Dolutegravir and Folic Acid Interaction during Neural System Development in Zebrafish Embryos.

Area of Science:

• Neuroscience
• Developmental Biology
• Pharmacology

Background:

• Dolutegravir (DTG) is a key antiretroviral for HIV, used by women of childbearing potential, but linked to potential neurodevelopmental concerns.
• Previous studies suggest a link between DTG, folic acid (FA) shortage, and congenital anomalies, though findings are not definitive.
• Mechanisms underlying DTG's neurodevelopmental and teratogenic effects remain unclear.

Purpose of the Study:

• To investigate the neurodevelopmental effects of DTG exposure in zebrafish embryos.
• To explore the potential protective role of folic acid (FA) against DTG-induced developmental abnormalities.
• To elucidate the underlying mechanisms of DTG's impact on the developing nervous system.

Main Methods:

• Zebrafish embryos were exposed to a subtherapeutic concentration of DTG (1 μM) from 4 to 144 hours post-fertilization (hpf).
• Folic acid (FA) was administered both before (2 hpf) and after (10 hpf) DTG exposure to assess protective and rescue effects.
• Gene expression analysis (whole-mount in situ hybridization) and visualization of transgenic lines (Tg(ngn1:EGFP)) were used to assess neurodevelopmental defects.

Main Results:

• DTG exposure disrupted anterior-posterior axis formation and caused morphological brain malformations, which were partially prevented/rescued by FA.
• DTG induced widespread neurodevelopmental defects across various nervous system regions, with FA providing partial rescue.
• DTG impaired expression of key neurodevelopmental genes, including those in dopaminergic pathways (e.g., tyrosine hydroxylase), leading to reduced larval locomotion.

Conclusions:

• DTG interferes with folic acid (FA) pathways, impacting neurodevelopment in zebrafish embryos.
• FA supplementation partially mitigates DTG-induced neurodevelopmental defects, suggesting a role in protecting against these effects.
• DTG's disruption of dopaminergic pathways may contribute to fetal neurodevelopmental risks and adverse neurologic outcomes observed in exposed children.