SAN JOSE, Calif. – Jill Escher, a dark-haired dynamo of smarts and stamina, was gently stopping her son, Jonny, 14, from ripping up the mail. He had just emptied spice bottles on the table to make finger paints.
Upstairs, her daughter, Sophie, 7, was sending out incomprehensible cries. It could mean that Sophie had opened a box of crayons, eaten some and rubbed the rest into the carpet, or smeared a tube of toothpaste on the mirror. And while Escher tried to calm Sophie, Jonny could be tossing his iPad over the fence, tearing all the ivories off the piano, chewing the furniture, or wandering out into traffic.
For Escher, the anguish of autism is doubled. Both Jonny and Sophie have been diagnosed with autism, the fast-growing category of neurological disease afflicting one in every 88 U.S. children. The Escher children's intellectual development is stalled at an early pre-school level, and they need constant care and protection.
For years, Escher and her husband, Christopher, worried about what could have gone wrong. Why would two of their three children wind up autistic, defying the odds? Was it their genes? Their environment? Their food? The couple tried to hunt down any health problems in their lineage but found none. A glass of wine while pregnant? Paint fumes? Pollution from freeways?
New studies appear with regularity, suggesting causes but offering no definitive answers.
“To be perfectly honest, I had given up trying to find out. I felt I would die never knowing what happened to my children. No one could tell me,” Escher said.
But three years ago, Jill Escher had an epiphany, one that now subsumes her waking hours and nighttime dreams. After prodding her mother for clues from her past, Escher discovered some hidden history: Her mother had sought help conceiving at a fertility clinic. As she grew in her mother's womb, Escher was bombarded with synthetic hormones and other drugs.
Now Escher’s dogged quest to unravel why this happened to her children has drawn the attention of scientists, and may ultimately lead to a greater understanding of how prescription drugs – and perhaps chemicals in the environment – may secretly and subtly harm the health of generations to come.
“The autism explosion has been with us for more than two decades, and we have little to show about what's causing it,” Escher said. “We have many hundreds of thousands of functionally disabled people who didn't exist before, and we have our heads in the sand.”
Jill Escher meets with Brad Boardman, executive director of the Morgan Autism Center, to discuss a grant from Escher's foundation. (Photo: Katy Raddatz)
From generation to generation
Scientists know that some chemicals can alter developing embryos and fetuses, which can lead to disease later in life.
But in recent years, they've learned that the damage doesn't necessarily stop there. Something a pregnant woman is exposed to may alter not just her children, but also her grandchildren – and possibly even subsequent generations.
This is how the "germ line" hypothesis works: Cells in what is called a “germ line” form eggs in the female fetus and precursors to sperm in the male fetus. The germ line establishes an unbroken link from generation to generation. But when a pregnant woman is exposed to chemicals, the germ line may be altered. That would mean that eggs developing in the fetus – the future third generation – could be changed, leading to abnormalities or disease. Also, the disrupted programming in how genes are turned on and off – the very genes that instruct cell growth and function – may be passed on to more descendants.
The power of pharmaceuticals to do just that came to light with a synthetic estrogen that harmed at least two generations of offspring of women who took it. DES, or diethylstilbestrol, was prescribed to up to 10 million pregnant women in the United States and the United Kingdom from 1938 to 1971 in an effort to prevent miscarriage and premature birth. DES daughters, exposed in the womb, are at an increased risk for a rare form of cancer of the vagina and cervix and other reproductive disorders, and the sons have increased risk for some reproductive problems. Startling scientists, DES granddaughters turned up with an increased incidence of urinary and genital malformations, irregular menstrual cycles and other abnormalities.
These findings were profound: A single exposure of a pregnant woman seemed to induce defects in her fetus's eggs, triggering health effects in the next generation.
Now health experts probing autism wonder: Could this be a clue? Could a pregnant woman’s exposure to something alter the brains of her grandchildren?
A personal quest
When Escher’s first child, Evan, was born in 1997, he met his developmental markers. Two years later came Jonathan. “He was really colicky, and always seemed to be in some pain that we couldn't soothe. He would sit in the backyard and pick up rocks and dirt,” she said.
She saw the ominous signs: no eye contact, no babbling as a baby. The Eschers took him for an assessment. As soon as the doctor walked into the waiting room, he suspected autism.
“Jonny is a brick. Nothing permeates his skull. He was just impervious to what we were trying to teach him. He was an affectionate little boy and remains so today,” Escher said.
Then when Sophie was born seven years after Jonathan, she showed similar signs. She didn't play or make eye contact. Her diagnosis came soon after. Genetic testing revealed no known abnormalities in either child, and no clinician could think of any reason for two children with such severe disabilities.
