Oct. 08--Two years ago, Jill Escher found evidence that she thinks might explain
why two of her three children have severe autism.
Ms. Escher, a onetime lawyer married to a former Silicon Valley marketing
executive, learned that when her mother was pregnant with her, she took a whole
host of fertility and anti-miscarriage drugs, including some that are no longer
Doctors had called her mother a "habitual aborter" because she had suffered two
miscarriages before she gave birth to Ms. Escher, and so they gave her mother
two fertility drugs to boost her ovulation, and then, once she had conceived,
they gave her a steroid and two synthetic sex hormone combinations to prevent
While she has no proof that the drugs led to her children's autism, she knows
that girls are born with all the eggs they will have for life, and she wonders
if the medications could have affected her eggs in such a way that it triggered
autism in her children, a 14-year-old boy and a 7-year-old girl.
This "transgenerational" effect may sound unlikely, but it has become a hot
topic in autism research as part of an emerging field known as epigenetics.
Mysteries of the Mind
--First part: Dealing with the different worlds of autism
--Second part: Researchers work to unravel causes of autism
"Epi" means above or around, and in this case, it suggests that environmental
factors -- infections, drugs, diet, toxins, or stress -- could affect the fetus
in ways that would change the child's DNA in the womb and lead to illnesses or
disorders ranging from diabetes to heart disease to mental disabilities.
There are intriguing hints from animal and human studies that these
environmental influences can sometimes have effects on future generations by
affecting a fetus's eggs or the precursor cells for sperm. In those cases, you
wouldn't know for sure that an epigenetic change had been passed along until the
grandchildren's generation, because it would be the first offspring not exposed
to the original stressor.
A key part of the epigenetics concept is that these factors will influence the
way a person's DNA is activated, but won't change the structure of the DNA
itself, which makes it different from a mutation that scrambles the letters of
the DNA alphabet.
While no one has made a convincing case yet that autism is one of those
transgenerational disorders, several researchers have said it is worth
investigating the possibility that pregnant women exposed to environmental
toxins from the 1950s to the 1970s, when air and water pollution were worse,
might have given birth to children whose eggs and sperm were altered by those
substances, who in turn gave birth in the next generation to the autistic
children we see today.
There are cases where environmental factors seem to have influenced future
In one frequently cited human study, Swedish scientist Lars Olov Bygren examined
children born in a remote Arctic region during years when there were either crop
failures or crop surpluses. Surprisingly, he found that the children and
grandchildren of men born in the abundant crop years had much shorter lifespans
than those born to men who had grown up in the lean years.
He has said that he does not know why prosperous years would cause shorter life
spans in future generations, but he noted that the grandfathers' diets could
have affected their sperm when those cells first formed between the ages of 9
and 12, and those changes could have affected the health of their sons and
grandsons. He noted that grandmothers in the abundant crop years did not pass
along similar disadvantages to female offspring.
There also have been animal studies showing epigenetic effects, and in March,
Ms. Escher's family foundation helped finance a conference at the MIND Institute
at the University of California at Davis that featured some of those studies.
One researcher who spoke there, Michael Skinner of Washington State University,
said he has found transgenerational effects in laboratory rodents exposed to
dioxin, an industrial toxin sometimes found in meat, fish and dairy products,
and vinclozidin, an antifungal agent used in the wine-making industry.
His group's 2012 dioxin study showed that when pregnant rats were exposed to the
pollutant, their offspring had higher rates of prostate and ovarian diseases
through the third generation, and that in that third generation of rats, 50
regions in the DNA controlling sperm production had been altered by an
epigenetic process known as methylation.
In the vinclozidin experiment, his team exposed pregnant rats to the antifungal
agent and found that even four generations later, the male offspring still had
poor sperm production and similar DNA methylation changes to those found in the
When an environmental insult causes DNA methylation, he said, it affects the way
the animal's genes are expressed, and "when that animal becomes an adult, it has
this shifted epigenome which gets transferred to the next generation through the
sperm or egg, and you now have a shift that's generated in every single cell
type, and when there's a tissue that is susceptible to that shift, you get a
He and other scientists at the California conference said they often run into
criticism and even disdain from other genetic researchers when they suggest that
these kinds of epigenetic changes might be linked to disorders like autism.
