional practice, among them Rehmanniae Radix Praeparata, Astragali Radix, Cuscutae Semen, Ligustri Lucidi Fructus, Rubi Fructus, Salviae Miltiorrhizae Radix et Rhizoma and Psoralea Fructus. Rather than administering the formula during pregnancy or directly to the descendants, the team gave it before conception to the PCOS-model animals. This distinction is central: the study was designed to investigate whether correcting maternal reproductive and metabolic abnormalities before pregnancy could be associated with effects in the next two generations.

The researchers assessed the treated animals, designated the F0 generation, and then examined male offspring in the F1 and F2 generations. They looked at several biological systems that are tightly connected in PCOS: reproduction, glucose handling, fat metabolism, liver function, kidney lipid deposition, testicular structure and the intestinal environment. To do so, they combined conventional physiological and biochemical measurements with tissue staining, oral glucose tolerance testing and calculations of the homeostatic model assessment of insulin resistance, or HOMA-IR. They also sequenced bacterial genetic material using 16S ribosomal RNA analysis to characterize the gut microbiota. Finally, untargeted liquid chromatography–mass spectrometry metabolomics was used to survey small molecules in the liver, while correlation analysis compared microbial changes with metabolite patterns. Together, these approaches allowed the team to search for a system-wide signature rather than focusing on a single hormone or organ.

In the F0 mice, preconceptional BSTJF treatment alleviated several PCOS-related reproductive features. The study’s broader implication begins here: a treatment that improved the condition of the original animals was associated with healthier measurements in their male descendants. In both F1 and F2 male offspring from the PCOS model, the researchers observed lower hyperandrogenemia, meaning that excessive androgen levels were reduced. They also reported lower HOMA-IR values, suggesting improved insulin sensitivity, and fewer lipid droplets in the liver. Insulin resistance is a major metabolic feature of PCOS and can promote elevated circulating insulin, abnormal fat storage and increased androgen production. The relationship can become self-reinforcing: high insulin levels may stimulate ovarian androgen production, while excess androgens and metabolic dysfunction can further disrupt reproductive physiology. In the male offspring examined here, the treatment-associated changes point to an influence on shared endocrine and metabolic pathways, even though the original disease model was based on maternal reproductive dysfunction.

The benefits were not identical in the two descendant generations, and that difference is scientifically important. In F1 males, BSTJF exposure in the preconceptional generation was associated with lower serum low-density lipoprotein cholesterol, reduced insulin levels, less lipid accumulation in the kidneys, protection against damage to the seminiferous tubules and a less impaired intestinal barrier. Seminiferous tubules are the structures within the testes where sperm-producing cells develop, so damage there can signal compromised reproductive potential. The intestinal barrier, formed by intestinal epithelial cells and their junctions, controls what passes from the gut into the circulation. When it becomes more permeable, microbial products and other compounds may enter tissues and stimulate inflammation or alter metabolism. In F2 males, the researchers reported reductions in total bilirubin and in the size of subcutaneous adipocytes, the cells that store fat beneath the skin. These generation-specific findings suggest that the biological legacy of an intervention may not be a simple copy of the original effect. Different traits may appear, fade or re-emerge depending on developmental context and inherited molecular regulation.

The gut microbiome and liver metabolism provided the study’s most provocative mechanistic clue. The researchers found that preconceptional BSTJF administration altered important microbial “hub” organisms and their associations with liver metabolites in both F1 and F2 males. One highlighted relationship was a negative correlation between the bacterium Akkermansia and lysophosphatidylcholine, or LysoPC. Akkermansia is a mucus-associated intestinal microbe that has attracted attention for its links to gut-barrier integrity and metabolic health, although associations in microbiome studies do not by themselves prove that the organism causes a physiological improvement. LysoPC is a bioactive lipid generated during phospholipid metabolism. It can participate in cell signaling, immune responses and inflammatory processes, and altered lysophosphatidylcholine profiles have been reported in metabolic disorders. The researchers’ correlation analysis therefore raises the possibility that BSTJF influenced a gut–liver axis: intestinal microbial communities may have changed the chemical signals reaching the liver, while altered liver metabolism may in turn have shaped the intestinal environment. The data do not yet establish the direction of that relationship, but they offer a testable model for future experiments.

