Examining etiologies underlying sex bias in autism spectrum disorder using preclinical rodent models: a narrative review



Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by social and communication challenges, along with repetitive behaviors. One of the enduring mysteries surrounding ASD is the significant sex bias, with males diagnosed at a much higher rate than females. A recent study published in the Ewha Medical Journal in April 2024 sheds light on this topic by investigating the underlying causes of this sex bias using preclinical rodent models.

Why the Sex Bias in ASD?


Despite extensive research, the exact cause of ASD remains elusive. Scientists believe it’s a combination of genetic and environmental factors. This study by Lee and Kim (2024) focuses on how these factors might interact differently in males and females, leading to the observed sex bias.

Preclinical Rodent Models: Unveiling the Maze


The study utilizes preclinical rodent models, essentially animal models used to simulate human diseases. These models allow researchers to manipulate genes, observe brain development, and assess behaviors related to ASD in a controlled setting. By studying these models, scientists can gain valuable insights into the mechanisms behind the sex bias in ASD. It’s important to note that these models have limitations, and findings need to be interpreted with caution. However, they serve as a crucial stepping stone for further research and drug discovery.


Unveiling the Mechanisms: Six Avenues of Exploration


The researchers categorize potential mechanisms contributing to the sex bias into six key areas:

  1. Sexually Dimorphic Phenotypes: This intriguing concept refers to how genetic mutations linked to ASD might have different effects on brain connections (synapses) in males and females. Essentially, the same mutation could lead to more significant disruptions in the male brain compared to the female brain, influencing the risk of ASD diagnosis.
  2. Microglial Activity: Microglia are immune cells in the brain that play a vital role in development and pruning of synapses. The study explores how sex-specific differences in microglial activity might influence neural circuit development in ASD. Microglia might function differently in males and females, potentially impacting how brain circuits are sculpted during development, leading to a sex bias in ASD presentation.
  3. Gonadal Hormones: Sex hormones like testosterone and estrogen are not just about physical development. They also influence how genes are expressed throughout the body, including the brain. The research explores how these hormones might contribute to the sex bias. Fluctuations in hormone levels during development or even later in life could potentially influence the risk of ASD in males and females.
  4. Environmental Exposures: Environmental factors during critical developmental periods can also influence the risk of ASD. The study investigates whether these exposures, such as pollutants or toxins, might have a differential impact on males and females. For instance, timing and intensity of exposure to certain environmental factors could interact with genes in a sex-specific way, increasing the risk of ASD in one sex over the other.
  5. Gene-Environment Interactions: This area delves deeper into the intricate interplay between genes and environmental factors. The study explores how interactions between genes linked to ASD and environmental exposures might contribute to the sex bias. For example, a specific genetic mutation might only increase the risk of ASD in males when combined with a particular environmental exposure during a critical developmental window.
  6. The Microbiome: The gut microbiome, the community of microbes living in our gut, has recently gained significant interest in its potential role in brain development and neurological disorders. This research explores how the microbiome might differ between males and females and how it might be linked to the sex bias in ASD. The gut microbiome might influence brain development through various pathways, and sex-based differences in this microbial community could contribute to the observed sex bias in ASD.

By examining these six areas, researchers hope to gain a deeper understanding of the biological underpinnings of the sex bias in ASD. This knowledge could pave the way for the development of more targeted therapies and interventions tailored to the specific needs of males and females with ASD.

Future Directions: Beyond the Rodent Maze


This research using preclinical rodent models provides valuable insights into the sex bias observed in ASD. It highlights the importance of considering sex as a biological variable in future studies. Here are some key areas for future research directions:

Translating findings to human studies: While rodent models offer valuable starting points, translating these findings to human studies is crucial. Researchers need to conduct clinical trials that consider sex as a variable from the outset. This will involve:

  • Sex-disaggregated data analysis: Separately analyzing data for males and females within clinical trials to identify potential differences in treatment response or symptom presentation.
  • Recruiting balanced participant pools: Ensuring clinical trials enroll participants who reflect the observed sex bias in ASD prevalence.
  • Developing sex-specific outcome measures: Tailoring assessments used in clinical trials to capture the nuances of ASD presentation in both males and females.

By conducting sex-specific clinical trials, researchers can develop more targeted treatment strategies that are effective for both males and females with ASD.


Investigating additional factors: This study explores six key areas, but there might be other factors contributing to the sex bias. Future research should explore additional biological and environmental factors that might influence the risk of ASD in males and females. This could involve:

  • Epigenetics: Investigating how environmental factors might influence gene expression differently in males and females, potentially affecting ASD risk.
  • The microbiome: Delving deeper into the potential link between the gut microbiome and ASD, considering sex-based differences in microbial composition.
  • Social and environmental factors: Examining how societal expectations and environmental exposures might interact with biological factors to contribute to the sex bias in diagnosis and treatment.

By exploring these additional avenues, researchers can gain a more comprehensive understanding of the complex interplay between sex and ASD.


Developing sex-specific interventions: Ultimately, the goal is to translate this knowledge into improved clinical care. By understanding the mechanisms behind the sex bias, researchers can develop more targeted therapies and interventions. This could involve:

  • Tailoring existing therapies: Adapting existing therapeutic approaches based on how ASD manifests differently in males and females.
  • Developing sex-specific treatments: Creating new therapies that target the specific biological underpinnings of ASD in each sex.
  • Personalized medicine: Moving towards a future of personalized medicine for ASD, where treatment plans are tailored to the individual’s unique biology and presentation, regardless of sex.

By developing sex-specific interventions, researchers can ensure that everyone with ASD has access to effective treatment and support.




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