In a recent study published in Nature Communications, researchers investigated the role of aromatase in the increased risk of autism spectrum disorder (ASD) observed in males prenatally exposed to bisphenol A (BPA).
Study: Male autism spectrum disorder is linked to brain aromatase disruption by prenatal BPA in multimodal investigations and 10-HDA ameliorates the related mouse phenotype. Image Credit: Ivan Marc / Shutterstock.com
Autism and the male fetal brain
ASD is a neurodevelopmental disorder that often causes restrictive and repetitive behaviors, as well as social deficits that impact social interactions and communication. In Western countries, the prevalence of autism is about 2%; however, recent research suggests that ASD incidence rates are increasing. Autism is associated with a sex bias, as about 80% of affected individuals are male, thus suggesting underlying sex-specific neurodevelopmental factors.
Aromatase is an enzyme encoded by the CYP19A1 gene that is expressed and regulated in the brain. Aromatase converts androgens to estrogens and is found in high levels in the amygdala of males during fetal development.
Endocrine-disrupting chemicals like BPA can disrupt aromatase function. Male fetal brains exhibit higher aromatase expression in the amygdala; therefore, prenatal exposure to BPA could impact male neurodevelopment.
Several studies have reported an association between maternal exposure to high levels of BPA and sex-specific neurodevelopmental issues in the child. Murine model studies have also reported dysregulation of gene expression in the hippocampus of males and cognitive and neuronal abnormalities associated with prenatal exposure to BPA.
Post-mortem analyses of males with autism have observed lower levels of aromatase activity than in the brains of age-matched healthy controls. A 38% reduction of CYP19A1 expression in the prefrontal cortex of males with autism was also observed.
About the study
Both in vitro and in vivo experiments were conducted to determine the effects of BPA exposure on aromatase activity. In vivo experiments involved exposing pregnant mice to 50 µg/kg/day VPA through subcutaneous injection, which matches the Tolerable Daily Intake (TDI) set by the European Food Safety Authority (EFSA) for pregnant women.
The current study's researchers hypothesized that BPA exposure causes epigenetic reprogramming, increases DNA methylation, and subsequently reduces cellular expression of aromatase. To this end, whole genome single nucleotide polymorphism arrays and DNA methylation patterns were analyzed to explore epigenetic modifications.
The researchers also proposed that estrogen supplementation in the form of 10-hydroxy-2-decenoic acid (10-HDA), which is commonly found in royal jelly from beehives, could ameliorate the impact of prenatal BPA exposure and improve ASD phenotypes in a murine model.
Data were also obtained from the Barwon Infant Study (BIS) on children with a confirmed diagnosis of ASD for whom BPA exposure measurements were available. These data were used to determine the interplay between prenatal exposure to BPA, sex, and aromatase function.
Study findings
Within the BIS cohort, Child Behavior Checklist (CBCL) data were available for 676 infants, 36.8% of whom exhibited autism spectrum problems (ASP). Male children with high prenatal BPA exposure levels and higher ASP scores exhibited low aromatase activity, which was identified by the presence of three or more genetic variants associated with lower estrogen levels. High levels of prenatal BPA exposure also resulted in hypermethylation of the brain-derived neurotrophic factor (BDNF) gene and reduced BDNF expression in males.
In vitro experiments using the human neuroblastoma cell line SH-SY5Y demonstrated that BPA exposure reduces aromatase expression levels by 50%. Compared to control mice, prenatal BPA exposure similarly reduced the expression of aromatase in the brains of male mice.
Male mice exposed to BPA in utero were also found to spend less time investigating sex- and age-matched stranger mice than control mice. These effects were particularly evident in male mice prenatally exposed to BPA at mid-gestation, which is when the amygdala of embryonic mice typically undergoes significant development. Female mice exposed to BPA in utero did not exhibit these behavioral characteristics.
Comparisons of BPA-exposed mice with aromatase-knockout mice showed that exposure to BPA disrupts aromatase function in male mouse brains, subsequently leading to reductions in dendritic lengths, neuronal numbers, and neuronal spine densities. In the amygdala, BPA exposure also reduced the excitatory postsynaptic potential.
Prenatal BPA exposure led to significant reductions in neurite length and spine density of cortical cells isolated from male fetal mouse brains; however, co-administration with 10-HDA reversed these effects. When prenatally exposed mice were treated with 10-HDA after birth, significant improvements in their social interactions were observed. Importantly, these effects were not permanent, as withdrawal of 10-HDA treatment caused the social deficits to return until subsequent 10-HDA treatment.
Conclusions
Prenatal BPA exposure significantly impacted aromatase activity in a male-specific manner in the mouse fetus, which subsequently led to anatomical, behavioral, and functional changes resembling autism. The study findings also suggest that the administration of 10-HDA has the potential to reverse these effects and ameliorate ASD symptoms.
Journal reference:
- Symeonides, C., Vacy, K., Thomson, S., et al. (2024). Male autism spectrum disorder is linked to brain aromatase disruption by prenatal BPA in multimodal investigations and 10-HDA ameliorates the related mouse phenotype. Nature Communications 15(1), 6367. doi:10.1038/s41467024488978.
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