• Placenta may hold clues for early autism

    From ScienceDaily@1:317/3 to All on Wed Feb 16 21:30:50 2022
    Placenta may hold clues for early autism diagnosis and intervention
    Study identifies new gene linked to autism in toddlers

    Date:
    February 16, 2022
    Source:
    University of California - Davis Health
    Summary:
    Researchers have identified a gene linked to fetal brain development
    and autism. Their work shows that the gene is influenced by the
    mother's early prenatal vitamins use and placental oxygen levels.



    FULL STORY ==========================================================================
    New UC Davis MIND Institute research has identified a novel human
    gene linked to fetal brain development and autism spectrum disorder
    (ASD). The discovery also links the gene to the mother's early prenatal
    vitamin use and placental oxygen levels.


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    In a study published Feb. 16 in Genome Biology, the researchers used
    genomic sequencing to find a DNA methylation signature in the placenta
    of newborns eventually diagnosed with autism. This signature mark was
    linked to early fetal neurodevelopment.

    "By taking an unbiased approach to investigating placental DNA methylation differences, we discovered a novel gene in a poorly mapped region of
    the genome associated with autism, " said Janine LaSalle, lead author on
    the study and professor of microbiology and immunology at UC Davis Health.

    ASD is a complex neurological condition linked to genetic and
    environmental factors. The U.S. Centers for Disease Control and Prevention (CDC) estimates that one in 44 children are diagnosed with ASD. It is
    much more prevalent in males than females.

    Why studying the placenta is important The placenta supports fetal
    development in the uterus. It regulates oxygen supply and metabolism
    and provides hormones and neurotransmitters critical for the fetus'
    developing brain.



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    "The placenta is an often misunderstood and overlooked tissue, despite
    its importance in regulating and thereby reflecting events critical to
    brain development in utero. It is like a time capsule for finding things
    that happened in utero. For decades, hospital births have thrown away
    placentae despite this tissue being a gold mine for finding molecular
    clues to child outcomes," LaSalle said.

    During pregnancy, the fetus might experience oxidative stress, an
    imbalance of free radicals and antioxidants in the body. This is
    common in normal brain development. However, in some cases, exposure
    to environmental factors such as air pollution and pesticides can lead
    to excessive oxidative stress. This state can lead to cell and tissue
    damage or delayed neurodevelopment.

    "Oxidative stress is normal. But excessive oxidative stress may come from environmental exposures linked to ASD such as air pollution, pesticides, maternal obesity and inflammation," LaSalle said.

    The epigenome is a set of chemical compounds and proteins that tell the
    DNA what to do. These compounds attach to DNA and modify its function. One
    such compound is CH3 (known as the methyl group) which leads to DNA methylation. The neonatal epigenome can reflect past interactions between genetic and environmental factors during early development. It may also influence future health outcomes.

    The placenta is a promising tissue for identifying DNA methylation changes
    at genes that also function in the fetal brain. This study examined the association of ASD with placental DNA methylation.



    ========================================================================== Finding factors in mother's placenta that might predict autism The
    researchers studied the development of 204 children born to mothers
    enrolled in the MARBLES and EARLI studies. These mothers had at least
    one older child with autism and were considered with higher probability
    of having another child with ASD. When these children were born, the
    mothers' placentae were preserved for future analysis.

    At 36 months, the children got diagnostic and developmental
    assessments. Based on these tests, the researchers grouped the
    children under "typically developing" (TD), "with ASD" and "non-typical development" (Non-TD).

    The researchers also extracted and quantified the DNA from the placenta tissues. They divided the placenta samples into discovery, replication
    and specificity replication groups.

    For the discovery group, they split and sequenced 92 samples (46 ASD,
    46 TD) from the MARBLES study using whole-genome bisulfite sequencing
    (WGBS) and whole-genome sequencing (WGS). To determine if differential methylation was reproducible in a different population, the replication
    group included WGBS data from 16 ASD and 31 TD samples from the EARLI
    study.