How could treatment before conception be linked to traits in grandchildren? The study was not designed to identify a definitive inheritance mechanism, and the authors describe the gut–liver axis as a possible explanation rather than a proven pathway. Several biological routes could be involved. Conditions before conception can affect the quality of eggs and sperm, the molecular packaging of reproductive cells and the early embryo’s developmental trajectory. Chemical marks that influence gene activity without changing DNA sequence—collectively described as epigenetic regulation—can sometimes respond to nutrition, hormones, stress or disease. In mammals, most epigenetic marks are extensively reset during the formation of reproductive cells and early development, but some regulatory information may escape complete erasure or may be recreated through altered maternal physiology. The intestinal microbiome can also influence bile acids, short-chain fatty acids, immune signaling and host metabolism. Bile acids act not only as digestive detergents but also as hormones through receptors such as the farnesoid X receptor. Changes in these signals could theoretically affect reproductive tissues, metabolism and development. These possibilities remain hypotheses in this study; no claim should be made that the herbal formula permanently rewrites the genomes of descendants.

The findings arrive with both excitement and caution because herbal medicines are chemically complex. A multi-ingredient formula may contain compounds that act on several pathways simultaneously, potentially explaining why the researchers detected changes across reproductive, metabolic, hepatic, renal, testicular and intestinal measurements. At the same time, complexity makes it harder to determine which constituents are active, which combinations are necessary and whether the preparation is consistent from batch to batch. The study used a controlled mouse model, not a randomized clinical trial in people, and the reported outcomes were measured in specific generations of male offspring rather than in a broad human population. The severity of the mouse phenotype, the dosing regimen, the timing of treatment and the composition of the microbiome may all differ from human circumstances. Correlations between bacteria and metabolites are valuable for generating mechanisms but cannot substitute for causal tests, such as selectively removing or restoring particular microbes, transferring microbiota between animals or tracing epigenetic changes in sperm and embryos.

Even with those limitations, the research highlights a rapidly expanding concept in reproductive medicine: the period before conception may be a biologically active window in which disease risk is shaped for more than one generation. The work also challenges the tendency to study PCOS solely as a disorder of ovarian function. Its effects can involve insulin signaling, lipid transport, liver fat, immune regulation, the intestinal barrier and the developmental health of offspring. BSTJF’s apparent association with improvements in male descendants suggests that interventions aimed at maternal reproductive health could have consequences extending beyond the treated individual, although that possibility requires rigorous confirmation. The next steps will be to identify the formula’s molecular constituents, determine whether microbiome changes are necessary for the observed effects, investigate sperm and embryo epigenetic profiles and test the findings in independent animal models. Human research would need careful safety monitoring and controlled designs before any multigenerational claims could be considered. For now, the study offers a striking message from mice: what happens before conception may reverberate through the family tree, and the gut and liver could be part of the signal.

Maternal age effects describe changes in an offspring’s physical traits, behavior, survival, reproduction or health that are associated with the age of its mother. These effects are widespread and are often harmful when mothers reproduce late in life. Offspring of older mothers may have shorter lifespans, lower reproductive success or reduced developmental performance. In humans and other mammals, maternal age is associated with several developmental and health outcomes, although the biological pathways are complex and influenced by many environmental and genetic factors. In rotifers, which are only a fraction of a millimeter long and reproduce rapidly, researchers can observe multiple generations in a relatively short time. Their simple body plan, short lifespan and controlled laboratory reproduction make them useful for investigating how information about a mother’s age reaches her offspring.

Kristin Gribble, an associate scientist in the Marine Biological Laboratory’s Bay Paul Center, and colleagues are using rotifers to examine whether maternal age effects are caused by permanent changes to DNA or by molecular mechanisms that alter the way existing genes function. DNA mutations change the genetic sequence itself and are generally stable once they occur. Epigenetic mechanisms work differently. They can influence whether genes are active or silent without changing the underlying DNA code. These regulatory systems include chemical modifications to DNA and changes to histone proteins, the molecular structures around which DNA is wrapped. By adjusting how tightly DNA is packaged, histone modifications can make particular genes more or less accessible to the cellular machinery that transcribes them into RNA.

The team’s experiments produced a result that challenges a common assumption about aging and inheritance. If maternal age effects were driven primarily by the gradual accumulation of damage inside aging mothers, their impact might be expected to become stronger across successive generations. Instead, research by postdoctoral scientist Alyssa Liguori found that the pattern did not consistently intensify in two different genotypes of the same rotifer species. In some cases, the effects could be reversed within a single generation. That rapid change is difficult to reconcile with a model based only on accumulated cellular damage or new DNA mutations, because such alterations would not normally disappear so quickly. The observations instead point toward a flexible regulatory process capable of being reset, modified or transmitted differently depending on genetic context.

