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The Unexpected Connection Between Estrogen and Autism

Science has been studying autism spectrum disorder for better part of a century, and yet there’s one thing they can’t seem to figure out: why the brain of people with autism develop differently. But because it’s more common in boys, some researchers have long suspected that testosterone levels in the womb are the key.

The only problem is, their evidence has become up short. Turns out they might have been looking at the wrong hormones. Just this week, a team of scientist at the University of Cambridge and the State Serum Institute in Denmark announced that they’ve identified a link between autism and a different sex hormone: estrogen.

While it might sound like the complete opposite of what you’d expect for something more prevalent in boys, it actually lines up with our understanding of autism better than you’d think.

Autism spectrum disorder affects about every on of 59 children, but even after correcting for underdiagnosis and misdiagnosis, it’s roughly three times more likely in boys than in girls. Girls with autism also generally have fewer autism traits than boys. And all that may imply that there’s some kind of connection between autism and the physiological difference that generally come with Y chromosome.

Some even suggested that autism is basically what happens when you take typically male neurological traits and dial them up to 11. This is what’s known as the “extreme male brain theory” of autism. Now, it’s important to note that this doesn’t mean that the autistic people are super masculine overall–it just mean that they have more of the traits that you see more frequently on average, in the brains of men. And the difference is very small.

Studies consistently show that men and women are more psychologically similar that they are different. But there are some traits that, again, on average more common or more pronounced in the brains of people with Y chromosome or who identify as me. And it does seem like the traits are amplified in people with autism. To give one example, the brains of men tend to have weaker connectivity in the brains default mode network.

There’s a group of brain region that’s most active when you’re not focused on the outside world. And it turns out that both men and women with autism have even lower connectivity on this region than the average neurotypical man. Because there does seem to be some merit to this extreme male brain idea, researchers have suggested that the biological pathways involved in the development of typically masculine traits might be at the root of autism. And all traces back to fetal sex differentation:

The biological cues that lead to the development of typically masculine or feminine traits So in recent years, researchers begin to look for clues to autism in fetal development and conditions fetuses experience in-utero. And at first, many thought androgens- the hormones involved in typically male traits- might be to blaim, which makes intuitive sense.

The thing is, studies on prenatal testosterone levels alone- which is arguably the most important androgen–have found no relationship between it and autistic features. Then in the study published in 2015, Cambridge and Danish researchers found elevated levels of several sex hormones in the amniotic fluid of male fetuses that went on to develop autism. And while that did include testosterone and another androgen, it also included progesterone: which got the researchers thinking maybe they needed to widen their scope. Which brings us to estrogen.

Estrogen actually refers to the group of hormones which includes estriol, estradiol, estrone, and estetrol–none of which tested in the 2015 study. And these so called “female” hormones are very important for fetal development regardless of sex. Estradiol, in particular, contributes a lot development. It helps to form and prune neurons and synapses, and it regulates the activity of neurotransmitter GABA. In the brains of people with autism, synapses and neuron formation and GABA regulation are all typical.

So it might make sense that estrogen levels in the womb could play a role in the development of autism, too. To find out, those same researchers returned to the amiotic fluid samples they used in their 2015 study. These initially came from the Danish Historic Birth Cohort: a set of biological samples are more than a hundred thousand pregnant people collected between 1980 and 2004 who were followed up with the monitor the children’s health overtime, including whether they were diagnosed with autism. The researchers ended up with amniotic fluid samples from 98 males with autism and 177 neurotypical males. They then analyzed the samples for various forms of estrogen.

They found that elevated levels of estradiol and estriol, and estrone were all associated with an autism diagnosis. Estradiol has the biggest effect: a rise in this hormone from the 25th to the 75th percentile came with an almost 50% increase in the likelihood of autism. What this study suggests is that high level of estrogen, at least at about 15 weeks gestation, it might lead to differences in the brain development. As for why estrogen levels are higher at that time, the researchers suggested the placenta may have something to do with it. It acts as a hormone regulator between mom and fetus, and it’s fetus’ main source of estrogen.

