Nearly two years ago I sent the following email to a large group of researchers and autism leaders (including Tom Insel at NIMH, Autism Speaks, and noted scientists from UCLA to Texas to Hopkins) outlining for the first time the germline disruption hypothesis of autism.
So much has happened since that time to confirm my suspicions — meeting many other autism parents with circa 1960s prenatal drug exposures just like mine, studies of multigenerational effects of endocrine disruptors and hypomethylation in animal models, findings of various multigenerational effects in human cohort studies, recognition of epigenetic involvement in some neurodevelopmental impairments, findings regarding
de novo alterations in germline in autism, increasing recognition of gene-environment interaction in autism, to name a few — and as we head into the holiday season let us hope for a 2014 filled with long-overdue public awareness about this most urgent issue.
Jill Escher
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Epigenetic Transgenerational Inheritance: How Old Pharmaceuticals May Be Contributing to the Autism Epidemic Today
Summary Document, January 20, 2012
Hypothesis
That the increasing rate of ASDs stems in part from epigenetic disturbance of fetal germ cells caused by
in-utero exposures
to various pharmaceuticals, including synthetic steroid hormones, used
in obstetric practice from roughly the 1950s to 1980s. In other words,
that gestating women given certain pharmaceutical drugs in roughly the
first half of pregnancy (likely window is weeks 6-18 of gestation) are
more likely to have neurologically impaired grandchildren, through the
action of epigenomic alterations of fetal germ cells.
Background
From the 1950s through 1970s, and even
before, it was common in obstetric practice to prescribe various
pharmaceuticals to pregnant women, even in the first trimester. The
drugs included, among other things, hormone-like compounds,
barbiturates, and morning-sickness medications.
In the post-war period chemists began synthesizing various
progesterone-like compounds. Based on theory that these compounds could
help prevent miscarriage or preterm birth, some obstetricians and early
fertility clinics began administering synthetic progestins to pregnant
women deemed to have at-risk pregnancies. Commonly, the patients had
suffered prior miscarriages or had complications such as bleeding. Use
of the compounds was relatively rare in the 1950s, but increased through
the 1960s and 70s, particularly in certain locales with a large
upper-middle class clientele who could afford the then-expensive
fertility treatments, including west Los Angeles and New Jersey, the
sites of cohort studies by Dr. June Reinisch.
There was no standard practice for use of these compounds, according
to Reinisch, it was more of an art than a science. Some physicians
administered multiple hormones, some used hormones early in pregnancy,
some later. There was no standard dosing.
Little thought was given to the impact of the various drugs,
including the progestins, on the exposed fetus. The progestins were
chemically similar to progesterone, except for a small “tail” or
“radical” hanging off the end of the molecule. They were not, like DES
(diethylstilbestrol), very chemically different from the natural
counterparts. While the idea of impact on fetal germ cells did come up,
it was thought at the time that the germ cells would be protected from
exogenous chemical exposures.
Dr. Reinisch and a few others did perform research on
first-generation impact of prenatal exposure to synthetic steroid
hormones. Impacts on brain development were found, though subtle
compared to a neurodevelopmental disorder like
autism.
The impacts were primarily on personality traits. See, eg, Reinisch
and Karow,“Prenatal exposure to synthetic progestins and estrogens:
Effects on human development.”
http://www.springerlink.com/content/k0552583r63776h2/ and “Prenatal exposure to synthetic progestins increases potential for aggression in humans,”
http://www.sciencemag.org/content/211/4487/1171.abstract?sid=792459ee-eacf-47d5-8dd3-9e5df26b6b85.
