BPA May Affect the Developing Brain by Disrupting Gene Regulation

Environmental exposure to bisphenol A (BPA), a widespread chemical found in plastics and resins, may suppress a gene vital to nerve cell function and to the development of the central nervous system, according to a study led by researchers at Duke Medicine.

The researchers published their findings - which were observed in cortical neurons of mice, rats and humans - in the journal Proceedings of the National Academy of Sciences on Feb. 25, 2013.

"Our study found that BPA may impair the development of the central nervous system, and raises the question as to whether exposure could predispose animals and humans to neurodevelopmental disorders," said lead author Wolfgang Liedtke, M.D., PhD, associate professor of medicine/neurology and neurobiology at Duke.

BPA, a molecule that mimics estrogen and interferes with the body’s endocrine system, can be found in a wide variety of manufactured products, including thermal printer paper, some plastic water bottles and the lining of metal cans. The chemical can be ingested if it seeps into the contents of food and beverage containers.

Research in animals has raised concerns that exposure to BPA may cause health problems such as behavioral issues, endocrine and reproductive disorders, obesity, cancer and immune system disorders. Some studies suggest that infants and young children may be the most vulnerable to the effects of BPA, which led the U.S. Food and Drug Administration to ban the use of the chemical in baby bottles and cups in July 2012.

While BPA has been shown to affect the developing nervous system, little is understood as to how this occurs. The research team developed a series of experiments in rodent and human nerve cells to learn how BPA induces changes that disrupt gene regulation.

During early development of neurons, high levels of chloride are present in the cells. These levels drop as neurons mature, thanks to a chloride transporter protein called KCC2, which churns chloride ions out of the cells. If the level of chloride within neurons remains elevated, it can damage neural circuits and compromise a developing nerve cell’s ability to migrate to its proper position in the brain.

Exposing neurons to minute amounts of BPA alters the chloride levels inside the cells by somehow shutting down the Kcc2 gene, which makes the KCC2 protein, thereby delaying the removal of chloride from neurons.

MECP2, another protein important for normal brain function, was found to be a possible culprit behind this change. When exposed to BPA, MECP2 is more abundant and binds to the Kcc2 gene at a higher rate, which might help to shut it down. This could contribute to problems in the developing brain due to a delay in chloride being removed.

These findings raise the question of whether BPA could contribute to neurodevelopmental disorders such as Rett syndrome, a severe autism spectrum disorder that is only found in girls and is characterized by mutations in the gene that produces MECP2.

While both male and female neurons were affected by BPA in the studies, female neurons were more susceptible to the chemical’s toxicity. Further research will dig deeper into the sex-specific effects of BPA exposure and whether certain sex hormone receptors are involved in BPA’s effect on KCC2.

"Our findings improve our understanding of how environmental exposure to BPA can affect the regulation of the Kcc2 gene. However, we expect future studies to focus on what targets aside from Kcc2 are affected by BPA," Liedtke said. "This is a chapter in an ongoing story."

Ultrasound reveals autism risk at birth

Low-birth-weight babies with a particular brain abnormality are at greater risk for autism, according to a new study that could provide doctors a signpost for early detection of the still poorly understood disorder.

Led by Michigan State University, the study found that low-birth-weight newborns were seven times more likely to be diagnosed with autism later in life if an ultrasound taken just after birth showed they had enlarged ventricles, cavities in the brain that store spinal fluid. The results appear in the Journal of Pediatrics.

“For many years there’s been a lot of controversy about whether vaccinations or environmental factors influence the development of autism, and there’s always the question of at what age a child begins to develop the disorder,” said lead author Tammy Movsas, clinical assistant professor of pediatrics at MSU and medical director of the Midland County Department of Public Health.

“What this study shows us is that an ultrasound scan within the first few days of life may already be able to detect brain abnormalities that indicate a higher risk of developing autism.”

Movsas and colleagues reached that conclusion by analyzing data from a cohort of 1,105 low-birth-weight infants born in the mid-1980s. The babies had cranial ultrasounds just after birth so the researchers could look for relationships between brain abnormalities in infancy and health disorders that showed up later. Participants also were screened for autism when they were 16 years old, and a subset of them had a more rigorous test at 21, which turned up 14 positive diagnoses.

Ventricular enlargement is found more often in premature babies and may indicate loss of a type of brain tissue called white matter.

“This study suggests further research is needed to better understand what it is about loss of white matter that interferes with the neurological processes that determine autism,” said co-author Nigel Paneth, an MSU epidemiologist who helped organize the cohort. “This is an important clue to the underlying brain issues in autism.”

Prior studies have shown an increased rate of autism in low-birth-weight and premature babies, and earlier research by Movsas and Paneth found a modest increase in symptoms among autistic children born early or late.

