by GreenMedInfo Research Group
October 13, 2018
The past of our ancestors lives on through us:
Groundbreaking research illustrates how parental
experience is not only epigenetically imprinted
onto offspring, but onto an unprecedented number
of future generations.
Rather than occurring over the elongated time scale
of millions of years, genetic change can transpire
in real biological time through nanoparticles known
Until recently, it was
believed that our genes dictate our 'destiny'...
That we are slated for
the diseases that will ultimately beset us based upon the pre-wired
indecipherable code written in stone in our genetic material.
field of epigenetics, however, is
overturning these tenets, and ushering in a school of thought where
nurture, not nature, is seen to be the predominant influence when it
comes to genetic expression and our freedom from or affliction by
The Demise of Biological Determinism
the study of the
physiological mechanisms that silence or activate genes,
encompasses processes which alter gene function without changing
the sequence of nucleotide base pairs in our DNA.
Translated literally to
"in addition to
changes in genetic sequence,"
processes such as,
...which can be
transmitted to daughter cells upon cell division. (1)
Methylation, for example, is the
attachment of simple methyl group tags to DNA molecules, which can
repress transcription of a gene when it occurs in the region of a
This simple methyl group,
or a carbon bound to three hydrogen molecules, effectively turns
the gene off.
Post-translational modifications of histone proteins is another
Histones help to package and
condense the DNA double helix into the cell nucleus in a complex
called chromatin, which can be modified by enzymes, acetyl groups,
and forms of RNA called small interfering RNAs and microRNAs.
modifications of chromatin influence its three-dimensional
structure, which in turn governs its accessibility for DNA
transcription and dictates whether genes are expressed or not.
We inherit one allele, or variant, of each gene from our mother and
the other from our father.
If the result of
epigenetic processes is imprinting, a phenomenon where one of the
two alleles of a gene pair is turned off, this can generate a
deleterious health outcome if the expressed allele is defective or
increases our susceptibility to infections or toxicants. (1)
For example, the cardiac
antiarrhythmic drug procainamide and the antihypertensive
agent hydralazine can cause lupus in some people by causing
aberrant patterns of DNA methylation and disrupting signaling
Genes Load the
Gun, Environment Pulls the Trigger
Pharmaceuticals, however, are not the only agents that can induce
Whether you were born via
vaginal birth or Cesarean section, breastfed or bottle-fed, raised
with a pet in the house, or infected with certain childhood
illnesses all influence your epigenetic expression.
are sedentary, pray,
smoke, mediate, do yoga, have an extensive network of social
support or are alienated from your community,
...all of your lifestyle
choices play into your risk for disease operating through mechanisms
In fact, the Centers for Disease Control (CDC) states that
genetics account for only 10% of disease, with the remaining 90%
owing to environmental variables. (2)
An article published in
the Public Library of Science One (PLoS One) entitled "Genetic
factors are not the major causes of chronic diseases"
echoes these claims, citing that chronic disease is only 16.4%
genetic, and 84.6% environmental. (3)
These concepts make sense
in light of research on the
exposome, the cumulative measure of
all the environmental insults an individual incurs during their life
course that determines susceptibility to disease. (4)
In delineating the totality of exposures to which an individual is
subjected over their lifetime, the exposome can be subdivided into
three overlapping and intertwined domains.
One segment of the
exposome called the internal environment is comprised of processes
innate to the body which impinge on the cellular milieu. This
encompasses hormones and other cellular messengers, oxidative
stress, inflammation, lipid peroxidation, bodily morphology, the gut
microbiota, aging and biochemical stress. (5)
Another portion of the exposome, the specific external environment,
consists of exposures including pathogens, radiation, chemical
contaminants and pollutants, and medical interventions, as well as
dietary, lifestyle, and occupational elements. (5)
At an even broader
sociocultural and ecological level is the segment of the exposome
called the general external environment, which may
circumscribe factors such as psychological stress, socioeconomic
status, geopolitical variables, educational attainment, urban or
rural residence, and climate. (5)
Transgenerational Inheritance of Epigenetic Change - Endocrine
Disruptors Trigger Infertility in Future Generations
Scientists formerly speculated that epigenetic changes disappear
with each new generation during gametogenesis, the formation of
sperm and ovum, and after fertilization.
However, this theory was
first challenged by research published in the journal Science which
demonstrated that transient exposure of pregnant rats to the
insecticide methoxychlor, an estrogenic compound, or the fungicide
vinclozolin, an antiandrogenic compound, resulted in increased
incidence of male infertility and decreased sperm production and
viability in 90% of the males of four subsequent generations that
were tracked. (1)
Most notably, these reproductive effects were associated with
derangements in DNA methylation patterns in the germ line,
suggesting that epigenetic changes are passed on to future
The authors concluded,
"The ability of an
environmental factor (for example, endocrine disruptor) to
reprogram the germ line and to promote a transgenerational
disease state has significant implications for evolutionary
biology and disease etiology".
