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Scientists Identify Mechanism That May Explain Why Males Have a Higher Risk for Neurodevelopmental Disorders

July 11, 2018

Tracy Bale, PhD

New Research Unravels Potential Genetic Mechanism Behind This Disparity

Researchers have recently begun to realize that biological sex plays a key role in disease risk. Sex differences play a role in hypertension, diabetes, arthritis – and in many neurological and psychiatric disorders. Depression and anxiety affect females more, while neurodevelopmental disorders, including autism spectrum disorders, early onset schizophrenia, and attention deficit hyperactivity, affect more males. Males are also more sensitive to issues during pregnancy, such as maternal stress, maternal infection and exposure to drugs.

To better understand the mechanisms driving this disparity, Tracy Bale, PhD, a professor in the University of Maryland School of Medicine (UMSOM) department of pharmacology and director of the UMSOM Center for Epigenetic Research in Child Health and Brain Development, along with several colleagues, focused on a molecule that plays a key role in placental health. In a study of mice, they found that the molecule works by establishing sex-specific patterns of genetic expression.

The study was published last week in the journal Nature Communications.

The molecule, which is called O-linked N-acetylglucosamine transferase (OGT), seems to work through an epigenetic modification, H3K27me3, which broadly controls the process by which DNA is translated into the molecules that eventually become enzymes and proteins. Epigenetics is the study of changes in how genes are expressed. Dr. Bale showed that in the female placenta, this modification can protect the mother from the effects of stress. This indicates at least one molecular pathway that allows females to be more resilient to maternal stress than males.

“This pathway could help explain why we see this profound neurodevelopmental difference in humans,” said Dr. Bale. “OGT and H3K27me3 in the placenta are crucial to a lot of protein encoding that occurs during pregnancy, and so this process has a lot of downstream effects. The OGT gene is on the X chromosome, and seems to provide a level of protection for the female fetus to perturbations in the maternal environment.”

Dr. Bale has focused much of her research on the links between stress and subsequent risk for neurodevelopmental disorders, including autism and schizophrenia in offspring. Her previous work on the placenta has found novel sex differences that may predict increased prenatal risk for disease in males.

She has previously found that, in mice, a father’s stress can affect the brain development of offspring. This stress can alter the father’s sperm, which can then alter the brain development of the child. Dr. Bale has also found that male mice experiencing chronic mild stress have offspring with a reduced hormonal response to stress; this response has been linked to some neuropsychiatric disorders, including PTSD. This suggests that even mild environmental challenges can have a significant effect on the health of offspring.

“We have long known that stress can play a crucial role in fetal brain development,” said E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs at the University of Maryland, Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine. “This new paper helps illuminate the complex ways in which males and females differ in their response to maternal stress.”

About the University of Maryland School of Medicine

Commemorating its 210th Anniversary, the University of Maryland School of Medicine was chartered in 1807 as the first public medical school in the United States. It continues today as one of the fastest growing, top-tier biomedical research enterprises in the world -- with 43 academic departments, centers, institutes, and programs; and a faculty of more than 3,000 physicians, scientists, and allied health professionals, including members of the National Academy of Medicine and the National Academy of Sciences, and a distinguished recipient of the Albert E. Lasker Award in Medical Research. With an operating budget of more than $1 billion, the School of Medicine works closely in partnership with the University of Maryland Medical Center and Medical System to provide research-intensive, academic and clinically-based care for more than 1.2 million patients each year. The School has over 2,500 students, residents, and fellows, and more than $500 million in extramural funding, with most of its academic departments highly ranked among all medical schools in the nation in research funding. As one of the seven professional schools that make up the University of Maryland Baltimore campus, the School of Medicine has a total workforce of nearly 7,000 individuals. The combined School and Medical System (“University of Maryland Medicine”) has an annual budget of nearly $6 billion and an economic impact in excess of $15 billion on the state and local community. The School of Medicine faculty, which ranks as the 8th highest among public medical schools in research productivity, is an innovator in translational medicine, with 600 active patents and 24 start-up companies. The School works locally, nationally, and globally, with research and treatment facilities in 36 countries around the world. Visit medschool.umaryland.edu/

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