Does transgenerational epigenetic inheritance occur in humans?

What is the strongest evidence that transgenerational epigenetic inheritance happens in mammals?

The cleanest experimental proof comes from a 2023 study in mice where researchers directly edited DNA methylation at specific genes (Ankyrin repeat domain 26 and low-density lipoprotein receptor) in embryonic stem cells. Mice created from these cells showed abnormal metabolic traits, and those traits—along with the specific DNA methylation patterns—were passed down through multiple generations [6]. This is powerful because the researchers controlled the epigenetic change, ruling out genetic mutations as the cause.

Another line of evidence comes from studies on folic acid supplementation in rodents. A 2023 review found that treating rats and mice with folic acid enhanced axonal regeneration after spinal cord injury, and this beneficial effect was inherited transgenerationally beyond the F3 generation, even without continued supplementation [5]. The effect was linked to DNA methylation changes, showing that an environmentally triggered epigenetic mark can be passed on.

What does the human evidence show, and where does it fall short?

Human studies are more circumstantial. A 2021 study on polycystic ovary syndrome (PCOS) found that women with PCOS and their daughters both show global genomic DNA hypomethylation (reduced DNA methylation across the genome). In a mouse model of PCOS, this hypomethylation persisted into the F3 generation (great-grandchildren), and feeding the mice methyl-donor supplements largely normalized the condition [4]. This suggests a transgenerational epigenetic component, but the human data is correlational—it cannot rule out shared genetics or environment.

A 2024 critical review of the field points out that while genome sequencing increasingly shows that most heritable traits are explained by DNA sequence, the evidence for environmentally induced epigenetic inheritance in humans remains 'inconclusive' [2]. The review notes that the assumption that environmental exposures can alter epigenetic marks in the germline and affect future generations is still controversial. Similarly, a 2024 review on early-life adversity states that whether transgenerational inheritance occurs in humans 'remains unclear,' despite suggestive evidence from non-human models [3].

How could epigenetic information be passed down, and why is it harder in humans?

Epigenetic information can be transmitted through DNA methylation, histone modifications, and non-coding RNAs [1]. In mammals, there is a major hurdle: the genome is 'reprogrammed' twice during early development—once in the germ cells and again after fertilization—erasing most epigenetic marks to give the next generation a clean slate [7]. For transgenerational inheritance to occur, some marks must escape this erasure.

A 2022 review explains that while mechanisms for transgenerational epigenetic inheritance exist in many organisms, they 'have a more limited effect in mammals than in plants and other animal species' [1]. The same review notes that transmission can occur either through direct replication of epigenetic marks or through indirect reconstruction in subsequent generations [1]. In humans, the piRNA (Piwi-interacting RNA) system helps guard against transposon activity, but its role in transmitting environmentally induced epigenetic changes is 'less distinct' than in other animals [7].

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