And all that said, the researchers didn’t find that amniotic fluid hormones perfectly predict autism.

Baby teeth link autism and heavy metals, NIH study suggests

Cross-section of toothCross-section of tooth showing laser removal of the dentine layer, in tan, for analysis of metal content.Mount Sinai Health System

Baby teeth from children with autism contain more toxic lead and less of the essential nutrients zinc and manganese, compared to teeth from children without autism, according to an innovative study funded by the National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health. The researchers studied twins to control genetic influences and focus on possible environmental contributors to the disease. The findings, published June 1 in the journal Nature Communications, suggest that differences in early-life exposure to metals, or more importantly how a child’s body processes them, may affect the risk of autism.

The differences in metal uptake between children with and without autism were especially notable during the months just before and after the children were born. The scientists determined this by using lasers to map the growth rings in baby teeth generated during different developmental periods.

The researchers observed higher levels of lead in children with autism throughout development, with the greatest disparity observed during the period following birth. They also observed lower uptake of manganese in children with autism, both before and after birth. The pattern was more complex for zinc. Children with autism had lower zinc levels earlier in the womb, but these levels then increased after birth, compared to children without autism.

The researchers note that replication in larger studies is needed to confirm the connection between metal uptake and autism.

“We think autism begins very early, most likely in the womb, and research suggests that our environment can increase a child’s risk. But by the time children are diagnosed at age 3 or 4, it’s hard to go back and know what the moms were exposed to,” said Cindy Lawler, Ph.D., head of the NIEHS Genes, Environment, and Health Branch. “With baby teeth, we can actually do that.”

Patterns of metal uptake were compared using teeth from 32 pairs of twins and 12 individual twins. The researchers compared patterns in twins where only one had autism, as well as in twins where both or neither had autism. Smaller differences in the patterns of metal uptake occurred when both twins had autism. Larger differences occurred in twins where only one sibling had autism.

The findings build on prior research showing that exposure to toxic metals, such as lead, and deficiencies of essential nutrients, like manganese, may harm brain development while in the womb or during early childhood. Although manganese is an essential nutrient, it can also be toxic at high doses. Exposure to both lead and high levels of manganese has been associated with autism traits and severity.

The study was led by Manish Arora, Ph.D., an environmental scientist and dentist at the Icahn School of Medicine at Mount Sinai in New York. With support from NIEHS, Arora and colleagues had previously developed a method that used naturally shed baby teeth to measure children’s exposure to lead and other metals while in the womb and during early childhood. The researchers use lasers to extract precise layers of dentine, the hard substance beneath tooth enamel, for metal analysis. The team previously showed that the amount of lead in different layers of dentine corresponds to lead exposure during different developmental periods.

Arora said that autism is a condition where both genes and environment play a role, but figuring out which environmental exposures may increase risk has been difficult.

“What is needed is a window into our fetal life,” he said. “Unlike genes, our environment is constantly changing, and our body’s response to environmental stressors not only depends on just how much we were exposed to, but at what age we experienced that exposure.”

Prior studies relating toxic metals and essential nutrients to autism have faced key limitations, such as estimating exposure based on blood levels after autism diagnosis rather than before, or not being able to control for differences that could be due to genetic factors.

“A lot of studies have compared current lead levels in kids that are already diagnosed,” said Lawler. “Being able to measure something the children were exposed to long before diagnosis is a major advantage.”

The method of using baby teeth to measure past exposure to metals also holds promise for other disorders, such as attention deficit hyperactivity disorder. “There is growing excitement about the potential of baby teeth as a rich record of a child’s early life exposure to both helpful and harmful factors in the environment,” said David Balshaw, Ph.D., head of the NIEHS Exposure, Response, and Technology Branch, which supported the development of the tooth method.