(6) - p. 1466
This may suggest that the
endocrine-disrupting, fragrance-laden personal care products and
commercial cleaning supplies to which we are all exposed may trigger
fertility problems in multiple future generations.
Transgenerational Inheritance of Traumatic Episodes - Parental
Experience Shapes Traits of Offspring
In addition, traumatic experiences may be transmitted to future
generations via epigenetics as a way to inform progeny about salient
information needed for their survival. (7)
In one study, researchers
wafted the cherry-like chemical
acetophenone into the chambers of
mice while administering electric shocks, conditioning the mice to
fear the scent. (7)
This reaction was passed
onto two successive generations, which shuddered significantly more
in the presence of acetophenone despite never having encountered it
compared to descendants of mice that had not received this
The study suggests that certain characteristics of the parental
sensory environment experienced before conception can remodel the
sensory nervous system and neuroanatomy in subsequently conceived
Alterations in brain
structures that process olfactory stimuli were observed, as well as
enhanced representation of the receptor that perceives the odor
compared to control mice and their progeny. (7)
These changes were
conveyed by epigenetic mechanisms, as illustrated by evidence that
the acetophenone-sensing genes in fearful mice were hypomethylated,
which may have enhanced expression of odorant-receptor genes during
development leading to acetophenone sensitivity. (7)
Experience of Famine and Tragedy Spans Generations
The mouse study, which illustrates how germ cells (egg and
sperm) exhibit dynamic plasticity and adaptability in response to
environmental signals, is mirrored by human studies.
For instance, exposures
to certain stressors such as starvation during the gestational
period are associated with poor health outcomes for offspring.
Women who undergo famine
before conception of her offspring have been demonstrated to give
birth to children with lower self-reported mental health and quality
of life, for example. (8)
Studies similarly highlight that,
exposure around the time of conception has been related to
prevalence of major affective disorders, antisocial personality
disorders, schizophrenia, decreased intracranial volume, and
congenital abnormalities of the central nervous system".
Gestational exposure to
the Dutch Famine of the mid-twentieth century is also associated
with lower perceived health (9) as well as enhanced
incidence of cardiovascular disease, hypertension, and obesity in
during pregnancy leads to neonatal adiposity, which is a predictor
of future obesity (10) in the grandchildren. (11)
The impact of epigenetics is also exemplified by research on the
intergenerational effects of trauma, which illuminates that
descendants of people who survived the Holocaust exhibit abnormal
stress hormone profiles, and low cortisol production in particular.
Because of their impaired
cortisol response and altered stress reactivity, children of
Holocaust survivors are often at enhanced risk for posttraumatic
stress disorder (PTSD),
anxiety, and depression. (13)
Intrauterine exposure to maternal stress in the form of intimate
partner violence during pregnancy can also lead to changes in the
methylation status of the glucocorticoid receptor (GR) of
their adolescent offspring. (14)
These studies suggest
that an individual's experience of trauma can predispose their
epigenetic programming of genes operating in the
...a complex set of
interactions among endocrine glands which determine stress response
and resilience. (14)
pass Genetic Information Directly into Sperm Cells
Not only that, but studies are illuminating that genetic information
can be transferred through the germ line cells of a species in real
findings overturn conventional logic which postulates that genetic
change occurs over the protracted time scale of hundreds of
thousands or even millions of years.
In a relatively recent
study, exosomes were found to be the medium through which
information was transferred from somatic cells to gametes.
This experiment entailed xenotransplantation, a process where living
cells from one species are grafted into a recipient of another
species. Specifically, human melanoma tumor cells genetically
engineered to express genes for a fluorescent tracer enzyme called
EGFP-encoding plasmid were transplanted into mice.
The experimenters found
that information-containing molecules containing the EGFP tracer
were released into the animals' blood. (15)
membranous nano-sized vesicles derived from endocytic
compartments that are released by many cell types" were found
among the EGFP trackable molecules.
(16) - p. 447
Exosomes, which are
synthesized by all plant and animal cells, contain distinct protein
repertoires and are created when inward budding occurs from the
membrane of multivesicular bodies (MVBs), a type of organelle that
serves as a membrane-bound sorting compartment within eukaryotic
Exosomes contain microRNA
(miRNA) and small RNA, types of non-coding RNA involved in
regulating gene expression. (16) In this study, exosomes
delivered RNAs to mature sperm cells (spermatozoa) and remained
stored there. (15)
The researchers highlight that this kind of RNA can behave as a,
determinant of inheritable epigenetic variations and that
spermatozoal RNA can carry and deliver information that cause
phenotypic variations in the progeny". (15)
In other words, the RNA
carried to sperm cells by exosomes can preside over gene expression
in a way that changes the observable traits and disease risk of the
offspring as well as its morphology, development, and physiology.
