Male autism spectrum disorder is linked to brain aromatase disruption by prenatal BPA in multimodal investigations and 10HDA ameliorates the related mouse phenotype

Symeonides, Christos; Vacy, Kristina; Thomson, Sarah; Tanner, Sam; Chua, Hui Kheng; Dixit, Shilpi; Mansell, Toby; O’Hely, Martin; Novakovic, Boris; Herbstman, Julie B.; Wang, Shuang; Guo, Jia; Chia, Jessalynn; Tran, Nhi Thao; Hwang, Sang Eun; Britt, Kara; Chen, Feng; Kim, Tae Hwan; Reid, Christopher A.; El-Bitar, Anthony; Bernasochi, Gabriel B.; Delbridge, Lea M. Durham; Harley, Vincent R.; Yap, Yann W.; Dewey, Deborah; Love, Chloe J.; Burgner, David; Tang, Mimi L. K.; Sly, Peter D.; Saffery, Richard; Mueller, Jochen F.; Rinehart, Nicole; Tonge, Bruce; Vuillermin, Peter; Ponsonby, Anne-Louise; Boon, Wah Chin

Male autism spectrum disorder is linked to brain aromatase disruption by prenatal BPA in multimodal investigations and 10HDA ameliorates the related mouse phenotype

Christos Symeonides, Kristina Vacy, Sarah Thomson, Sam Tanner, Hui Kheng Chua, Shilpi Dixit, Toby Mansell, Martin O’Hely, Boris Novakovic, Julie B. Herbstman, Shuang Wang, Jia Guo, Jessalynn Chia, Nhi Thao Tran, Sang Eun Hwang, Kara Britt, Feng Chen, Tae Hwan Kim, Christopher A. Reid, Anthony El-Bitar, Gabriel B. Bernasochi, Lea M. Durham Delbridge, Vincent R. Harley, Yann W. Yap, Deborah Dewey, Chloe J. Love, David Burgner, Mimi L. K. Tang, Peter D. Sly, Richard Saffery, Jochen F. Mueller, Nicole Rinehart, Bruce Tonge, Peter Vuillermin, Anne-Louise Ponsonby and Wah Chin Boon ()
Additional contact information
Christos Symeonides: Minderoo Foundation
Kristina Vacy: The Florey Institute of Neuroscience and Mental Health
Sarah Thomson: The Florey Institute of Neuroscience and Mental Health
Sam Tanner: The Florey Institute of Neuroscience and Mental Health
Hui Kheng Chua: The Florey Institute of Neuroscience and Mental Health
Shilpi Dixit: The Florey Institute of Neuroscience and Mental Health
Toby Mansell: Murdoch Children’s Research Institute
Martin O’Hely: Murdoch Children’s Research Institute
Boris Novakovic: Murdoch Children’s Research Institute
Julie B. Herbstman: Columbia University
Shuang Wang: Columbia University
Jia Guo: Columbia University
Jessalynn Chia: The Florey Institute of Neuroscience and Mental Health
Nhi Thao Tran: The Florey Institute of Neuroscience and Mental Health
Sang Eun Hwang: The Florey Institute of Neuroscience and Mental Health
Kara Britt: Monash University
Feng Chen: The Florey Institute of Neuroscience and Mental Health
Tae Hwan Kim: The Florey Institute of Neuroscience and Mental Health
Christopher A. Reid: The Florey Institute of Neuroscience and Mental Health
Anthony El-Bitar: The Florey Institute of Neuroscience and Mental Health
Gabriel B. Bernasochi: The Florey Institute of Neuroscience and Mental Health
Lea M. Durham Delbridge: University of Melbourne
Vincent R. Harley: Monash University
Yann W. Yap: The Hudson Institute of Medical Research
Deborah Dewey: The University of Calgary
Chloe J. Love: Deakin University
David Burgner: Murdoch Children’s Research Institute
Mimi L. K. Tang: Murdoch Children’s Research Institute
Peter D. Sly: Deakin University
Richard Saffery: Murdoch Children’s Research Institute
Jochen F. Mueller: The University of Queensland
Nicole Rinehart: Monash University
Bruce Tonge: Monash University
Peter Vuillermin: Murdoch Children’s Research Institute
Anne-Louise Ponsonby: Murdoch Children’s Research Institute
Wah Chin Boon: The Florey Institute of Neuroscience and Mental Health

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract Male sex, early life chemical exposure and the brain aromatase enzyme have been implicated in autism spectrum disorder (ASD). In the Barwon Infant Study birth cohort (n = 1074), higher prenatal maternal bisphenol A (BPA) levels are associated with higher ASD symptoms at age 2 and diagnosis at age 9 only in males with low aromatase genetic pathway activity scores. Higher prenatal BPA levels are predictive of higher cord blood methylation across the CYP19A1 brain promoter I.f region (P = 0.009) and aromatase gene methylation mediates (P = 0.01) the link between higher prenatal BPA and brain-derived neurotrophic factor methylation, with independent cohort replication. BPA suppressed aromatase expression in vitro and in vivo. Male mice exposed to mid-gestation BPA or with aromatase knockout have ASD-like behaviors with structural and functional brain changes. 10-hydroxy-2-decenoic acid (10HDA), an estrogenic fatty acid alleviated these features and reversed detrimental neurodevelopmental gene expression. Here we demonstrate that prenatal BPA exposure is associated with impaired brain aromatase function and ASD-related behaviors and brain abnormalities in males that may be reversible through postnatal 10HDA intervention.

Date: 2024
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DOI: 10.1038/s41467-024-48897-8

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