Some of the pharmaceuticals used
According to Prenatal
Exposure to Synthetic Progestins and Estrogens: Effects on Human
Development, Archives of Sexual Behavior, Vol 6, No. 4, 1977, p. 267,
the most common synthetic steroid hormones used in pregnancies deemed
at-risk appear to have been (progestins) Colprosterone, Delalutin,
Deluteval, Norlutin Acetate, Provera, Provest, and (additional
estrogens) Stilbestrol. Full list from that study:
Progestins
Broxorone (Squibb)
Colprosterone (e)
Deladroxate 110 (Squibb)
Deladroxate 130 (Squibb)
Deladroxate 150 (Squibb)
Delalutin 142 (Squibb)
Delaxadrone (Squibb)
Deluteval (b) (Squibb)
Depo-Provera (Upjohn)
MK665(c) (Merck) ethymerone
19NET, Norlutin (Syntex)
Norlutin Acetate (Parke Davis)
Norethynodrel (b) (Searle)
Pranone (Schering)
Provera (Upjohn)
Provest (b) (Upjohn)
RS1280 (c, e) (progestogen)
SC4641 (c) (Searle) 19 NET
SC4642 (c) (Searle) norethynodrel
SC9022 (c) (Searle) methylnortestosterone
SC10230 (c,g) (Searle)
SC11800 (c) (Searle) ethyndiol
1 142.53 (e) aqueous progesterone
Additional estrogens (d)
Allyl Estranol (Organon)
Amestrogen (Squibb)
Delestrogen (Squibb)
Estrone (a)
Hexestrol (e)
Mestranol (e)
Stilbestrol (e)
Other drugs
Thyroid (Armour)
Cytomel (Smith, Klein& French)
Methergine (Sandoz)
Prednisone (McKesson)
Proloid (Wamer-Chilcott)
Sterane (Pfizer)
Synthroid (Flint)
Notes:
a Many mothers received more than one drug.
b Compounds that have estrogens included.
C Experimental compounds.
d Not including estrogen found in combination with progestin.
e Company not identified.
f Number of pregnancies in which medication was administered (omitted in this list, see article)
g 21-Fluoro-17-hydr oxy-6-methylpregna-4,6-diene-
3,20-dione acetate.
Other
pharmaceuticals, such as the barbiturates and morning sickness
medications, were also prevalent, however I do not have a list of those
medications at this time.
The “Hidden History”
Reinisch calls the past use of
these hormone-like pharmaceuticals, as well as the barbiturates and
morning sickness drugs, the “hidden” history for several reasons:
--The records have largely been destroyed
--The women who received the medications often did not know what they were getting
--The women have largely forgotten taking the medications
--The exposed children were never told of their exposure
--The practice was very little studied, and has been forgotten by contemporary researchers and medical practitioners
Case Study
By the end of 1964 a well-to-do 27 year-old
mother of one son in Los Angeles had suffered two miscarriages and
badly wanted another child. She sought treatment at a pioneering
private fertility clinic in west Los Angeles which was associated with
UCLA. She conceived after being given clomiphene and Pergonal to induce
ovulation. Through at least the first two trimesters, she was then
given regular doses of a synthetic progestin, Deluteval 2x, manufactured
by Squibb, for the ostensible prevention of miscarriage (these
compounds were never actually proven to promote gestation). It appears
Prednisone was also administered at some point. She delivered a healthy
baby girl in September 1965.
This child now has three children of her own (“grandchildren”), two
of whom have markedly abnormal neurological development (label used is
autism).
All genetic tests have been negative, including tests for cnv’s and
microdeletions. All pregnancies and deliveries were normal, and Apgar
scores were high. The families of the grandchildren have no history of
neurological problems or mental illness. There were no unusual
exposures during the pregnancies. In spite of the very evident
neurological dysfunction, the children are robustly healthy and
normal-looking.
The child born in 1965 also has a younger brother, born in 1968.
He, too, was exposed to exogenous synthetic steroid hormones. He is the
father of two children, one of whom has a mysterious neurological
disorder that is similar to NF1, though apparently not genetic in
origin. The older brother, unexposed to any hormones, has two normal
children.
Several other
autism parents (both mothers and fathers) are also aware of their own in-utero exposures to synthetic steroid hormones:
symptoms reported in the offspring include Aspergers, autism, sensory processing disorder, and learning disorders. Many of these second-generation offspring also have no apparent, or very mild, symptoms.
However, the vast majority of the parents who were exposed have no
idea about their prenatal histories--nearly all records have long ago
been destroyed, and it appears to have been uncommon for a mother to
think of the medication as worth mentioning to her offspring.
Background Research
It has been postulated that common
pharmaceuticals could have epigenetic side-effects that appear only
years or decades after the exposure. See, eg, Szyf, M “Epigenetic
side-effects of common pharmaceuticals: A potential new field in
medicine and pharmacology.”
http://www.medical-hypotheses.com/article/S0306-9877%2809%2900291-6/abstract
Researchers such as Michael Skinner, Andrea Gore, Moshe Szyf, and
Joseph Nadeau have looked into transgenerational epigenetic impact of
chemical exposures and have found early evidence for the phenomenon.
