Are We Paying for the Sins of our Ancestors: Transgenerational Epigenetic Inheritance?

OVERVIEW AND BACKGROUND

There is a growing body of research that shows our health today is not only determined by the actions we take and protocols we follow, but by the actions that our parents, grandparents, etc. may have taken as well.  Much of this research is covered under the discipline of Transgenerational Epigenetic Inheritance (TEI).  TEI can be defined more formally as “the transmission of information through the germline without changing the genome sequence, through factors such as non-coding RNAs and chromatin modifications”, or “stochastic or signal-induced changes to parental germline epigenome modulate phenotypic output in one or more subsequent generations, independently of mutations in the genomic DNA.”, or “the phenomenon that phenotypic traits, such as changes in fertility, metabolic function, or behavior, induced by environmental factors (e.g., parental care, pathogens, pollutants, climate change), can be transferred to offspring generations via epigenetic mechanisms.” In this context, “Epigenetics is the study of how your behaviors and environment can cause changes that affect the way your genes work. Unlike genetic changes, epigenetic changes are reversible and do not change your DNA sequence, but they can change how your body reads a DNA sequence.”

Tracking of these changes to validate the TEI concept is complex and time-consuming.  For humans, if a generation is defined as ~twenty years, then tracking actions taken or behaviors from one generation of humans on multiple progeny generations can take on the order of a century or more.  For toxicology experiments, where safety (or lack thereof) of potentially toxic substances on multiple generations is the target, experiments that require a substantial fraction of a century (or more) would not be practical or acceptable.  Thus, most TEI experiments in the biomedical literature involve the use of non-human living creatures (e.g., mice, rats, fish, insects, etc.), and the extrapolation from the test results on these creatures to humans is not completely clear.  In some sense, these experiments constitute proxy clinical trials of multigenerational toxic impacts.

For example, Van Otterdijk and Michels conclude: “Several processes that may be part of intergenerational epigenetic inheritance have been identified in mice.  However, much uncertainty remains as to whether these processes are truly epigenetically inherited or are influenced by other factors, such as intrauterine exposures and genetics, and whether these epigenetic marks can be maintained over several subsequent generations. As a result, proof of principle of a widespread transgenerational epigenetic inheritance is lacking to date. Because of differences in the epigenome between mice and humans and the limited number of studies performed in humans, the concept of transgenerational epigenetic inheritance in humans remains equivocal.”

The last sentence of their conclusion can be augmented by the findings in a 2023 Trial Site News Op-ed. Five factors were presented that could influence the validity of extrapolating from laboratory animal experimental results to humans: 1) Uncertainty Factor; 2) Limits of Single Stressor Studies; 3A) Effects of Breeding Protocols on Biology (Telomeres) and Response to Toxicants; 3B) Effects of Housing of Laboratory Animals on Toxicology Results; 4) Impacts of Different Strains on Toxicology Results; 5) Impacts of Multiple Factors Above on Toxicology and Clinical Trial Results.  Any one of these factors could impact the validity of extrapolating TEI results from non-humans to humans, much less all five factors operating in concert!

Nevertheless, these multigenerational/transgenerational experiments do offer some insights on the mechanisms of trait inheritance across generations, and have intrinsic value.  Given the limitations and uncertainties of these experiments on non-humans identified in the previous paragraph, all of which will exacerbate the adverse effects of these toxins on future generations and reduce the accuracy of their extrapolations to humans, the results of these experiments should be viewed as a low “floor” on what types of adverse effects can be expected.

The remainder of the present Op-ed consists of two TEI analyses: 1) examples of the types of experiments that have been conducted, especially on the transgenerational effects of toxic substances and behaviors, and 2) a text clustering-based analysis of the TEI biomedical literature, which provides an overall perspective of what has been, and is being, done in this burgeoning field.

METHODOLOGY

Two similar queries (not identical) were used to retrieve Pubmed articles for 1) the types of TEI experiments that have been conducted and 2) for the text clustering-based analysis of the TEI biomedical literature and the resulting hierarchical taxonomy.  The period covered ranged from 1 January 1983 to 31 December 2023.  The specific queries used are shown in Appendices 1A and 1B.

RESULTS AND DISCUSSION

TEI Findings from Selected Experiments on Toxic Substances

Appendix 2 contains 100+ examples of TEI findings from toxic substance experiments.  Thousands of articles served as the source for the selected examples.  The main selection criterion was how well the article illustrated the approach and findings.  No topical balance or emphasis was used.  The larger picture of TEI will be presented in the next section on a text-based taxonomy of the TEI literature.

The format for each finding (in Appendix 2) is 1) substance name CAPITALIZED AND BOLDED, 2) reference title for substance With Each Word Capitalized, 3) excerpts from reference abstract “in quotes”, and 4) URL link to reference.  In general, most studies examine effects of toxicity on reproduction (since species depletion may be of interest) and the effects of toxicity on health biomarkers.  There tend to be two types of these studies.  One type consists of an initial exposure to the potential toxin on the F0 generation, and then following multiple generations with no further exposures to see the downstream consequences.  The second type consists of the initial exposure to the potential toxin and then subsequent exposures as well, which tends to reflect what happens in the real world.

In some cases, the adverse effects will reverse after a few generations, in some cases many generations will be required for reversal, in some cases with accumulated exposures the adverse effects will continue to increase, and in some cases there will be no reversal.  The general conclusion that can be drawn is, under real-world conditions, adverse effects of these toxic substances will be transmitted for at least a few generations.  Further, the effects will probably be much more severe for humans because of the reasons mentioned previously and presented in the recent Op-ed on the credibility of animal models for human toxicology studies.

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Ronald Neil Kostoff received a Ph. D. in Aerospace and Mechanical Sciences from Princeton University in 1967. He has worked for Bell Laboratories, Department of Energy, Office of Naval Research, and MITRE Corp.

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