Autism Speaks Through Gene Expression

Autism spectrum disorders affect nearly 1 in 88 children, with symptoms ranging from mild personality traits to severe intellectual disability and seizures. Understanding the altered genetic pathways is critical for diagnosis and treatment. New work to examine which genes are responsible for autism disorders will be presented at the 57th Annual Meeting of the Biophysical Society (BPS), held Feb. 2-6, 2013, in Philadelphia, Pa.

“Autism is the most inheritable of neurodevelopmental disorders,” explains Rajini Rao of Johns Hopkins University in Baltimore, Md., “but identifying the underlying genes is difficult since no single gene contributes more than a tiny fraction of autism cases.” Rather, she continues, “mutations in many different genes variably affect a few common pathways.”

A team of scientists at Johns Hopkins and Tel Aviv University in Israel looked at genetic variations in DNA sequence in the ion transporter NHE9 and found that autism-associated variants in NHE9 result in a profound loss of transporter function. “Altering levels of this transporter at the synapse may modulate critical proteins on the cell surface that bring in nutrients or neurotransmitters such as glutamate,” says Rao. “Elevated glutamate levels are known to trigger seizures, possibly explaining why autistic patients with mutations in these ion transporters also have seizures.”

A unique aspect of the team’s approach was that they exploited decades of basic research done in bacteria and yeast to study a complex human neurological disorder. First, the group at Tel Aviv University, led by Nir Ben-Tal, built structural models of NHE9 using a bacterial relative as a template, allowing the Rao laboratory at Johns Hopkins to use the simple baker’s yeast for screening the mutations. In the future, as genomic information becomes readily available for everyone, such easy, inexpensive, and rapid screening methods will be essential to evaluate rare genetic variants in autism and other disorders.

Rao and her team are optimistic about the potential benefits of their latest findings. “Although the research is still at an early stage, drugs that target the cellular pathways regulated by NHE9 could compensate for its loss of function and lead to potential therapy in the future,” Rao says. “These findings add a new candidate for genetic screening of at-risk patients that may lead to better diagnosis or treatment of autism.”

New Discovery in Autism-Related Disorder Reveals Key Mechanism in Brain Development and Disease

A new finding in neuroscience for the first time points to a developmental mechanism linking the disease-causing mutation in an autism-related disorder, Timothy syndrome, and observed defects in brain wiring, according to a study led by scientist Ricardo Dolmetsch and published online yesterday in Nature Neuroscience. These findings may be at the heart of the mechanisms underlying intellectual disability and many other brain disorders.

The present study reveals that a mutation of the disease-causing gene throws a key process of neurodevelopment into reverse. That is, the mutation underlying Timothy syndrome causes shrinkage, rather than growth, of the wiring needed for the development of neural circuits that underlie cognition.

“In addition to the implications for autism, what’s really exciting is that we now have a way to get at the core mechanisms tying genes and environmental influences to development and disease processes in the brain,” said Dolmetsch, Senior Director of Molecular Networks at the Allen Institute for Brain Science.

“Imagine what we can learn if we do this hundreds and hundreds of times for many different human genetic variations in a large-scale, systematic way. That’s what we are doing now at the Allen Institute,” Dolmetsch continued.

In normal brain development, brain activity causes branches emanating from neural cells to stretch or expand. In cells with the mutation, these branched extensions, called dendrites, instead retract in response to neural activity, according to this study. This results in abnormal brain circuitry favoring connections with nearby neurons rather than farther-reaching connections. Further, the study identified a previously unknown mode of signaling to uncover the chemical pathway that causes the dendritic retraction.

This finding may have wide-reaching implications in neuroscience, as impaired dendrite formation is a common feature of many neurodevelopmental disorders. Further, the same gene has been implicated in other disorders including bipolar disorder and schizophrenia.

Under Dolmetsch’s leadership, the Molecular Networks program at the Allen Institute, one of three major new initiatives announced by the Institute last March, is using similar methods on a grand scale. The Institute is probing a large number of human genetic variations and many pathways in the brain to untangle the cellular mechanisms of neurodevelopment and disease. In addition to identifying the molecular and environmental rules that shape how the brain is built, the program will create new research tools and data sets that it will share publicly with the global research community.

Timothy syndrome is a neurodevelopmental disorder associated with autism spectrum disorders and caused by a mutation in a single gene. In addition to autism, it is also characterized by cardiac arrhythmias, webbed fingers and toes, and hypoglycemia, and often leads to death in early childhood.

(Image: iStock)

Professor Discovers New Information in the Understanding of Autism and Genetics

Research out of the George Washington University (GW), published in the journal Proceedings of the National Academy of Sciences (PNAS), reveals another piece of the puzzle in a genetic developmental disorder that causes behavioral diseases such as autism. Anthony-Samuel LaMantia, Ph.D., professor of pharmacology and physiology at the GW School of Medicine and Health Sciences (SMHS) and director of the GW Institute for Neuroscience, along with post-doctoral fellow Daniel Meechan, Ph.D. and Thomas Maynard, Ph.D., associate research professor of pharmacology and physiology at GW SMHS, authored the study titled “Cxcr4 regulation of interneuron migration is disrupted in 22q11.2 deletion syndrome.”