This study was the first to elucidate RNA-mediated transfer of
information from somatic to germ cells, which fundamentally
overturns what is known as the
Weisman barrier, a principle which
states that the movement of hereditary information from genes to
body cells is unidirectional, and that the information transmitted
by egg and sperm to future generations remains independent of
somatic cells and parental experience. (15)
Further, this may bear implications for cancer risk, as exosomes
contain vast amounts of genetic information which can be source of
lateral gene transfer. (17) and are abundantly liberated
from tumor cells. (18)
This can be reconciled
with the fact that exosome-resembling vesicles have been observed in
various mammals (19), including humans, in close
proximity to sperm in anatomical structures such as the epididymis
as well as in seminal fluid. (19)
These exosomes may
thereafter be propagated to future generations with fertilization
and augment cancer risk in the offspring. (20)
The researchers concluded that sperm cells can act as the final
repositories of somatic cell-derived information, which suggests
that epigenetic insults to our body cells can be relayed to future
This notion is
confirmatory of the evolutionary theory of "soft inheritance"
proposed by French naturalist Jean-Baptiste Lamarck, whereby
characteristics acquired over the life of an organism are
transmitted to offspring, a concept which modern genetics previously
rejected before the epigenetics arrived on the scene.
In this way, the sperm
are able to spontaneously assimilate exogenous DNA and RNA
molecules, behaving both as vector of their native genome and of
extrachromosomal foreign genetic material which is,
"then delivered to
oocytes at fertilization with the ensuing generation of
phenotypically modified animals". (15)
Changes Endure Longer than Ever Predicted
In a recent study, nematode worms were manipulated to harbor a
transgene for a fluorescent protein, which made the worms glow under
ultraviolet light when the gene was activated. (21)
When the worms were
incubated under the ambient temperature of 20° Celsius (68°
Fahrenheit), negligible glowing was observed, indicating low
activity of the transgene. (21)
However, transferring the
worms to a warmer climate of 25°C (77° F) stimulated expression of
the gene, as the worms glowed brightly. (22)
In addition, this temperature-induced alteration in gene expression
was found to persist for at least 14 generations,
representing the preservation of epigenetic memories of
environmental change across an unprecedented number of generations.
In other words, the worms
transmitted memories of past environmental conditions to their
descendants, through the vehicle of epigenetic change, as a way to
prepare their offspring for prevailing environmental conditions and
ensure their survivability.
Directions: Where Do We Go From Here?
Taken cumulatively, the aforementioned research challenges
Mendelian laws of genetics, which
postulate that genetic inheritance occurs exclusively through sexual
reproduction and that traits are passed to offspring through the
chromosomes contained in germ line cells, and never through somatic
Effectively, this proves
the existence of non-Mendelian transgenerational inheritance,
where traits separate from chromosomal genes are transmitted to
progeny, resulting in persistent phenotypes that endure across
This research imparts new meaning to the principle of seven
generation stewardship taught by Native Americans, which mandates
that we consider the welfare of seven generations to come in
each of our decisions.
Not only should we embody
this approach in practices of environmental sustainability, but we
would be wise to consider how the conditions to which we subject our
the pollution and
toxicants which permeate the landscape and pervade our
nutrient-devoid soil that engenders micronutrient-poor food
to our circadian rhythm due to the ubiquity of electronic
our divorce from
nature and the demise of our tribal affiliations,
...may translate into ill
health effects and diminished quality of life for a previously
unfathomed number of subsequent generations.
Hazards of modern agriculture, the industrial revolution, and
contemporary living are the,
"known or suspected
drivers behind epigenetic processes… including heavy metals,
pesticides, diesel exhaust, tobacco smoke, polycyclic aromatic
hydrocarbons, hormones, radioactivity, viruses, bacteria, and
(1) - p. A160
many inputs such as exercise, mindfulness, and bioactive components
in fruits and vegetables such as,
...can favorably modify
"either by directly
inhibiting enzymes that catalyze DNA methylation or histone
modifications, or by altering the availability of substrates
necessary for those enzymatic reactions".
(23), p. 8
...may persevere in our
descendants and remain in our progeny long after we are gone.
We must be cognizant
of the effects of our actions, as they elicit a
ripple effect through the
proverbial sands of time...
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