See, for example, Nadeau “Transgenerational genetic effects on
phenotypic variation and disease risk,”
http://m.hmg.oxfordjournals.org/content/18/R2/R202.abstract, Skinner et al, “Endocrine Disruptor Vinclozolin Induced Epigenetic Transgenerational Adult-Onset Disease,”
http://endo.endojournals.org/content/147/12/5515.short, and Skinner, “Role of Epigenetics in Developmental Biology and Transgenerational Inheritance,”
http://onlinelibrary.wiley.com/doi/10.1002/bdrc.20199/full.
New studies on endocrine disruptors, some yet unpublished, point to
differing epigenetic impacts on the F2 and F3 generations, likely due to
impact on developing germ cells. (Interviews with Szyf and Gore,
December 2011, and Skinner, January 2012.)
There is broad agreement, even among traditional geneticists, that
it is biochemically plausible that the synthetic hormones, or their
metabolites, or other prenatal pharmaceuticals, could have had a
deleterious impact on germ cell reprogramming. Various theories were
espoused, including altered methylation patterns and impact on histone
tails during reprogramming. It is agreed that at a minimum, synthetic
steroid hormones would cross the placenta, enter fetal tissues, and
likely bind to receptors in ways that vary from natural, endogenous
steroids. The reasons for epigenetic alterations of germ cells to lead
specifically to a phenotype of abnormal neurodevelopment are unknown.
Professor Skinner summarizes the core biochemical issue in his
article cited above, “Role of Epigenetics in Developmental Biology and
Transgenerational Inheritance” as follows (emphasis added):
“
[T]he
basic mechanism of epigenetic transgenerational inheritance involves
the actions of an environmental factor (e.g., chemical or nutrition)
during germ line remethylation at gonadal sex determination to
permanently alter the germ line epigenome (Anway et al., 2005;
Guerrero-Bosagna C et al., 2010; Skinner et al., 2010) to then transmit
this altered germ line epigenome to subsequent generations (Anway et
al., 2005; Anway et al., 2006a,b; Anway and Skinner, 2008;
Guerrero-Bosagna C et al., 2010; Skinner et al., 2010). As the embryonic
stem cell epigenome is altered due to this germ line transmission, all
cell populations and tissues will have an altered epigenome and
corresponding transcriptome (Anway et al., 2008; Skinner et al., 2010).
The germ line generated by the next generation will also have this
altered epigenome and transmit it to the subsequent generation
(Guerrero-Bosagna C et al., 2010; Skinner et al., 2010). Exposure to the
endocrine disruptors at other times of development do not appear to
have the capacity to permanently alter the germ line epigenome (Anway et
al., 2005; Anway and Skinner, 2008; Skinner et al., 2010). Of course,
the vast majority of exposures will alter the somatic cells at critical
periods of development to modify later cellular development and
potential adult onset disease, Figure 1, but this does not have the
capacity to become transgenerational as the germ line is not involved
(Skinner et al., 2010). Epigenetic transgenerational inheritance through
a permanently altered epigenome of the germ line has the capacity to
have a dramatic influence on developmental biology, as well as other
areas of biology such as evolution.
“
In the event the base-line epigenome is altered, then the
cascade of epigenetic and genetic steps during development will be
altered and a modified differentiated or developmental state achieved, Figure 1.
Therefore,
epigenetic transgenerational inheritance has a dramatic effect on the
developmental biology of all cells and tissues derived from the germ
line transmitting this modified baseline epigenome. Although not all
cell types or tissues will develop a disease state, those tissues that
have a sufficiently altered transcriptome will have a greater
susceptibility to develop disease (Skinner et al., 2010). As all
development and differentiation processes involve a cascade of
epigenetic and genetic steps, alteration of the baseline epigenome,
similar to alteration in the genetic baseline, will have the capacity to
promote abnormal development which may lead to disease later in life.
For this reason, environmentally induced epigenetic transgenerational
inheritance through the germ line will have a significant impact on
developmental biology. This mechanism and consideration of the cascade
of integrated epigenetic and genetic events during development, Figure
1, will be an important factor in disease etiology not previously
considered (Skinner et al., 2010).”
