Male autism spectrum disorder is linked to brain aromatase disruption by prenatal BPA in multimodal investigations and 10HDA ameliorates the related mouse phenotype.
Level 3 - non-randomized controlled study
Prospective birth cohort combined with mechanistic animal and in vitro models
PubMed 39112449 · doi:10.1038/s41467-024-48897-8
What was done
In the Barwon Infant Study birth cohort (n = 1074), researchers analyzed associations between prenatal maternal bisphenol A (BPA) levels, aromatase genetic pathway activity scores, ASD symptoms at age 2, and ASD diagnosis at age 9. They evaluated cord blood methylation across the CYP19A1 brain promoter I.f region and BDNF methylation, replicating findings in an independent cohort. Mechanistic experiments tested BPA effects in vitro and in vivo in mid-gestation-exposed or aromatase-knockout male mice, including rescue experiments with the estrogenic fatty acid 10-hydroxy-2-decenoic acid (10HDA).
What was found
Higher prenatal maternal BPA was associated with increased ASD symptoms at age 2 and clinical diagnosis at age 9 exclusively in males with low aromatase genetic pathway activity scores. Higher prenatal BPA predicted increased cord blood methylation at the CYP19A1 brain promoter I.f region (P = 0.009), and aromatase gene methylation mediated the link to BDNF methylation (P = 0.01). In male mice, prenatal BPA exposure or aromatase knockout induced ASD-like behaviors and brain changes, which were reversed by postnatal 10HDA administration.
Why it matters
It identifies a mechanistic gene-environment pathway—brain aromatase disruption and epigenetic silencing—that may explain male vulnerability to endocrine-disrupting chemicals in ASD etiology.
Limits
The abstract does not provide effect sizes, odds ratios, confidence intervals, or the exact number of ASD cases at age 9. Human findings are observational and subject to residual confounding. The therapeutic effect of 10HDA was evaluated only in preclinical mouse models, not in humans.