According to the Centers for Disease Control and Prevention, parents who have a child with autism have only a 2 to 18 percent chance of having a second autistic child.
In 2000 and 2002, one in every 150 U.S. children was diagnosed with autism spectrum disorders, which affect the brain’s normal development of social and communication skills. But the rate climbed to one in 88 in 2008, according to the CDC. Many experts believe the rise is due to a combination of a real increase in prevalence plus improved diagnoses.
“We don't know why the numbers are increasing, and we don't know which portions of the brain are affected when a person has autism,” said neuroscientist David Amaral, research director at the University of California, Davis, MIND Institute.
“Twenty years ago, the view in the field was that autism was totally a genetic disorder, and if you could figure out which genes were involved, then you would understand the cause of autism. Now we've gotten to the point where we're saying environmental factors have just as much influence as genetics,” he said.
With no scientific training, Escher, 47, has educated herself enough to discuss new research with Amaral and other autism experts. She has a law degree from the University of California, Berkeley, and five years' experience as a clerk in the U.S. District Court in San Jose. Five years ago, Escher and her husband founded a small family fund that first financed school recreational activities for autistic children, then research into its causes.
To her horror, she learned that researchers had discovered an autism cluster in West Los Angeles, where she grew up. In her search for answers, Escher came across a Tel Aviv University study linking in vitro fertilization with increased risk of autism.
“That's when it hit me that I might have been a fertility kid,” she said. She remembered a scrap of information tucked away. At 13, the cover of Time magazine featured a test tube to illustrate creating a baby with the aid of science. Someone – she thinks it was her dad – said to her, “You were just like that baby. You were a miracle child. You were wanted very badly.” She wasn’t a test tube baby, but she wondered if her mother had taken fertility drugs.
Escher called her mother, and asked. “They gave me a whole bunch of stuff. I don't know what it was,” her mother said.
At Escher's request, her mother called her former obstetrician. Four pages of records, stored on microfilm, were sent to Escher. Scrawled over the pages was a list of synthetic hormone drugs that her mother took. Over and over, she saw steroid hormones: Deluteval (a progestin with estradiol) and prednisolone. Escher learned that her mother had gone to a West Los Angeles fertility clinic run by Dr. Edward Tyler, who had prescribed Pergonol and Clomid to induce ovulation to help her conceive. And it was Tyler who had prescribed a continuing regimen of hormones and steroids, including weekly injections, as a way to prevent miscarriage during the pregnancy.
Escher asked some autism researchers about the fertility drugs, but got no encouragement, so she set the records aside.
But when the sister of a friend who had been exposed to DES in the womb died of breast cancer, she realized that the effects of some drugs could last for generations. “DES was a real eye opener in terms of transgenerational effects of prenatal exposure to drugs,” she said.
“I was listening to a podcast, and a health guru explained that a pregnant woman's nutrition affects not only her fetus but also her grandchildren because of exposure of the germ cells. I heard her say, 'A girl is born with all her eggs.'”
She was stunned. “Something's happened to my eggs,” she thought.
Searching the epigenome for answers
Millions and millions of women who are now grandmothers took heavy doses of drugs during their pregnancies in the '50s and '60s. Escher wondered: Could the fertility, nausea and miscarriage drugs heavily prescribed in the past decades alter the fetus and lead to lasting, transgenerational abnormalities such as autism?
So far, no one has looked, although one ambitious study is about to be launched in Europe.
“Right now research looks at environment and it looks at genetics. But it doesn't look at the environmental effects on the germ line. These are critical questions. So far we're silent on them,” Escher said.
Science is very compartmentalized, she said.
“We already have all the pieces. We just need to put them in order. But you don't have one person stringing it all together,” she said.
Escher is trying to be the one to do that.
One of the first scientists she contacted was Michael Skinner (at right), a professor in the School of Molecular Biosciences at Washington State University.
Skinner laid out the shift in thinking that is setting off waves of disagreement among geneticists. For more than a century, scientists believed that only alterations in the DNA sequence could be passed on to subsequent generations. Now they are considering a change in that thinking: The way in which normal genes are expressed, or turned on and off, may be passed on, too. An abnormal exposure to a pregnant woman – a toxicant or smoking, for instance – might change the genetic switching that controls the development of a fetus. These alterations then may be passed on to multiple generations.
This is called epigenetic inheritance.
Scientists believe that molecules called the “epigenome” modify a person's instruction-giving genome in a way that tells it what to do, where to do it and when to do it. Environmental factors can more easily interact with the epigenome than the genome, and these changes can be passed on from cell to cell as cells divide.
Skinner explained it to Escher this way: “Think of the genome as the computer, and the epigenome as the software.”