What this hypothesis might explain
It goes without saying that there are many roads to the various phenotypes we lump together under the label of
autism.
Among them: genetic disorders, prenatal and perinatal complications,
prematurity and multiple birth, prenatal exposure to certain pathogens
or chemicals, and seizure disorders. However, it is worth noting that
the pharmaceutical/epigenetic
hypothesis is consistent with a great many research findings, as follows:
--Abnormally high rates of
autism in west Los Angeles (the site of early, aggressive fertility and prenatal treatments beginning in the 50s)
--Abnormally high rates of
autism in New Jersey (same)
--Rising rates of
autism
diagnoses after about 1990 (the time when the early crop of
grandchildren of the growing number of women treated in the 1960s were
entering their preschool years)
--Findings of certain epigenetic signatures in
autism brains
--The lack of evidence for a genetic root of most cases of ASD
--Findings implicating very early neurological development in ASDs
--Certain
demographic patterns, eg, why certain religious or ethnic populations
that had little access to or interest in prenatal care have lower
autism rates
--The vast heterogeneity of the ASD syndrome
Some of the
researchers with whom I spoke agreed that pharmaceuticals could be
playing a role, but that other low-level environmental exposures such as
to plastics, endocrine disruptors, stress and hydrocarbons could also
be contributing. I feel the need for an editorial comment here: I
cannot fathom how ubiquitous and low-level exposures like those can
possibly compare to the sometimes huge direct doses of potent (though
forgotten) pharmaceuticals injected directly into our mothers during the
first half of pregnancy. The study of the pharmaceutical impacts
appears to be of much greater urgency.
Early Initiatives
Various early initiatives have been proposed:
Epidemiology.
There is broad agreement that epidemiological work should be done.
There exist at least four distinct cohorts of individuals known to have
been exposed to exogenous hormones in utero. It would be important to
do prospective studies (starting with obstetric records of the
grandmothers, and working downward), and not retrospective studies
(starting with autistic kids, and working up the family tree). This is
due to the absence of reliable information of past pharmaceutical use of
the grandmothers. To do meaningful epidemiological work, one would need
not only the basic knowledge of “exposure” but also the identities of
the drugs used, the dosages, and the timing.
--Denmark (Dr. Reinisch is looking into the possibility of a
second-generation study on this cohort, which is part of the Prenatal
Development Project at Kinsey)
--Finland (Dr. Brown is looking into
the possibility of a second-generation study on this cohort, which had
been identified by E Hemminki as part of a study into the fertility
rates in this cohort)
--Los Angeles (Dr. Reinisch’s detailed files on individuals exposed in
utero to synthetic steroid hormones, in the 1960s and 70s, still exist,
in storage at the Kinsey Institute)
--New Jersey (same as above)
Quite possibly, with some sleuthing, cohorts exposed
in utero to various pharmaceuticals could be found within initiatives at Kaiser and at Johns Hopkins as well.
Broader epidemiological work, looking at data from several countries
at once, was also suggested. However, the integrity of the data
regarding the F1 (grandmother) pharmaceutical use is in question.
History.
A few researchers suggested doing a basic history of past obstetric
pharmaceutical use around the world, since it is so poorly understood,
and attempting to make connections to the development of various
diseases, including ASDs, increasing in prevalence today.
Animal models. A great many researchers suggested
three-generation animal modeling. This way, different compounds and
different timing of exposure could be tested for resulting changes in
behavior, brain morphology, and epigenetic changes.
Case studies. A few researchers suggested doing direct
epigenetic studies on affected families. However, others cautioned that
such studies would be difficult owing to the complexity involved in
studying the epigenome.
In summary
Long-forgotten pharmaceutical use may be playing a significant role in the
autism
epidemic today. If this is the case, there is urgent work to be done
in terms of prevention, family planning, changing fertility and
obstetric medical practice, reducing pharmaceutical use by women of
childbearing age by shifting emphasis to natural treatments of chronic
conditions, ensuring all prenatal medical records remain available and
never discarded, and possibly, finding targeted therapies for the many
disabled individuals suffering from artificially altered epigenomes.
Therefore, expediting research into this
hypothesis is critical.