Grant Numbers: DP2ES025453, R00ES019597, P30ES023515 (NIEHS); HD073978 (NICHD); MH097849 (NIMH)

NIEHS supports research to understand the effects of the environment on human health and is part of NIH. For more information on environmental health topics, visit www.niehs.nih.gov. Subscribe to one or more of the NIEHS news lists to stay current on NIEHS news, press releases, grant opportunities, training, events, and publications.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health, also provided funding for the study.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH…Turning Discovery Into Health®

Vitamin D Deficiency During Pregnancy Linked to Increased Risk of Autism Traits in Offspring

Summary: A new study reveals lower levels of vitamin D at 20 weeks of pregnancy is linked to an increased risk of autism traits in the offspring.

Source: University of Queensland.

Researchers at The University of Queensland’s Queensland Brain Institute have found a link between Vitamin D deficiency in pregnancy and increased autism traits.

The study, led by QBI researcher Professor John McGrath and involving Dr Henning Tiemeier from the Erasmus Medical Centre in The Netherlands, found that pregnant women with low Vitamin D levels at 20 weeks’ gestation were more likely to have a child with autistic traits by the age of six.

“This study provides further evidence that low vitamin D is associated with neurodevelopmental disorders,” Professor McGrath said.

“Just as taking folate in pregnancy has reduced the incidence of spina bifida, the result of this study suggests that prenatal Vitamin D supplements may reduce the incidence of autism.”

While it is widely known that Vitamin D is vital for maintaining healthy bones, there is now a solid body of evidence linking it to brain growth.

Vitamin D usually comes from exposure to the sun, but it can also be found in some foods and supplements.

The study examined approximately 4200 blood samples from pregnant women and their children, who were closely monitored as part of the long-term “Generation R” study in Rotterdam, The Netherlands.

“This research could have important implications from a public health perspective,” Professor McGrath said.

Image shows a pregnant woman.

“We would not recommend more sun exposure, because of the increased risk of skin cancer in countries like Australia.

“Instead, it’s feasible that a safe, inexpensive, and publicly accessible vitamin D supplement in at-risk groups may reduce the prevalence of this risk factor.”

Autism – or autism spectrum disorder – is used to describe lifelong developmental disabilities including an inability to communicate with others, interact socially, or fully comprehend the world.

Professor McGrath’s team has previously found a link between low Vitamin D in neonatal blood and an increased risk of schizophrenia.

ABOUT THIS AUTISM RESEARCH ARTICLE

Funding: The study is published in Molecular Psychiatry and is funded by the National Health and Medical Research Council (NHMRC).

Source: John McGrath – University of Queensland
Image Source: NeuroscienceNews.com image is adapted from the University of Queensland press release.
Original Research: Full open access research for “Gestational vitamin D deficiency and autism-related traits: the Generation R Study” by A A E Vinkhuyzen, D W Eyles, T H J Burne, L M E Blanken, C J Kruithof, F Verhulst, V W Jaddoe, H Tiemeier and J J McGrath in Molecular Psychiatry. Published online November 29 2016 doi:10.1038/mp.2016.213

CITE THIS NEUROSCIENCENEWS.COM ARTICLE
University of Queensland. “Vitamin D Deficiency During Pregnancy Linked to Increased Risk of Autism Traits in Offspring.” NeuroscienceNews. NeuroscienceNews, 14 December 2016.
<http://neurosciencenews.com/vitmain-d-pregnancy-autism-5747/&gt;.

Abstract

Gestational vitamin D deficiency and autism-related traits: the Generation R Study

