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How environmental stresses cause birth defects

For the first time, scientists believe they've discovered a direct cause for multiple birth defects from environmental stresses lowering embryo oxygen levels which stops protein production and normal development.


The research led by Sally Dunwoodie PhD, professor of Medicine in the School of Biotechnology, Biotechnoloy and Biomolecular Sciences at the Victor Chang Cardiac Research Institute, Sydney, Australia, analysed the effects of short term oxygen deficiency on heart development in mice embryos. Her team of scientists reduced oxygen supporting mice embryos inside a chamber over an eight hour period, from a normal level of 21 percent to as low as 5.5 percent.


"We discovered that reduced oxygen triggered a stress response in the embryonic cells.

"The cells try to relieve the stress by stopping protein production. Suddenly those proteins aren't available to make the heart at a critical moment in time and the heart couldn't develop properly.

"We strongly suspect [oxygen deprivation] is an underlying mechanism for many different types of birth defects, including those of the vertebrae, kidney and others."


Sally L. Dunwoodie BSc, (Hons.), PhD, Professor, Victor Chang Cardiac Research Institute; St Vincent's Clinical School, Faculty of Medicine, School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, Australia


The breakthrough shows how cellular stress could be key to understanding why babies are born with defects of the heart, vertebrae and kidney, among other organ systems. Affecting 1 in 100 babies, childhood heart disease is the most common form of birth defect in the world. Despite its prevalence, surprisingly, genetic and environmental causes are very poorly understood.

The types of heart defects that developed are the same found most commonly in humans. Crucially, Dunwoodie's team worked out exactly how the low oxygen caused the damage. The study is published in the journal Development.


"We obviously know that smoking is terrible for an unborn baby's health. But oxygen deficiency in an embryo can be caused by many things: prescription medications, high blood pressure, high altitude, a tangled umbilical cord, as well as carbon monoxide."

Sally L. Dunwoodie BSc, (Hons.), PhD


Importantly, oxygen deficiency isn't the only trigger of this cellular stress. Multiple factors such as a viral infections, increased temperature, high blood glucose, poor nutrition, and pollution can set it off.

"Surprisingly this cellular stress response has been around for hundreds of millions of years and it is only now that we have discovered that it can cause organs, such as the heart, not to form properly," adds Professor Dunwoodie.

Abstract
Congenital heart disease (CHD) is an enigma. It is the most common human birth defect and yet, even with the application of modern genetic and genomic technologies, only a minority of cases can be explained genetically. This is because environmental stressors also cause CHD. Here we propose a plausible non-genetic mechanism for induction of CHD by environmental stressors. We show that exposure of mouse embryos to short-term gestational hypoxia induces the most common types of heart defect. This is mediated by the rapid induction of the unfolded protein response (UPR), which profoundly reduces FGF signaling in cardiac progenitor cells of the second heart field. Thus, UPR activation during human pregnancy might be a common cause of CHD. Our findings have far-reaching consequences because the UPR is activated by a myriad of environmental or pathophysiological conditions. Ultimately, our discovery could lead to preventative strategies to reduce the incidence of human CHD.
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Jul 25, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   



A frontal section of a mouse heart at embryonic day 17.5 showing normal anatomy, which can be
disrupted by short-term hypoxia during gestation. Image generated using optical projection tomography.
Image Credit: Company of Biologists


 


 

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