For the past nine years, LaMantia and his colleagues have been investigating how behavioral disorders such as autism, attention deficit hyperactivity disorder (ADHD), and schizophrenia arise during early brain development. His work published in PNAS focuses specifically on the effects diminished 22q11.2 gene dosage has on cortical circuit development.

This research shows for the first time that genetic lesions known to be associated with autism and other behavioral diseases disrupt cellular and molecular mechanisms that ensure normal development of a key type of cortical neuron: the interneuron. LaMantia and his colleagues had found previously that one type of cortical neuron, the projection neuron, is not generated in appropriate numbers during development in a mouse model of 22q11 Deletion Syndrome. In the current study published in PNAS, LaMantia found that interneurons, while made in the right numbers at their birthplace outside of the cortex, are not able to move properly into the cortex where they are needed to control cortical circuit activity. The research shows that the main reason they don’t move properly is due to diminished expression of activity of a key regulatory pathway for migration, the Cxcr4 cytokine receptor.

“This gives us two pieces of the puzzle for this genetic developmental disorder,” said LaMantia. “These two pieces tell us that in very early development, those with 22q11.2 deletion syndrome do not make enough cells in one case, and do not put the other cells in the right place. This occurs not because of some degenerative change, but because the mechanisms that make these cells and put them in the right place during the first step of development have gone awry due to mutation.”

The next step in LaMantia’s research is to probe further into the molecular mechanisms that disrupt the proliferation of projection neurons and migration of interneurons. “If we understand that better and understand its consequences, we can go about fixing it,” said LaMantia. “We want to understand why cortical circuits don’t get built properly due to the genetic deletion of chromosome 22.”

LaMantia recently received the latest installment of a 10-year RO1 grant from the National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health & Human Development for his project, titled “Regulation of 22q11 Genes in Embryonic and Adult Forebrain.” This will allow him to further his research.

(Image: iStockphoto)

Doctor Dolphin

Dolphin-assisted therapy for children with mental disabilities has made a splash in the West, and China is now riding the experimental tide. Shi Yingying and Erik Nilsson examine the impact these marine mammals have on the children they come into contact with.

Zheng Jun says 15 sessions with a pair of bottle-nosed dolphins at Hangzhou Polar Ocean Park have helped his 5-year-old autistic son become “aware” and “alert” enough to become his kindergarten’s class monitor. The father believes the dolphin-assisted therapy has been more effective than any other treatment. “Now, you can’t tell he’s different from his classmates,” he says. Zheng became a believer after he visited an Australian dolphin-swim program years ago. He says his son is elated when he splashes with the creatures in the park in Zhejiang province’s capital.

More than 80 parents of children with severe mental disabilities have booked all of next year’s spots in the program (sessions only run in the summer because the water temperatures are too cold for the kids in other seasons).

So, newcomers must wait until 2014, says Liu Quansheng, manager of the park’s owner, Zhejiang Aquarium Investment Group. Despite the demand, dolphin-assisted therapy has not been scientifically proven. Still, many experts and parents of special-needs children swear by it.

(Image: dolphin-therapy.org)

Social Synchronicity

Humans have a tendency to spontaneously synchronize their movements. For example, the footsteps of two friends walking together may synchronize, although neither individual is consciously aware that it is happening. Similarly, the clapping hands of an audience will naturally fall into synch. Although this type of synchronous body movement has been observed widely, its neurological mechanism and its role in social interactions remain obscure. In a new study, led by cognitive neuroscientists at the California Institute of Technology (Caltech), researchers found that body-movement synchronization between two participants increases following a short session of cooperative training, suggesting that our ability to synchronize body movements is a measurable indicator of social interaction.

"Our findings may provide a powerful tool for identifying the neural underpinnings of both normal social interactions and impaired social interactions, such as the deficits that are often associated with autism," says Shinsuke Shimojo, Gertrude Baltimore Professor of Experimental Psychology at Caltech and senior author of the study.

Shimojo, along with former postdoctoral scholar Kyongsik Yun, and Katsumi Watanabe, an associate professor at the University of Tokyo, presented their work in a paper published December 11 in Scientific Reports, an online and open-access journal from the Nature Publishing Group.

"The most striking outcome of our study is that not only the body-body synchrony but also the brain-brain synchrony between the two participants increased after a short period of social interaction," says Yun. "This may open new vistas to study the brain-brain interface. It appears that when a cooperative relationship exists, two brains form a loose dynamic system."

The team says this information may be potentially useful for romantic or business partner selection.

"Because we can quantify implicit social bonding between two people using our experimental paradigm, we may be able to suggest a more socially compatible partnership in order to maximize matchmaking success rates, by preexamining body synchrony and its increase during a short cooperative session" explains Yun.