    The specificity replication group had 21 ASD, 13 Non-TD and 31 TD placenta samples from the MARBLES study. The researchers used these samples to
    determine if methylation changes were specific to ASD.

    Finally, they performed whole genome sequencing on 41 ASD and 37 TD
    MARBLES children.

    Placenta to reveal insights into genes related to ASD The researchers identified a block of differential methylation in ASD at 22q13.33, a
    region in chromosome 22 not previously linked to ASD. They located and characterized a novel gene known as LOC105373085 within that region and
    renamed it NHIP (neuronal hypoxia inducible, placenta associated).

    To understand the function of this gene, they detected the levels of
    NHIP expression in human cell lines and brain tissue. They tested the responsiveness of NHIP to hypoxia, a state of low oxygen levels in the
    tissues. The researchers found that NHIP is a gene that gets turned
    on in neurons following hypoxia and regulates other gene pathways with functions in neuronal development and response to oxidative stress. Higher
    NHIP levels increased the cell division in an embryonic cell line.

    This is important because in the placenta, hypoxia triggers placental
    cell division to make further contact with maternal blood vessels to
    supply enough oxygen for the developing brain.

    The researchers also discovered that NHIP was less activated in ASD
    placenta and brain compared to TD samples, supporting a protective role
    for NHIP in preventing ASD.

    "We found that the NHIP gene is active in the brain, responsive
    to oxidative stress, and influences expression of other known genes
    associated with autism," LaSalle said. "In most pregnancies, the placenta experiences some inevitable levels of stress. We think that NHIP is there
    to buffer the effects of excessive oxidative stress." Prenatal vitamins
    and autism Another remarkable finding from the study was the role prenatal vitamins play in regulating the work of NHIP. Prenatal vitamins are high
    in folic acid and can reduce oxidative stress.

    Prenatal vitamins use during the first month of pregnancy showed a
    significant protective effect among individuals with genetic differences
    at 22q13.33 NHIP region. Taking prenatal vitamins in the first month of pregnancy seems to provide essential metabolic elements to counteract the genetic inheritance of reduced NHIP responsiveness to oxidative stress.

    "In line with previous studies, we found that taking a prenatal vitamin
    is essential when planning a pregnancy," said LaSalle. "Findings from our
    study provide key insights that may help in identifying newborns more
    likely to develop autism and getting them into an earlier intervention
    or just knowing to watch them sooner." The researchers pointed out
    that these results will require further replication before being used diagnostically.

    This work was supported by National Institutes of Health (NIH)
    grants (P01ES011269, R01ES020392, R01ES025574, R01ES029213); Canadian Institutes of Health Research (CIHR) postdoctoral fellowships (MFE-146824, BPF-162684); Environmental Protection Agency (83543201); Intellectual
    and Developmental Disability Research Centers (U54 HD079125); UC Davis Environmental Health Sciences Center (P30 ES023513); and Environmental Influences on Child Health Outcomes (ECHO) Consortium (UH3 ES023365).

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    ========================================================================== Journal Reference:
    1. Yihui Zhu, J. Antonio Gomez, Benjamin I. Laufer, Charles
    E. Mordaunt,
    Julia S. Mouat, Daniela C. Soto, Megan Y. Dennis, Kelly S. Benke,
    Kelly M. Bakulski, John Dou, Ria Marathe, Julia M. Jianu, Logan
    A. Williams, Orangel J. Gutierrez Fugo'n, Cheryl K. Walker, Sally
    Ozonoff, Jason Daniels, Luke P. Grosvenor, Heather E. Volk, Jason
    I. Feinberg, M.

    Daniele Fallin, Irva Hertz-Picciotto, Rebecca J. Schmidt, Dag
    H. Yasui, Janine M. LaSalle. Placental methylome reveals a 22q13.33
    brain regulatory gene locus associated with autism. Genome Biology,
    2022; 23 (1) DOI: 10.1186/s13059-022-02613-1 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/02/220216103038.htm

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