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Dolutegravir induces FOLR1 expression during brain organoid development
Carlo Donato Caiaffa1,2, Gabriel Tukeman1, Christian Zevallos Delgado3
1Center for Precision Environmental Health, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States.
Frontiers in Molecular Neuroscience
|June 3, 2024
Summary
Dolutegravir (DTG) use in early pregnancy may increase neural tube defect (NTD) risk by altering brain development. DTG impacts folate receptor expression and neurogenesis genes in organoids, suggesting a potential mechanism for NTDs.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Neural tube defects (NTDs) are congenital abnormalities impacting brain and spinal cord development.
- Dolutegravir (DTG), an antiretroviral medication, has been associated with an increased risk of NTDs in infants born to mothers using it during early pregnancy.
- Botswana, with high HIV rates and no mandatory food folate fortification, observed this association, prompting global health advisories.
Purpose of the Study:
- To investigate the potential neurotoxicity of dolutegravir (DTG) in human stem cell-derived brain organoids.
- To elucidate the molecular and biomechanical mechanisms by which DTG might induce NTDs.
Main Methods:
- Gene expression analysis of brain organoids using RNA sequencing.
- Assessment of organoid structure and mechanics via Optical Coherence Tomography (OCT), Optical Coherence Elastography (OCE), and Brillouin microscopy.
Main Results:
- DTG exposure altered gene expression, notably inducing folate receptor 1 (FOLR1) and modifying genes crucial for neurogenesis.
- Brillouin microscopy revealed increased superficial tissue stiffness in DTG-exposed organoids.
- OCE measurements indicated reduced organoid volumes and internal stiffness.
Conclusions:
- DTG exposure in brain organoids affects key developmental pathways and alters tissue biomechanics.
- Findings suggest DTG's potential neurotoxicity, providing insights into mechanisms underlying DTG-associated NTDs.