"It's not surprising if you have studied classic genetics for 30 or 40 years and
someone comes along and says that's not the whole story, there will be a knee
jerk reaction" against it, he said.
Sometimes, DNA methylation changes can be positive.
In a 2003 study at the University of North Carolina, Randy Jirtle and his
colleagues took a breed of mice that was genetically prone to be overweight and
have yellow fur, known as Agouti mice, and fed pregnant mothers supplements of B
vitamins. They gave birth to lean, brown mice, and the Jirtle team was able to
show that the B vitamins had silenced the gene that normally made the mice fat
Even though there isn't evidence yet of environmental stresses causing brain
disorders in multiple generations, there are studies showing they can have an
impact in children whose mothers had certain illnesses.
Alan Brown, a psychiatrist and epidemiologist at Columbia University, found with
colleagues at Kaiser Permanente that when they looked at a large group of babies
born in California in the 1950s and 1960s, children whose mothers had been
exposed to the flu during pregnancy had a threefold greater risk of getting
schizophrenia decades later.
He is now working with a large birth registry in Finland. Along with researchers
at Turku University and the National Institute for Health and Welfare there, he
has found that mothers with higher levels of a liver substance known as C.
reactive protein, which can be caused by infectious or inflammatory illnesses,
had about a 50 percent greater rate of giving birth to children with autism.
In an interview at the epigenetics conference, Dr. Brown said that the flu virus
itself doesn't usually cross over from mother to fetus, but inflammatory
substances known as cytokines in the developing baby might create damaging
inflammation in the baby's brain.
"I take a fairly agnostic approach," on what triggers autism, he said. "I'm
interested in understanding the causes, whether they are natural or imposed. If
that exposure is toxic and there is strong evidence that it is related to
autism, efforts need to be made to reduce or eliminate it from the population,
whether it's due to man-made causes or natural causes."
Finally, in a study published just last month in the journal Molecular
Psychiatry, a group at Johns Hopkins University in Baltimore autopsied the
brains of 21 people with autism and of 19 people without autism, and found four
regions of the autistic people's brains that had a sharply different pattern of
Because people have been taught for years that genes govern all our biological
functions and only change when there are rare mutations or inherited diseases,
the idea that illnesses or diet could alter our genes within a generation can be
hard for some to accept.
But Scott Selleck, a genetics researcher at Penn State University, said that
scientists who have worked with fruit flies, as he has, don't find the idea
strange at all.
Fruit flies are used to study how genes control development and behavior, and
researchers are acutely aware of how environmental conditions such as crowding,
temperature and diet can change the way the flies' genes function.
In one case, he remembered, his lab had identified a strain of flies whose
nervous system genes were so abnormal that they didn't survive to adulthood. But
when a Japanese doctoral student took the strain of flies to his home country,
where the labs used a much richer type of fly food, the flies routinely lived to
adulthood, even though they often had major defects like an extra wing or
If environmental conditions can affect the lowly fruit fly so easily, it's
possible they might alter the development of humans, too, Jill Escher believes.
When she discovered her mother's pregnancy medication history, she also learned
that she and her mother had been part of a study on the impact of those drugs on
The woman heading up that study was June Reinisch, who was then a doctoral
student and went on to become head of the Kinsey Institute for sexual research.
Now retired from that position, she is continuing her investigation into
possible links between prenatal drugs and disorders like autism, working with a
large Danish birth registry.
After the March conference, Ms. Escher said: "I think if there was a major
message from these sessions, it is that we cannot look at genetics in a vacuum."
"Genetics has to be looked at in the context of the environmental impacts that
affect genetic expression. This is not a genetics vs. environment question. A
lot of this is a genetics and environmental effect question, and because of the
germline effect [on eggs and sperm], we can see impacts long after the initial
Just in the past year, she said, "I find that people are very open to this idea
now. There is an increasing appreciation that our germline is not this
imperturbable little marble of genes, but it's a vulnerable and sensitive tissue
that is susceptible to damage by exogenous influences."
Mark Roth: email@example.com or 412-263-1130. Twitter: @markomar.
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