Summary: A new study shows how maternal obesity before pregnancy can influence autistic behavior in offspring through long-term epigenetic changes in oocytes. Using IVF and embryo transfer in mice, the researchers isolated the effects before conception and discovered altered DNA methylation patterns that affect genes such as Homer1.
In male offspring, these changes lead to impaired social behavior and repetitive behaviors consistent with autism spectrum disorder. The findings highlight the importance of maternal health before conception, and could pave the way for interventions that begin even before pregnancy.
Key facts
- Epigenetic link: Pre-pregnancy obesity caused changes in DNA methylation in eggs, which altered the expression of neurodevelopmental genes in the offspring.
- Attitudes related to autism: The male offspring exhibited disruptive social behavior and frequent grooming, which is associated with overexpression of Homer1a.
- Isolation effect: IVF and embryo transfer models confirmed that the changes occurred before pregnancy and not during pregnancy.
Source: University of Hawaii
In a landmark study conducted at the University of Hawaii at Manoa, researchers from the John A. Burns School of Medicine (JABSOM) have discovered a mechanistic link between prenatal obesity and autism-related behaviors in offspring.
The research, led by Dr. Alika K. Monaki and Dr. Monica Ward, professors in the Department of Anatomy, Biochemistry and Physiology at the Yanagimachi Institute for Biogenesis Research (YIBR), sheds new light on how maternal health, even before conception, can shape children’s long-term neurodevelopmental programs.
The researchers showed that obesity-induced changes in the mother’s metabolic environment lead to long-lasting epigenetic changes in oocytes, the precursors of egg cells. These changes, specifically changes in DNA methylation patterns, were transmitted to the developing fetus and ultimately altered the expression of genes important for neurodevelopment, such as Homer 1.
The study showed that the male offspring had increased expression of the short isoform Homer1a. This form is known to disrupt synaptic function, resulting in behavior consistent with autism spectrum disorder (ASD).
“This research highlights that a mother’s health before pregnancy, not just during pregnancy, can have a profound impact on her child’s brain development,” said Dr. Monakia. “We were surprised to find that even without direct maternal contact after conception, these epigenetic marks on the egg were influential enough to alter behavior.”
Using an in vitro fertilization (IVF) embryo transfer model, the team was able to separate the effects of maternal obesity before conception from those during pregnancy, providing a more accurate picture of how early epigenetic programming develops.
Behavioral tests in male adolescents revealed disruptive social behavior and repetitive grooming patterns suggestive of ASD, which were associated with altered gene regulation in the cortex and hippocampus.
“This discovery reflects the core mission of YIBR,” said Dr. Ward. “By leveraging our institution’s expertise in developmental biology, reproductive science, and epigenetics, we are beginning to understand how early programming can be passed down through generations.”
The Yanagimachi Institute for Biogenesis Research, named after world-renowned fertility pioneer Dr. Ryuzo Yanagimachi, promotes interdisciplinary collaboration in reproductive and developmental biology.
This study, which reflects the synergy between Dr. Ward’s expertise in reproductive science and Dr. Monakia’s research in neurogenetics, exemplifies the Institute’s commitment to translational discoveries with long-term health outcomes.
Given the increasing global rates of obesity and autism spectrum disorders (ASD), these findings may present new opportunities for early intervention, possibly even before conception. The researchers hope that future studies will explore treatment strategies that can reverse or reduce these effects through nutritional or pharmacological interventions.
The research has been accepted for publication in Cell, a leading peer-reviewed journal, and represents a significant step in our understanding of how early life factors influence brain development.
About this genetics, obesity, and autism research news
Author: Matthew Campbell
Source: University of Hawaii
Contact: Matthew Campbell – University of Hawaii
Image: The image is credited to StackZone Neuro
Original Research: Open access.
“Pre-Conception Maternal Obesity Confers Autism Spectrum Disorder-like Behaviors in Mice Offspring Through Neuroepigenetic Dysregulation” by Alika K. Maunakea et al. Cells
Abstract
Prenatal obesity causes autism spectrum disorder-like behavior in mouse offspring through neuroepigenetic dysregulation.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that begins in early childhood. However, the mechanism and timing of this susceptibility are unclear.
Using a mouse model combining in vitro fertilization (IVF) and embryo transfer, we were able to distinguish between the effects of preconception and gestational obesity.
We found that maternal high-fat diet (HFD) consumption before pregnancy was sufficient by itself to induce ASD-like behaviors in male offspring (including altered vocalization, impaired social skills, and frequent licking) without anxiety-related changes.
These phenotypes were absent in female offspring and only in offspring exposed during pregnancy. Cortical transcriptome analysis revealed dysregulation and alterations in gene isoforms implicated in ASD, such as Homer1 and Zswim6.
Whole-genome sequencing of hippocampal tissue revealed hypomethylation of an alternative Homer1 promoter, associated with increased expression of the short Homer1A isoform, which is known to disrupt synaptic scaffolding. This pattern was specific to mice with ASD-like behavior.
Our results suggest that maternal obesity before pregnancy can lead to long-lasting, isoform-specific epigenetic and transcriptomic changes in the offspring brain.
These findings highlight the importance of prenatal health as an important and modifiable factor in ASD risk.