There is intense interest in identifying modifiable risk factors associated with autism-spectrum disorders (ASD). Autism-related traits, which can be assessed in a continuous fashion, share risk factors with ASD, and thus can serve as informative phenotypes in population-based cohort studies. Based on the growing body of research linking gestational vitamin D deficiency with altered brain development, this common exposure is a candidate modifiable risk factor for ASD and autism-related traits. The association between gestational vitamin D deficiency and a continuous measure of autism-related traits at ~6 years (Social Responsiveness Scale; SRS) was determined in a large population-based cohort of mothers and their children (n=4229). 25-hydroxyvitamin D (25OHD) was assessed from maternal mid-gestation sera and from neonatal sera (collected from cord blood). Vitamin D deficiency was defined as 25OHD concentrations less than 25 nmol l−1. Compared with the 25OHD sufficient group (25OHD>50 nmol l−1), those who were 25OHD deficient had significantly higher (more abnormal) SRS scores (mid-gestation n=2866, β=0.06, P<0.001; cord blood n=1712, β=0.03, P=0.01). The findings persisted (a) when we restricted the models to offspring with European ancestry, (b) when we adjusted for sample structure using genetic data, (c) when 25OHD was entered as a continuous measure in the models and (d) when we corrected for the effect of season of blood sampling. Gestational vitamin D deficiency was associated with autism-related traits in a large population-based sample. Because gestational vitamin D deficiency is readily preventable with safe, cheap and accessible supplements, this candidate risk factor warrants closer scrutiny.

“Gestational vitamin D deficiency and autism-related traits: the Generation R Study” by A A E Vinkhuyzen, D W Eyles, T H J Burne, L M E Blanken, C J Kruithof, F Verhulst, V W Jaddoe, H Tiemeier and J J McGrath in Molecular Psychiatry. Published online November 29 2016 doi:10.1038/mp.2016.213

Mothers With Diabetes More Likely to Have Anti-Fetal Brain Autoantibodies

Summary: A new study reports women with diabetes were 3 times more likely to have anti-fetal autoantibodies, especially those whose children’s autism fell on the severe end of the spectrum.

Source: UC Davis.

Diabetic women were 3 times more likely to have anti-fetal brain autoantibodies, particularly those whose children’s autism fell on the severe end of the spectrum.

Mothers of children with autism and were diagnosed with metabolic conditions during pregnancy, particularly gestational and type 2 diabetes, were more likely to have anti-fetal brain autoantibodies in their blood compared to healthy women of children with autism. The presence of these anti-fetal brain autoantibodies has been previously found to be specific to some mothers of children with autism and rare among mothers of children without autism, researchers with the UC Davis MIND Institute have found.

In this study, researchers found that diabetic women were three times more likely to have anti-fetal brain autoantibodies, particularly those whose children’s autism fell on the severe end of the spectrum. Women with other metabolic conditions, such as high blood pressure and elevated body mass index (BMI) also had a higher prevalence of anti-fetal brain autoantibodies, the researchers found.

The research is published online today in the journal Autism Research.

“We found a three-fold increase in the prevalence of anti-fetal brain antibodies among the mothers of children with autism who were diagnosed with gestational diabetes or type 2 diabetes,” said Paula Krakowiak, a post-doctoral fellow in the UC Davis Department of Public Health Sciences and a researcher affiliated with the MIND Institute.

Earlier MIND Institute research found that approximately 23 percent of women with a child diagnosed with autism had specific patterns of autoantibodies that target proteins highly expressed in the fetal brain. These autoantibody patterns were detected in only 1 percent of women who did not have children with autism. The finding, reported in 2013, was the first to identify a specific risk factor for a significant subset of autism cases, as well as a potential biomarker for drug development and early diagnosis.

In the current study, the researchers examined 227 mother/child pairs who are participants in the Childhood Autism Risk from Genetics and the Environment (CHARGE) Study, which examines the environmental and genetic causes of autism. The study found that autism-specific maternal autoantibodies were more prevalent among mothers diagnosed with diabetes, hypertensive disorders, or who were moderately overweight compared to healthy mothers.

Among the study participants, 145 mothers had children who exhibited symptoms of severe autism. Of these mothers, those diagnosed with type 2 or gestational diabetes were nearly three times more likely to have the autism-specific anti-fetal brain antibodies, when compared with healthy mothers.

Approximately 5 to 9 percent of women in the United States are diagnosed with gestational diabeteseach year, according to the U.S. Centers for Disease Control and Prevention (CDC); the CDC estimates that between 4.5 and 9 percent of women in the prime childbearing years of 18 to 44 have gestational diabetes.

Image shows a pair of baby shoes.

