{"id":305,"date":"2023-08-10T15:21:22","date_gmt":"2023-08-10T15:21:22","guid":{"rendered":"https:\/\/pediatricbrainfoundation.org\/archive\/penn-team-links-placental-marker-prenatal-stress-neurodevelopmental-problems\/"},"modified":"2023-08-10T15:21:22","modified_gmt":"2023-08-10T15:21:22","slug":"penn-team-links-placental-marker-prenatal-stress-neurodevelopmental-problems","status":"publish","type":"page","link":"https:\/\/pediatricbrainfoundation.org\/archive\/penn-team-links-placental-marker-prenatal-stress-neurodevelopmental-problems\/","title":{"rendered":"Penn Team Links Placental Marker of Prenatal Stress to Neurodevelopmental Problems"},"content":{"rendered":"
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\u00ab Back to Scientific News<\/a><\/div>\n<\/section><\/div>\n
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Penn Team Links Placental Marker of Prenatal Stress to Neurodevelopmental Problems <\/h1>\n<\/section><\/div>\n
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\n Wednesday, June 18, 2014<\/span>  \u00b7  Posted by University of Pennsylvania <\/a> <\/div>\n

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When a woman experiences a stressful event early in pregnancy, the risk of her child developing autism spectrum disorders or schizophrenia increases. Yet how maternal stress is transmitted to the brain of the developing fetus, leading to these problems in neurodevelopment, is poorly understood. <\/div>\n<\/p><\/div>\n<\/div>\n

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When a woman experiences a stressful event early in pregnancy, the risk of her child developing autism spectrum disorders or schizophrenia increases. Yet how maternal stress is transmitted to the brain of the developing fetus, leading to these problems in neurodevelopment, is poorly understood.\u00a0
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New findings by University of Pennsylvania School of Veterinary Medicine scientists suggest that an enzyme found in the placenta is likely playing an important role. This enzyme, O-linked-N-acetylglucosamine transferase, or OGT, translates maternal stress into a reprogramming signal for the brain before birth. \u00a0<\/p>\n

\u201cBy manipulating this one gene, we were able to recapitulate many aspects of early prenatal stress,\u201d said Tracy L. Bale, senior author on the paper and a professor in the Department of Animal Biology at Penn Vet. \u201cOGT seems to be serving a role as the \u2018canary in the coal mine,\u2019 offering a readout of mom\u2019s stress to change the baby\u2019s developing brain.\u201d<\/p>\n

Bale also holds an appointment in the Department of Psychiatry in Penn\u2019s Perelman School of Medicine. Her co-author is postdoctoral researcher Christopher L. Howerton. The paper was published online in PNAS this week.<\/p>\n

OGT is known to play a role in gene expression through chromatin remodeling, a process that makes some genes more or less available to be converted into proteins. In a study published last year in PNAS, Bale\u2019s lab found that placentas from male mice pups had lower levels of OGT than those from female pups, and placentas from mothers that had been exposed to stress early in gestation had lower overall levels of OGT than placentas from the mothers\u2019 unstressed counterparts.<\/p>\n

\u201cPeople think that the placenta only serves to promote blood flow between a mom and her baby, but that\u2019s really not all it\u2019s doing,\u201d Bale said. \u201cIt\u2019s a very dynamic endocrine tissue and it\u2019s sex-specific, and we\u2019ve shown that tampering with it can dramatically affect a baby\u2019s developing brain.\u201d<\/p>\n

To elucidate how reduced levels of OGT might be transmitting signals through the placenta to a fetus, Bale and Howerton bred mice that partially or fully lacked OGT in the placenta. They then compared these transgenic mice to animals that had been subjected to mild stressors during early gestation, such as predator odor, unfamiliar objects or unusual noises, during the first week of their pregnancies.<\/p>\n

The researchers performed a genome-wide search for genes that were affected by the altered levels of OGT and were also affected by exposure to early prenatal stress using a specific activational histone mark and found a broad swath of common gene expression patterns.<\/p>\n