The findings do not yet prove that histone modifications are the mechanism responsible, but they provide a strong direction for further investigation. Histones act as molecular spools that organize the long DNA molecules inside cells. Chemical groups added to or removed from histones can alter the structure of chromatin, the combined complex of DNA and proteins. When chromatin becomes more open, genes may be easier to transcribe; when it becomes more condensed, gene activity may be reduced. If maternal aging changes histone marks in eggs or in reproductive tissues, those changes could influence the development and physiology of offspring without altering their DNA sequences. The researchers are now examining whether particular histone modifications correlate with the lifespan, reproduction and other traits associated with maternal age.

Another possible route involves mitochondria, the energy-producing structures found inside cells. Mitochondria contain their own small genomes, known as mitochondrial DNA, and in many animals these genomes are inherited primarily from the mother. Because mitochondria regulate energy production, metabolism and several processes linked to aging, changes in mitochondrial DNA or mitochondrial condition could provide a way for maternal age information to affect offspring. Older mothers may pass on mitochondria with altered performance, or they may transmit molecular signals that influence how mitochondria function in the next generation. Gribble’s laboratory is considering this possibility alongside histone regulation, although the relative contribution of mitochondrial DNA remains unresolved.

Genetic variation also appears to shape whether maternal age effects are harmful, neutral or even beneficial. The researchers found that different rotifer genotypes did not respond identically to maternal age. In one strain, offspring produced by older mothers lived longer, a result that contrasts with the more common pattern of reduced longevity. This observation suggests that some genetic variants may protect offspring from the negative consequences of advanced maternal age or may convert an age-related signal into a physiological advantage. The result also emphasizes why maternal age cannot be understood as a universal biological switch. The same maternal condition may produce different outcomes depending on the inherited genome and the interaction between genes, epigenetic regulation and the environment.

The persistence of maternal age effects presents an evolutionary puzzle. If offspring of older mothers are often less likely to survive and reproduce, natural selection might be expected to remove the genetic or physiological processes that generate these outcomes. Yet maternal age effects have been documented across a remarkable range of species. One explanation is that natural selection becomes weaker late in life. In rotifers, most reproduction takes place early, and females may have already produced the majority of their offspring by the time they reach advanced age. Variants that harm late-born offspring may therefore experience limited evolutionary pressure if they have little effect on the number of descendants produced earlier. The same principle, in different forms, could help explain why age-related reproductive effects remain common across animal populations.

The most far-reaching implication of the work is that biological information may travel across more than one generation through mechanisms that do not fit a simple DNA-centered model of inheritance. If a grandmother’s environment or age alters molecular states in her offspring’s reproductive cells, those changes could potentially influence grandchildren or even later descendants. Such transgenerational effects are difficult to distinguish from direct maternal effects, because researchers must determine whether the observed trait is caused by the mother’s condition, by exposure during development, or by a change that persists through the germ line. Rotifers offer a practical system for separating these possibilities because their generations are short and their ancestry can be monitored under controlled conditions.

The researchers stress that results from rotifers cannot be transferred directly to humans, whose development, reproduction and aging are far more complex. Nevertheless, the basic biological principles under investigation—chromatin regulation, mitochondrial inheritance, genetic variation and the weakening of selection at later ages—are shared across many forms of life. Understanding how maternal age information is encoded and transmitted could eventually improve scientific models of health risk and disease susceptibility. It may also clarify why an individual’s biology is influenced not only by their own genome, but by the reproductive history and environments of previous generations. For now, the rotifer experiments are revealing that maternal age effects are neither necessarily permanent nor genetically uniform, and that their hidden mechanism may lie in the cell’s control systems rather than in the DNA sequence itself.

Subject of Research: Maternal age effects, epigenetic inheritance, histone modifications, mitochondrial inheritance and genotype-specific transgenerational effects in rotifers.

Article Title: Transgenerational and Intergenerational Maternal Age Effects Exhibit Complex, Genotype-Specific Patterns of Inheritance

News Publication Date: 13-Aug-2026

Web References: https://doi.org/10.1086/742104

References: Liguori et al., “Transgenerational and Intergenerational Maternal Age Effects Exhibit Complex, Genotype-Specific Patterns of Inheritance,” DOI: 10.1086/742104.

Image Credits: Michael Shribak; female Brachionus manjavacas rotifer and offspring.

Keywords: Maternal age effects, rotifers, Brachionus manjavacas, epigenetics, histone modifications, transgenerational inheritance, intergenerational effects, mitochondrial DNA, genetics, aging, longevity, natural selection.