The hypothesis is that if the germ cells are affected in the fetus, disruptions in signals can be transmitted to subsequent generations, without affecting the DNA sequence. If at least three generations of offspring are affected, Skinner calls it "transgenerational."
“In essence, what your grandmother was exposed to when she was pregnant may cause disease in you and your grandchildren. Therefore, the potential hazard of environmental toxicants is dramatically increased, in particular for pregnant women in mid-gestation, six to 18 weeks,” Skinner said at a symposium on epigenetics and autism at UC Davis in March, partly supported by a grant from the Escher Fund for Autism.
In lab animals, Skinner and other scientists have linked a dozen chemicals – including bisphenol A, which is an ingredient of polhycarbonate plastics, phthalates used as plasticizers, the insecticide DEET and a fungicide – to transgenerational epigenetic changes that have led to tumors, prostate disease, reproductive problems and other problems in at least three generations of offspring.
Environmental epigenetics may have an important role in the origins of autism, Skinner said. “The majority of brain disease has been shown not to be genetically based, and autism is likely environmentally induced during some period of development,” he said.
However, study of possible links between autism and multigenerational effects of environmental exposures is in the early stages, and the links remain a topic of debate among scientists.
"So far there are only a handful of gene mutations that are found in the human autism population. For the majority of patients we know something else is going on, and that might be epigenetic changes,” said Emilie Rissman, professor of biochemistry and molecular genetics at the University of Virginia School of Medicine.
Many diseases have increased faster than can be explained from normal genetic mechanisms. The epigenetic phenomenon could be a reason.
“If environmental factors influence gene expression, the risk of someone having autism could increase,” said Amaral of the University of California, Davis.
But Amaral said more basic science is needed to figure out the possible effects of environmental toxicants and pharmaceuticals. “Not enough is being done,” he said.
One large study, published earlier this year, reported that children of women who took valproate, prescribed for epilepsy and psychiatric disorders, had a significantly higher risk of autism spectrum disorders than other children. The study didn't look at epigenetic effects, however.
“There are many pieces of information learned from more than a decade of study that need to be connected before any conclusion can be made about autism,” said Andrea Gore, professor of pharmacology and toxicology at the University of Texas at Austin. Gore was one of the first to show in lab animals that prenatal exposure to hormone-like chemicals interfered with development of the neurological and reproductive systems, leading to abnormalities, including social and neurobehavioral disorders.
“It's too soon to make a direct connection between exposure to synthetic reproductive hormones and autism,” Gore said. “We think most behavioral disorders are a combination of genetic predisposition, natural differences in reproductive hormones and differences in environmental exposures.”
University of California, Davis, autism researcher Janine M. LaSalle said human studies over many generations would be needed to determine whether genomes and epigenomes may be increasingly susceptible to autism due to a multitude of environmental factors.
With lab animals, Gore and her colleagues will conduct transgenerational studies of hormone-mimicking chemicals to try to understand molecular changes in the brain and the connection between nerve cells and behavior.
“The caveat is that animals don't get autism spectrum disorders. All we can do is look at perturbations of normal behavior in ways that we believe may mimic some aspects of autism,” she said.
“The human is very special. We are different from other species… When it comes to these really complicated neurological biological disorders, we have to interpret the animal results in that context.”
Antidepressants under the microscope
Escher started doing some sleuthing of her own. Suspicious of links between pharmaceuticals and autism, she surveyed other autism families to ferret out exposures during pregnancy. Over months, she communicated with 70 parents, mostly mothers. Nine women told her they had taken antidepressants, including drugs known as SSRIs.
“The stories were the same again and again and again. The mother was mildly depressed. The doctor would always say it's more important for you to stay on the drug, and there is no sign of risk to the fetus,” Escher said.
Prenatal use of SSRIs, or selective serotonin reuptake inhibitors such as Prozac and Zoloft, have surged since their introduction in the late 1980s.
She came across a post by Dr. Adam Urato, assistant professor and clinician at Tufts University School of Medicine, saying that there was a body of science linking SSRIs to autism, birth defects and other effects.
“If you look at the DES tragedy, you see many of the same hallmarks that you see today. I'm concerned that the warning voices aren't being heard, and the evidence of harm is being drowned out,” Urato said.
Antidepressants are believed to block serotonin, which is essential for brain growth, from being taken up by neurons, the basic cells of the brain. Autism is characterized by changes in the serotonin system.
Studies in animals and humans suggest that fetal exposure to SSRIs may be linked to neurological and developmental disorders, including an increased risk for autism syndrome disorders, Urato said.
For example, researchers in Sweden reported a link between antidepressants and autism. Pregnant women taking SSRIs showed a more-than-triple increase in risk of offspring with autism spectrum disorder.
