Obesity before pregnancy, not just during, may shape a child’s brain and raise the risk of autism spectrum disorder, a new study has found. Epigenetic changes in eggs triggered gene shifts linked to autism-like behaviors, revealing a critical window for prevention.
Autism spectrum disorder (ASD) is characterized by deficits in social communication, impaired social interactions, and restricted repetitive behaviors. While the exact cause of ASD is not known, recent studies have suggested that a mother’s metabolic status, particularly obesity, may increase the risk of ASD in children.
A new study by researchers from the John A Burns School of Medicine (JABSOM) at the University of Hawai’i investigated whether maternal obesity before pregnancy, rather than during pregnancy, could cause autism-like traits in offspring, and how that might happen in the brain.
“This work highlights how a mother’s health prior to pregnancy – not just during gestation – can shape her child’s brain development in profound ways,” said co-corresponding author Alika Maunakea, PhD, from the Yanagimachi Institute for Biogenesis Research (YIBR) at JABSOM. “We were surprised to find that even without direct maternal contact after conception, these epigenetic imprints from the egg carried enough weight to alter behavior.”
The researchers used a mouse model with in vitro fertilization (IVF) and embryo transfer to separate the two time periods, pre-pregnancy and gestation. In the control group, eggs and sperm from healthy-weight mice were gestated in healthy-weight surrogates. In the pre-conception obesity group, eggs from obese females and sperm from healthy males were gestated in healthy surrogates. And in the gestational obesity group, eggs and sperm from healthy mice were gestated in obese surrogates. All of the pups born were fostered by healthy-weight mothers after birth to remove differences in post-natal care.
The offspring’s behavior was tested, including communication, sociability, repetitive behaviors, and anxiety. Their brains were analyzed, including RNA sequencing of the cortex to uncover gene activity, and whole genome DNA methylation mapping of the hippocampus for epigenetic changes. Epigenetics is the study of how behaviors and environment can cause changes that affect the way genes work. It’s akin to adding “tags” to DNA that turn genes on or off, influencing what traits are expressed without altering the DNA sequence itself. Methylation is the name of the chemical process where a tag, a methyl group, is added to a DNA base to alter gene expression.
The researchers found that male offspring from the pre-conception obesity group showed autism-like traits, such as altered vocal patterns, reduced sociability, and more repetitive grooming behaviors. These changes didn’t occur in males from the gestational obesity group or in females from any group. Anxiety behaviors were unchanged, meaning the social and communication deficits weren’t due to general anxiety. Not all males in the pre-conception obesity group were affected; some showed normal behavior (“nested”), reflecting the variability seen in human ASD.
Regarding changes in gene activity, eight key genes were uniquely altered in affected males, including Homer1 and Zswim6, both of which have been linked to ASD in human studies. Pathways involved in synaptic plasticity, circadian rhythm, and fatty acid metabolism were disrupted. Some genes showed a shift in isoform usage (using different versions of the same gene), especially Homer1.
In affected males, a usually hidden “on-switch” within the Homer1 gene was completely unmethylated (it had no chemical tag), which turned on a short version of the gene, Homer1a, that is linked to problems with the way nerve cell connections are built and maintained. In unaffected mice, this on-switch was either partly methylated (in unaffected pre-conception obesity mice) or fully methylated and switched off (in controls). This suggests that obesity before pregnancy can change epigenetic marks in the mother’s eggs, which in turn alter how certain brain genes work in the next generation.
“This discovery exemplifies the core mission of the YIBR,” said post-doctoral fellow Monika Ward, PhD, another of the study’s corresponding authors. “By leveraging our institute’s expertise in developmental biology, reproductive science, and epigenetics, we are beginning to understand how early-life programming can ripple through generations.”
The study had limitations. Only male offspring were analyzed in detail because females showed no autism-like behaviors, and the study used a small sample size for molecular work. Additionally, bulk tissue analysis meant that changes in specific brain cell types weren’t resolved, and follow-up ended at postnatal day 41, so persistence of the behaviors into adulthood is unknown. Also, the researchers couldn’t trace each affected pup back to its exact oocyte (precursor to an egg) donor because eggs were pooled. And while correlation between methylation and gene expression was strong, causality was not proven.
However, with global rates of both obesity and ASD rising, the study’s findings could have real-world implications. It suggests that maternal health before pregnancy is a critical – and potentially modifiable – factor in a child’s neurodevelopmental risk. Additionally, the molecular signals the researchers identified, like Homer1a, could become early biomarkers for ASD. And understanding these pathways may open the door to pre-conception interventions, through diet, lifestyle, or targeted therapies, to reduce autism risk.
The study was published in the journal Cells.
Source: University of Hawai’i
