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.
Exposure to BPA may disrupt development of the
central nervous system by slowing down the removal
of chloride from neurons. As an organism matures and
the brain develops, chloride levels inside nerve
cells drop. However, when exposed to BPA, the
chloride is removed more slowly from neurons.
Researchers also found female neurons to be more
susceptible to the effects of BPA.
Credit: Michele Yeo, 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."
In addition to Liedtke, study authors include
Michele Yeo and Ken Berglund of the Liedtke Lab in
the Division of Neurology at Duke Medicine; Michael
Hanna, Maria D. Torres and Jorge Busciglio of the
University of California, Irvine; Junjie U. Guo and
Yuan Gao of the Lieber Institute for Brain
Development and Johns Hopkins University in
Baltimore, Md.; and Jaya Kittur, Joel Abramowitz and
Lutz Birnbaumer of the National Institute of
Environmental Health Sciences in Research Triangle
Park, N.C.
The research received funding from Duke University,
the Klingenstein Fund, the National Institutes of
Health (R21NS066307, HD38466 and AG16573), and
intramural funds from the National Institute of
Environmental Health Sciences.
IMAGE: Exposure to BPA may disrupt development of
the central nervous system by slowing down the
removal of chloride from neurons. As an organism
matures and the brain develops, chloride levels
inside nerve cells drop. However, when exposed to
BPA, the chloride is removed more slowly from
neurons. Researchers also found female neurons to be
more susceptible to the effects of BPA.
Credit: Michele Yeo, Duke Medicine
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