Pre-Pregnancy Obesity: The Link Between Maternal Weight And Autism

A mouse study showed that maternal obesity before pregnancy, and not just during pregnancy, can increase the risk of autism-like behaviors in offspring, especially in males. This is because prior obesity can alter the way certain brain genes function, leaving lasting chemical imprints that affect development and behavior.

Autism spectrum disorder is a group of conditions that affect brain development from a very early age. People with this disorder have difficulty communicating and interacting socially, in addition to exhibiting repetitive behaviors and very restricted interests.

In the United States, it is estimated that about one in thirty-six children receives the diagnosis, with boys being more common than girls by a ratio of approximately three to one.

Although genetic factors are important, only a small proportion of cases are caused by very specific and strong genetic mutations, indicating that environmental influences and chemical changes that regulate gene activity, known as epigenetic alterations, also play a role.

Recent studies suggest that a mother's health status before and during pregnancy, especially obesity, may increase the risk of autism in her offspring. This idea fits with a medical hypothesis known as the "Developmental Origins of Health and Disease."

This hypothesis proposes that the environment a baby is exposed to from the egg and sperm stage through life in the womb can "program" development and influence health throughout life. Despite epidemiological evidence, it is still unclear how exactly maternal obesity increases this risk, nor whether the most critical phase of exposure is before conception or during pregnancy.

To investigate this question, scientists at the University of Hawaiʻi at Mānoa, USA, used mice as an experimental model, as they allow for strict control of variables and detailed observation of the effects. They applied a method that combines in vitro fertilization (i.e., the fertilization of the egg outside the female's body) with the transfer of the resulting embryos to adoptive mothers.

With this, they were able to separate two types of influence: that from the eggs and sperm of obese mothers even before pregnancy, and that from the uterine environment of an obese mother during pregnancy. This allowed them to identify whether the risk stemmed from changes already present in the reproductive cells or whether it arose due to the in-utero environment.

The researchers fed some females a high-fat diet before conception, while others only received this diet during pregnancy. Then, they monitored the behavior of their offspring.

They found that obesity before pregnancy alone, even without obesity during pregnancy, was enough to cause behaviors in male offspring similar to those observed in human autism: changes in vocalization, decreased interest in social interactions, and increased repetitive behaviors, such as excessive grooming.

These effects were not seen in female offspring or in those exposed to maternal obesity only during pregnancy.

By investigating the brains of these animals, the scientists analyzed which genes were active and how they were regulated. In the cortex, a region important for cognitive and social functions, they found changes in the activity and functioning of genes already linked to autism, such as Homer1 and Zswim6.

Furthermore, by studying the hippocampus, an area crucial for memory and learning, using a method that examines DNA methylation (a chemical marker that regulates gene activity), they discovered that there was less methylation in a specific region of the Homer1 gene.

This change was associated with an increase in a short form of the Homer1a protein, which is known to disrupt the structure and function of connections between neurons.

These findings show that maternal obesity before pregnancy can leave lasting chemical marks on DNA and alter the activity of genes essential for brain development. This reinforces the importance of taking care of a woman's health even before she becomes pregnant, as this period can have a decisive impact on the risk of autism in her children.

READ MORE:

Pre-Conception Maternal Obesity Confers Autism Spectrum Disorder-like Behaviors in Mice Offspring Through Neuroepigenetic Dysregulation

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

Cells, 2025, 14(15), 1201

https://doi.org/10.3390/cells14151201

Abstract: 

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with early-life origins. Maternal obesity has been associated with increased ASD risk, yet the mechanisms and timing of susceptibility remain unclear. Using a mouse model combining in vitro fertilization (IVF) and embryo transfer, we separated the effects of pre-conception and gestational obesity. We found that maternal high fat diet (HFD) exposure prior to conception alone was sufficient to induce ASD-like behaviors in male offspring—including altered vocalizations, reduced sociability, and increased repetitive grooming—without anxiety-related changes. These phenotypes were absent in female offspring and those exposed only during gestation. Cortical transcriptome analysis revealed dysregulation and isoform shifts in genes implicated in ASD, including 

Homer1 and Zswim6. Whole-genome bisulfite sequencing of hippocampal tissue showed hypomethylation of an alternative Homer1 promoter,

correlating with increased expression of the short isoform Homer1a, which is known to disrupt synaptic scaffolding. This pattern was specific to mice with ASD-like behaviors. Our findings show that pre-conceptional maternal obesity can lead to lasting, isoform-specific transcriptomic and epigenetic changes in the offspring’s brain. These results underscore the importance of maternal health before pregnancy as a critical and modifiable factor in ASD risk.