Environmental Toxicology and Chemistry—Volume 38, Number 6—pp.
1149–1151, 2019
Received: 18 March 2018 | Accepted: 20 March 2019
ET&C
POINTS OF REFERENCE
Points of Reference are part of a regular series intended to address emerging or controversial topics of
interest to the scientific community.
An Ecotoxicological Perspective on Transgenerational
Epigenetic Inheritance
Jessica Head*
Department of Natural Resource Sciences, McGill University, Ste. Anne‐de‐Bellevue, Quebec, Canada
Transgenerational epigenetic inheritance is an unconven-
tional finding that challenges paradigms in fields as diverse as
medicine and evolutionary biology. It suggests that the en-
vironmental experiences of individuals can affect the health of
their descendants through mechanisms other than alteration of
DNA code. Imagine, for example, that your great‐grandmother
was exposed to an environmental stressor while pregnant and
that this single exposure left marks on your grandfather's
and then your father's DNA, which were passed down to you
and have influenced your health. In the past decade, a number
of groups have reported the observation of this type of trans-
generational inheritance, albeit in laboratory‐based model or-
ganisms (Nilsson and Skinner 2015). How significant are these
new findings to the field of ecotoxicology, and what is
their potential impact on our ability to assess risk to natural
populations?
At its simplest, epigenetic inheritance implies that experi-
ences from our past can affect our present and future through
mechanisms other than alterations to the DNA code. This idea
has garnered a lot of attention in both public and scientific
spheres in the last decade. Perhaps it fascinates us because it is
both deeply intuitive (we may have a gut feeling that experi-
ences of our ancestors mark us in some way), and contrary to
what is traditionally taught about DNA and inheritance.
To better grasp what is implied by epigenetic inheritance,
one must understand the molecular mechanisms behind this
phenomenon (see Head et al. 2012; Brander et al. 2017). In
general terms, epigenetics refers to a layer of instructions as-
sociated with DNA that help control which genes are expressed
or “turned on.” Epigenetic marks are heritable mitotically as
cells divide and are susceptible to change due to environ-
mental stressors such as contaminants. It is this unusual com-
bination of characteristics that can allow stressors to cause
* Address correspondence to Jessica.head@mcgill.ca
Published online in Wiley Online Library
(wileyonlinelibrary.com).
DOI: 10.1002/etc.4424
wileyonlinelibrary.com/ETC
1149
persistent, and sometimes transgenerational, effects in organ-
isms. Epigenetic inheritance is considered to be transgenera-
tional when stressor‐induced phenotypes appear in individuals
that were never directly exposed themselves (Figure 1).
Skepticism over initial reports of transgenerational epige-
netic inheritance took several forms. One criticism stemmed
from the fact that epigenetic marks such as DNA methylation
were known to be wiped clean and re‐established early in de-
velopment. It now appears that some epigenetic marks can
escape developmental reprogramming. A second criticism is
that contaminant concentrations used in foundational studies
far exceeded the lowest observable effect level for other
endpoints, and were orders of magnitude higher than what
could be considered environmentally relevant. Nevertheless,
recent studies have demonstrated that transgenerational ef-
fects can occur at environmentally relevant concentrations of a
variety of chemicals (e.g., Carvan et al. 2017; Vera‐Chang
et al. 2018).
The current literature suggests that transgenerational effects
are possible. However, are they common or consequential in
the natural world? Are there ecologically relevant effects im-
pacting populations? To demonstrate transgenerational in-
heritance of epigenetic marks, experiments generally include at
least 1 exposed generation followed by 2 to 3 unexposed
generations (Figure 1). This design rarely mimics natural con-
ditions, where organisms are exposed to complex mixtures of
contaminants across generations. Because epigenetic marks
are reversible, there is an opportunity for them to be reinforced
or reset at each generation in response to the same or different
environmental signals. Moreover, the vertebrates demon-
strating transgenerational epigenetic inheritance in laboratory
studies each had a single great‐grandparent exposed to the
chemical stressor whereas their other ancestors came from a
control population with a uniform genetic background and
environmental experience. This does not happen in nature. In a
natural environment, vertebrates generally have 8 genetically
diverse great‐grandparents, each with their own complex and
© 2019 SETAC
1150 Environmental Toxicology and Chemistry, 2019;38:1149–1151—J. Head