They chose to focus on one particular differentially regulated gene called Hsd17b3, which encodes an enzyme that converts androstenedione, a steroid hormone, to testosterone. The researchers found this gene to be particularly interesting in part because neurodevelopmental disorders such as autism and schizophrenia have strong gender biases, where they either predominantly affect males or present earlier in males.<\/p>\n

Placentas associated with male mice pups born to stressed mothers had reduced levels of the enzyme Hsd17b3, and, as a result, had higher levels of androstenedione and lower levels of testosterone than normal mice.<\/p>\n

\u201cThis could mean that, with early prenatal stress, males have less masculinization,\u201d Bale said. \u201cThis is important because autism tends to be thought of as the brain in a hypermasculinized state, and schizophrenia is thought of as a hypomasculinized state. It makes sense that there is something about this process of testosterone synthesis that is being disrupted.\u201d<\/p>\n

Furthermore, the mice born to mothers with disrupted OGT looked like the offspring of stressed mothers in other ways. Although they were born at a normal weight, their growth slowed at weaning. Their body weight as adults was 10-20 percent lower than control mice.<\/p>\n

Because of the key role that that the hypothalamus plays in controlling growth and many other critical survival functions, the Penn Vet researchers then screened the mouse genome for genes with differential expression in the hypothalamus, comparing normal mice, mice with reduced OGT and mice born to stressed mothers.<\/p>\n

They identified several gene sets related to the structure and function of mitochrondria, the powerhouses of cells that are responsible for producing energy. And indeed, when compared by an enzymatic assay that examines mitochondria biogenesis, both the mice born to stressed mothers and mice born to mothers with reduced OGT had dramatically reduced mitochondrial function in their hypothalamus compared to normal mice. These studies were done in collaboration with Narayan Avadhani\u2019s lab at Penn Vet.<\/p>\n

Such reduced function could explain why the growth patterns of mice appeared similar until weaning, at which point energy demands go up.<\/p>\n

\u201cIf you have a really bad furnace you might be okay if temperatures are mild,\u201d Bale said. \u201cBut, if it\u2019s very cold, it can\u2019t meet demand. It could be the same for these mice. If you\u2019re in a litter close to your siblings and mom, you don\u2019t need to produce a lot of heat, but once you wean you have an extra demand for producing heat. They\u2019re just not keeping up.\u201d<\/p>\n

Bale points out that mitochondrial dysfunction in the brain has been reported in both schizophrenia and autism patients.<\/p>\n

In future work, Bale hopes to identify a suite of maternal plasma stress biomarkers that could signal an increased risk of neurodevelopmental disease for the baby.<\/p>\n

\u201cWith that kind of a signature, we\u2019d have a way to detect at-risk pregnancies and think about ways to intervene much earlier than waiting to look at the term placenta,\u201d she said.<\/p>\n<\/div><\/div>\n<\/div>\n

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stress<\/a><\/div>\n
pregnancy<\/a><\/div>\n
Autism Spectrum Disorders<\/a><\/div>\n
autism<\/a><\/div>\n
fetus<\/a><\/div>\n
maternal stress<\/a><\/div>\n
neurodevelopment<\/a><\/div>\n
enzyme<\/a><\/div>\n
placenta<\/a><\/div>\n
o-linked-n-acetylglucosamine transferase<\/a><\/div>\n
OGT<\/a><\/div>\n
prenatal stress<\/a><\/div>\n
chromatin remodeling<\/a><\/div>\n
proteins<\/a><\/div>\n
developing brain<\/a><\/div>\n
activational histone<\/a><\/div>\n
Hsd17b3<\/a><\/div>\n
androstenedione<\/a><\/div>\n
mitochondria<\/a><\/div>\n
hypothalamus<\/a><\/div>\n
mitochondria biogenesis<\/a><\/div>\n<\/p><\/div>\n<\/div>\n