Other researchers in the San Francisco Bay Area examined the association between autism and antidepressants during pregnancy. In a study published last year, they found a more than two-fold increased risk of autism associated with SSRIs with the strongest effect found in the first trimester.
One research group concluded that “fetal and infant exposure to SSRIs should be examined in humans, particularly those with developmental dysfunction, such as autism.“
When asked about any ongoing studies by the U.S. Food and Drug Administration, spokeswoman Andrea Fischer responded: “The FDA is not aware of any studies demonstrating that antidepressant use causes autism.”
There have been no studies on the epigenetic or germ line effects of SSRIs.
Skinner is intrigued, and wants to study germ line changes related to pharmaceuticals but says the research funds aren't there. “In my opinion, it's a Catch-22. If we can't find research money to do the studies, then the medical community is not going to pay attention. All it would take is a few good publications to raise the red flag. Then the industry would respond accordingly, and the FDA would respond,” he said.
Escher is impatient with the FDA, saying it is missing an opportunity to explore a hypothesis that autism researchers call viable.
“We know pregnant women are taking SSRIs. We know that SSRIs have endocrine-disrupting effects. We know that endocrine-disrupting chemicals can disrupt germ line development. It only stands to reason that SSRIs can have transgenerational effects.
“It makes sense on paper. But nobody's asking the question,” she said.
FDA petitioned, NIH involved
Two months ago, Escher petitioned the FDA. She is seeking revocation of the first anti-nausea drug approved for pregnant women, Diclegis, until it is tested for effects on the fetus's developing germ cells.
Escher also wants wording on drug labels that alerts pregnant women that the medication has not been tested for damage to the baby's vulnerable egg or sperm precursors, and bears the risk of causing disease or developmental disorders in the next generation.
“I chose Diclegis as a poster child because it had been approved as though there are no risks to the fetus,” she said. She is particularly concerned that it is prescribed during the first half of pregnancy, when germ lines develop.
Her cause is supported by some scientists, including Tel Aviv University theoretical biologist Eva Jablonka, who has been studying transgenerational epigenetic effects for years.
Jablonka wrote a letter to the FDA saying the understanding of epigenetic inheritance and fetal vulnerability “should alert us and urge us to take cautionary measures until research reveals whether or not the drugs affect the relevant grand-offspring generation.”
A representative of Duchesnay Inc. said the Canadian pharmaceutical company worked closely with the FDA in evaluating Diclegis. The drug has not shown an increased risk to the fetus during pregnancy, according to an emailed statement. The drug maker didn't respond to questions about possible effects on the fetal germ line.
At the FDA, Fischer said the combination of active ingredients in Diclegis – doxylamine succinate and pyridoxine hydrochloride – has been the subject of many epidemiological studies designed to detect the potential to cause birth defects in the fetus. Based on these and other studies, “there are no concerns for an increased risk for malformations from first trimester exposure to these ingredients,” Fischer said.
But Jablonka and other scientists say the testing of drugs should not be stopping with the exposed fetus, because perhaps only the subsequent generations are harmed. Asked about that, Fischer said, “the science of epigenetics is new, and initial work in animal models suggests it may provide additional approaches to better understand environmental influences for human health. As with all emerging science, the FDA will review data and consider its potential for impact on regulatory decisions.” She said the agency is reviewing Escher’s petition.
Earlier this month, Escher, along with Alycia Halladay of the national nonprofit Autism Speaks, presented the germ line disruption hypothesis to a committee of the National Institute of Mental Health, which is congressionally mandated to deal with the autism crisis.
The National Institutes of Health has begun funding some epigenetics studies related to autism and prescription drugs.
A large study in Europe, led by the Mount Sinai School of Medicine, is looking at medications taken by mothers and the health of their offspring. University of California, Davis, researchers are examining links between exposure to air pollution and pesticides, epigenetic changes and autism. Johns Hopkins University researchers are testing for epigenetic changes in autistic children associated with prenatal exposures to environmental chemicals. The National Institute of Mental Health is financing some studies on pharmaceuticals, including an investigation of whether antidepressants are causing epigenetic changes.
Also, an ambitious, first-of-its kind study of 8,000 people in Denmark, partially paid for by Escher’s fund, will look for connections between any pharmaceuticals they were exposed to in the womb and neurological disorders in their children.
Scientists, Escher said, have access to a treasure trove: the parents and grandparents of autistic children.
“Most autism families can generate very strong clues about what could have happened with their children. But it requires probing deep into ancestral exposures. The clues are there,” she said.
As for her own inspiration, “I love my kids. But I don't want this to happen to anyone else. It's too hard. It's too damaging.
"We have unwittingly experienced this mass disruption in evolution. It has to stop. We have to be much better caretakers of our genetic legacy.”
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