FIGURE 1: Transgenerational epigenetic inheritance of environmental signals in male and female vertebrates. A stressor‐induced phenotype is
considered to be transgenerationally inherited when it occurs in an individual that was never directly exposed itself. For a pregnant female mammal
(A), this would be the F3 generation, because both the embryo (F1, blue) and the embryo's reproductive cells (F2, red) were exposed to the stressor
in the F0 female. For male mammals or nonmammalian vertebrates (B), transgenerational effects first appear in F2 individuals. Cubiceps caeruleus
(Blue fathead). This article uses material from the Wikipedia article https://en.wikipedia.org/wiki/Blue_fathead and vector diagram https://commons.
wikimedia.org/wiki/File:Vector_diagram_of_laboratory_mouse_(black_and_white).svg which are released under the Creative Commons Attribution
ShareAlike license.

varied epigenetic backgrounds and histories of environmental
exposures.
Given this complexity, we are lacking an understanding of
how transgenerational effects of environmental chemicals re-
ported in the laboratory manifest in natural populations. We
could begin to address this data gap by exploring how likely
and for how long the epigenetic message is maintained under
different multigenerational exposure scenarios and by in-
vestigating the stochastic nature of inheritance of epigenetic
marks. One challenge with this design is that as the number of
conditions to be tested increases, a multigenerational study
balloons in size, and sample numbers become prohibitive. This
challenge could be met by using more convenient invertebrate
models, or by addressing smaller questions related to the
molecular basis of maintenance or reversal of epigenetic marks
under a variety of environmental conditions. A second limiting
factor is that there are no strong examples of specific epige-
netic mechanisms linking chemical exposures with transge-
nerational outcomes. If such epigenetic biomarkers are
developed, it will become much easier to trace factors con-
tributing to transgenerational transmission or reversal.
Beyond laboratory studies, there are no compelling ex-
amples of transgenerational epigenetic inheritance occurring
in nature. The human epidemiological literature suggests links
between low food supply in ancestors and disease in their
descendants, but these studies have not demonstrated an
epigenetic mechanism of action, true transgenerational
inheritance, or the absence of genetic, cultural, or persistent
environmental factors contributing to phenotypes. The field of
ecotoxicology has a great deal to offer in terms of models for
exploring how epigenetic inheritance might behave under
natural conditions. Collectively, we have widespread ex-
pertise in relevant manipulative experiments in natural set-
tings (e.g., cross‐fostering experiments, mesocosms, in situ
exposures, whole‐lake experiments). Moreover, the life history
of some species commonly studied makes them natural sub-
jects for this research (e.g., colonial birds returning to the
same location to breed over multiple generations). Although
the challenges of isolating precise epigenetic mechanisms in
these more natural contexts remains daunting, such models
could be used to study whether persistent transgenerational
phenotypes are observed at all, irrespective of their under-
lying cause.
The jury is out on the direct relevance of transgenerational
epigenetic inheritance to the field of ecological risk assess-
ment, but what is becoming increasingly clear is that this mode
of inheritance is not uncommonly detected in a laboratory
setting, and that we need more research to establish its im-
portance in nature. Beyond the transgenerational aspects of
epigenetic inheritance, it is also important to understand how
early life contaminant exposures may affect individuals
throughout their lives. This is an area of research that is likely to
have direct relevance to ecological risk assessment, and de-
serves more attention.

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An Ecotoxicological Perspective on Transgenerational Epigenetic Inheritance—Environmental Toxicology and Chemistry, 2019;38:1149–1151
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© 2019 SETAC