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Dolutegravir induces FOLR1 expression during brain organoid development.

Carlo Donato Caiaffa1,2, Gabriel Tukeman1, Christian Zevallos Delgado3

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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.

Keywords:
HIVbrain organoidsdolutegravirneural tube defectsneurulation

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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.