A new study published in the journal Cells provides evidence that maternal obesity prior to pregnancy—rather than during it—may influence the development of autism-like traits in offspring. Researchers found that male mice born from obese egg donors showed altered social behaviors and repetitive grooming patterns, even when gestated and raised by healthy mothers. These changes were associated with shifts in brain gene activity and epigenetic modifications, suggesting that a mother’s health before conception can shape her child’s neurodevelopment in lasting ways.
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by difficulties with social interaction and communication, along with restricted or repetitive behaviors. It affects about one in 36 children in the United States and is diagnosed more often in boys than in girls.
While there is a strong genetic component to ASD, most individuals do not carry known high-impact mutations. This has led researchers to explore how environmental and epigenetic factors—those that influence gene expression without altering DNA sequences—might contribute to its development, especially during early stages of life.
Previous studies have suggested that maternal obesity is associated with a higher risk of ASD in children. However, it has remained unclear whether this link is driven by conditions present before conception, during pregnancy, or both. Researchers were also unsure how these environmental exposures might influence the brain’s development at a molecular level. The new study, led by University of Hawaii professors Alika Maunakea and Monika Ward, aimed to address this uncertainty by using a mouse model that could separate the effects of maternal health before and during pregnancy.
“We were concerned about what is driving the worldwide increasing rates of ASD, and knew from prior epidemiologic studies (in humans) that maternal obesity leads to an increased risk of children with autism by 50-60%. (It is not the only risk factor, but one of many). But whether maternal obesity before or during pregnancy introduced that risk was not known. Autism is one area where we know both genetics and environment play roles, but the timing of environmental influences is still a mystery,” the researchers told PsyPost.
“Our lab realized we could use a mouse model with in vitro fertilization to isolate those two periods, leveraging the expertise in this field at the Yanagimachi Institute for Biogenesis Research, and that opened the door to finding out exactly when and how maternal health might affect neurodevelopment.”
To isolate the effects of maternal obesity before conception from those during pregnancy, the researchers used in vitro fertilization (IVF) and embryo transfer techniques. They first fed female mice either a high-fat diet (to induce obesity) or a normal diet for 8–10 weeks. Eggs from these females were fertilized in the lab with sperm from healthy males and implanted into healthy surrogate mothers that had not been exposed to obesity.
This setup allowed the researchers to compare three groups: one in which the egg donor was obese (but the surrogate was not), one in which the surrogate was obese (but the egg donor was not), and one where both were healthy. All offspring were then fostered by normal mothers to eliminate differences in postnatal care. The team monitored behavioral development in male and female offspring from early life into adolescence.
The researchers found that male mice whose biological mothers were obese before conception—but who were gestated and raised by healthy mothers—showed behavioral signs associated with ASD. These included changes in vocal communication during infancy, reduced social interaction in adolescence, and repetitive self-grooming behaviors. These behavioral traits were not observed in male offspring from obese surrogates or in female offspring, regardless of maternal obesity exposure.
“The biggest surprise was that obesity during pregnancy alone didn’t produce the same effects,” Maunakea and Ward told PsyPost. “We expected both pre-conception and gestational obesity to have an impact, but in our model, only preconception exposure led to autism-like behaviors. That really highlights how sensitive the egg is to the mother’s health before conception, and it shifts how we think about timing for prevention.”
The researchers also ran tests for anxiety-like behaviors, which showed no differences between groups, suggesting that the behavioral changes were specific to domains relevant to autism rather than general distress or emotional reactivity.
Not all male offspring in the pre-conception obesity group showed these traits, which the authors say reflects the variability often seen in autism presentations. They classified the most affected mice as the “ASD” subgroup and conducted additional molecular analyses on this group compared to unaffected “NESTED” mice.
To understand the biological basis for these behaviors, the researchers examined the brains of the male offspring. They focused on two regions—the cortex and hippocampus—that are known to be involved in social behavior and learning.
In the cortex, they found that male offspring with autism-like traits showed changes in the expression of several genes. Two genes in particular—Homer1 and Zswim6—stood out because of their known roles in synaptic function and prior links to autism in humans. The short form of Homer1, known as Homer1a, was elevated in the ASD group and is known to interfere with the scaffolding of synapses, potentially altering how neurons communicate.
To find out what might be driving these changes, the team looked at DNA methylation, a chemical modification that helps regulate whether genes are turned on or off. Using tissue from the hippocampus, they discovered that the promoter region of the alternative Homer1a isoform was significantly less methylated—meaning more “open” for expression—in ASD-classified mice. This was not the case in unaffected mice from the same group or in controls.
These findings suggest that maternal obesity prior to conception can reprogram gene expression in the developing brain through epigenetic changes, particularly affecting isoform usage—where different versions of a gene are produced with different functions.
The researchers argue that their results highlight a sensitive developmental window that has received relatively little attention: the period before conception. This study suggests that the mother’s health at the time her eggs are maturing may play a key role in shaping long-term outcomes in offspring, especially for neurodevelopmental conditions like autism.
The findings also suggest that specific molecular markers, such as the methylation pattern and isoform expression of Homer1, could potentially be used as early indicators of atypical brain development.
“One clear takeaway is that a mother’s health before pregnancy matters—not just during pregnancy,” Maunakea and Ward explained. “The months leading up to conception may be a sensitive time for setting the stage for a child’s brain development. That doesn’t mean every child born to a mother with obesity will have autism—far from it. But it does mean that taking steps to improve overall health before pregnancy, such as good nutrition, regular activity, and managing conditions like diabetes, could have benefits beyond what we previously appreciated.”
As with all research, there are limitations. The sample size for molecular analyses was relatively small, and only male offspring were included due to the absence of strong behavioral effects in females. The analyses also used bulk brain tissue, which doesn’t account for differences across specific cell types. In addition, although the observed associations between DNA methylation and gene expression were compelling, causality was not directly tested.
“This is an animal study, so we can’t assume the findings apply exactly the same way in humans,” the researchers noted. “We also only looked at first-generation offspring and stopped at early adolescence in the mice. We don’t yet know if these effects last into adulthood or if they might be passed down to the next generation.”
“And importantly, autism is complex—many children with autism are born to mothers who had healthy weights, and many children of mothers with obesity do not develop autism. This is about understanding one possible pathway, not the whole picture.”
Future research will focus on several open questions. The team plans to investigate whether these changes persist into adulthood and how they evolve over time. They also hope to pinpoint the specific molecular pathways through which maternal obesity affects egg development and whether interventions—such as dietary changes or supplements—can reduce or reverse these effects.
One long-term goal is to identify early biomarkers that could help guide personalized prenatal care. The researchers are also exploring whether these epigenetic changes can be passed on to the next generation, which would suggest a transgenerational impact of pre-conceptional health.
“I think it’s important to remember that this research is about opportunity, not blame,” Maunakea and Ward added. “Maternal obesity is shaped by many factors outside individual control—like access to healthy foods, safe spaces to exercise, and healthcare resources. Our findings point to a window where supportive health policies, community programs, and healthcare guidance could make a difference for both mothers and children. And beyond autism, improving metabolic health before conception is likely to benefit many aspects of lifelong health for both mother and child.”
The study, “Pre-Conception Maternal Obesity Confers Autism Spectrum Disorder-like Behaviors in Mice Offspring Through Neuroepigenetic Dysregulation,” was authored by Nina P. Allan, Amada Torres, Michael J. Corley, Brennan Y. Yamamoto, Chantell Balaan, Yasuhiro Yamauchi, Rafael Peres, Yujia Qin, Vedbar S. Khadka, Youping Deng, Monika A. Ward, and Alika K. Maunakea/
