The debate began when Chiapperino and Paneni highlighted a fundamental technical obstacle: epigenetic studies are largely unable to incorporate fine-grained mapping data of an individual’s surrounding social milieu. The same limitation, they noted, afflicts genomics. Zaina accepts this diagnosis and praises the authors for elevating questions of scientific epistemology into public debate. His response, however, goes a step further. He argues that because epigenetic marks are tightly coupled to DNA sequence, epigenetics is structurally doomed to reproduce the very shortcomings of genomics that Chiapperino and Paneni identified. If the sequence sets the stage for most methylation patterns, then no amount of interdisciplinary ingenuity will allow epigenetics to serve as a clean molecular record of social experience.

To understand why, Zaina insists, one must revisit the history of the concept. The term epigenetics traces back to Conrad Waddington’s definition of epigenesis in the 1940s, a description of molecular development that, in Zaina’s view, sits awkwardly with the modern scientific community’s intuition of what the field does. Epigenetics remained poorly understood until genomic imprinting revived it, because DNA methylation offered a mechanism to explain that clearly non-genetic phenomenon. The next breakthrough came with the demonstration that epigenetic marks can be modified by exogenous factors, notably through studies showing that early nutrition could alter methylation of transposable elements. From these milestones emerged the definition now taught in textbooks: a DNA sequence-independent, environmentally sensitive mode of gene regulation, widely adopted as a tool to hunt for markers of non-communicable diseases, particularly in light of genetics’ notorious missing heritability problem.

That definition, Zaina argues, can be dismantled with the field’s own data. The decisive evidence comes from methylation quantitative trait loci, or methylation QTL, first documented by Tycko’s group in 2008. These are genetic variants that predict methylation states at nearby or distant sites, and subsequent surveys show they account for the vast majority of DNA methylation variation in humans. A comprehensive analysis of human tissues found roughly twice as many methylation QTL as expression QTL colocalizing with genetic variants identified by genome-wide association studies. Even a textbook example of sequence dependence has long been available but rarely stated: mammalian CpG islands, the GC-rich regions surrounding many gene promoters, remain generally unmethylated precisely because of their peculiar sequence composition. The genetic grip on epigenetics is further tightened by methodology. Mendelian randomization, which exploits genetic variants as instruments, is currently the best available tool for assessing whether any given DNA methylation profile causally influences a phenotype, a dependence on genetics that Zaina finds telling.

There is also a quantitative prediction that follows from this tight coupling. If methylation is largely sequence-driven, then individual differentially methylated CpG sites should exert comparatively small phenotypic effects, echoing the missing heritability problem that has frustrated geneticists for decades. The available evidence, Zaina notes, suggests that this prediction is correct. He also flags a conceptual confusion at the heart of the field’s self-description: independence from changes in DNA sequence is often cited as the main difference between epigenetics and genetics, yet genetics deals with sequence variation in populations rather than sequence changes, mutations being a relatively minor topic. The distinction, in other words, is less clean than the standard rhetoric implies.

The second pillar of the popular narrative, the idea that the epigenome is an open book on which the environment can freely write, erase, or rewrite information, fares no better in Zaina’s assessment. He points to the controversy surrounding a famous New Yorker article that proposed epigenetics as the mechanism underlying phenotypic divergence between identical twins, an interpretation that drew sharp criticism from prominent epigeneticists. Even more contentious is the hypothesis of epigenetic transgenerational inheritance in humans, the notion that methylation patterns altered by a grandparent’s environment could be transmitted across generations. Reviews of the evidence describe it as highly controversial, with mechanisms in mammals poorly established and human data difficult to disentangle from genetic and cultural confounding.

What remains, once these assumptions are stripped away? In Zaina’s formulation, epigenetics describes a highly sequence-dependent and comparatively weakly environmentally sensitive mode of transcriptional regulation, functionally closer to the activity of transcription factors or DNA-binding long non-coding RNAs than to a free-floating environmental ledger. He even suggests the field might be more accurately renamed paragenetics. Adding micro-RNAs and non-coding RNAs to the definition, he argues, has only deepened the confusion. The counterfactual he poses is striking: had methylation QTL been documented forty years ago rather than in 2008, the current enthusiasm for epigenetics might never have taken hold. Had the higher affinity of DNA methyltransferases for RNA relative to DNA been appreciated earlier, textbooks might describe those enzymes as RNA-binding proteins that modify DNA chemistry.

The stakes of this conceptual housekeeping extend well beyond taxonomy. Zaina’s central concern is that biosocial epigenetics, the quest to find molecular signatures of adverse social environments, whether politically or economically adverse, is likely to uncover genetics-related phenomena rather than pure environmental imprints. Researchers searching for DNA methylation profiles written exclusively by an adverse milieu to explain how social circumstances create and maintain disadvantaged groups will, on his reading, inevitably bump into sequence-dependent variation. Such findings would be highly controversial if they appeared to clash with dominant views in identity politics or social constructivism. The devils of genetics when applied to social sciences and economics are obvious, he writes, but hidden ones may lurk in epigenetics, precisely because the field’s environmental framing can mask its genetic dependencies.

Zaina is careful not to dismiss the enterprise entirely. Reducing the daylight between epigenetics and fine-grained mapping of the social milieu remains, in his words, a noble and useful pursuit, and he credits Chiapperino and Paneni with correctly identifying the problem and acknowledging its difficulty even for the best interdisciplinary research and technological advances. But he insists that the hurdles will only be overcome after a correct understanding of the essence of epigenetics, however dynamic that essence proves to be. His closing question is deliberately uncomfortable: this territory feels remote from pipettes and tubes, and scientists must decide whether they should walk that far at all. The reply, published open access in Epigenetics Communications, ensures that the debate over whether epigenetics can ever truly bridge biology and society will continue, and that any future biosocial science will have to reckon with the sequence it inherits along with the environment it measures.

Subject of Research: The debate over whether epigenetics can function as a biosocial science given its dependence on DNA sequence

Article Title: Will epigenetics ever be a biosocial science? A reply to Chiapperino and Paneni

Article References: Zaina, S. (2023). Will epigenetics ever be a biosocial science? A reply to Chiapperino and Paneni. Epigenetics Communications, 3(1), Article 2. https://doi.org/10.1186/s43682-023-00018-0

Image Credits: AI Generated

DOI: 10.1186/s43682-023-00018-0

Keywords: epigenetics, DNA methylation, methylation QTL, biosocial science, genomics, social epigenomics, transgenerational inheritance, Mendelian randomization, gene regulation, missing heritability, Waddington, CpG islands

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.