“There are several take-away messages from this study,” Krakowiak said. “One is that metabolic conditions are characterized by increased inflammation and a number of studies have established links between metabolic conditions during pregnancy and neurodevelopmental conditions in children. Therefore, it is also reasonable to presume that these conditions may alter the maternal immune tolerance to the fetus during pregnancy, Krakowiak said.

“Another is to encourage women who are planning a pregnancy to achieve a healthier pre-pregnancy weight through changes in diet and physical activity, and if a mother was diagnosed with a metabolic condition to keep a closer watch of the baby’s development,” she said.

“We need to look into how their health is being managed, and how we can help them to be healthier,” Krakowiak said.

ABOUT THIS AUTISM RESEARCH ARTICLE

Other study authors include Cheryl K. Walker, Daniel Tancredi, Irva Hertz-Picciotto and Judy Van de Water, all of UC Davis.

Funding: The research was supported by National Institute of Environmental Health Sciences grants 1R01-ES015359; 1P30-ES023513; 2P01-ES011269; U.S. Environmental Protection Agency Science to Achieve Results (STAR) grants #R-829388 & R-833292; National Institute of Child Health and Development grants U54-HD079125; NIH-UL1-TR000002; and the University of California Davis MIND Institute.

Source: Phyllis Brown – UC Davis
Image Source: This NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Autism-specific maternal anti-fetal brain autoantibodies are associated with metabolic conditions” by Paula Krakowiak, Cheryl K. Walker, Daniel Tancredi, Irva Hertz-Picciotto and Judy Van de Water in Autism Research. Published online June 17 2016 doi:10.1002/aur.1657

CITE THIS NEUROSCIENCENEWS.COM ARTICLE
UC Davis. “Mothers With Diabetes More Likely to Have Anti-Fetal Brain Autoantibodies.” NeuroscienceNews. NeuroscienceNews, 17 June 2016.
<http://neurosciencenews.com/diabetes-fetal-brain-autoantibodies-4508/&gt;.

Abstract

Autism-specific maternal anti-fetal brain autoantibodies are associated with metabolic conditions

Approximately 23% of mothers of children with autism spectrum disorder (ASD) produce specific patterns of autoantibodies to fetal brain proteins that have been detected in only 1% of mothers of typically developing children. The biological mechanisms underlying the development of ASD-specific maternal autoantibodies are poorly understood. We sought to determine whether ASD-specific maternal autoantibodies identified postnatally were associated with metabolic conditions (MCs) during gestation. Participants were 227 mothers of 2–5 year old children with confirmed ASD, enrolled in CHARGE (Childhood Autism Risk from Genetics and the Environment) between January 2003 and April 2008, and from whom blood samples were collected and analyzed for anti-fetal brain autoantibodies (Ab+). MCs included diabetes, hypertensive disorders, and prepregnancy obesity or overweight, ascertained from medical records or structured telephone interviews. Log-linear regression models were performed to estimate prevalence ratios and 95% confidence intervals (CI) based on robust standard errors. Fifty-six (25%) mothers were Ab+. Ab+ prevalence was higher among mothers with diabetes, hypertensive disorders, or overweight compared to healthy mothers, but differences were not statistically significant. In a subset of 145 mothers whose children exhibited severe ASD (31 Ab+), those diagnosed with type 2 or gestational diabetes were 2.7-fold more likely to be Ab+ (95% CI 1.1, 6.6), controlling for delivery payer and smoking. Gestational diabetes specifically was associated with a 3.2-fold increased Ab+ prevalence (95% CI 1.2, 8.6). In this exploratory study, mothers whose children had severe ASD and who experienced diabetes were more likely to have anti-fetal brain autoantibodies 2–5 years later.

“Autism-specific maternal anti-fetal brain autoantibodies are associated with metabolic conditions” by Paula Krakowiak, Cheryl K. Walker, Daniel Tancredi, Irva Hertz-Picciotto and Judy Van de Water in Autism Research. Published online June 17 2016 doi:10.1002/aur.1657