Folate deficiency increases the incidence of dolutegravir-associated foetal defects in a mouse pregnancy model

Mohan, Haneesha; Nguyen, Jessica; MacKenzie, Ben; Yee, Audrey; Laurette, Evelyn Yukino; Sanghvi, Tanvi; Tejada, Oscar; Dontsova, Valeriya; Leung, Kit-Yi; Goddard, Cameron; De Young, Taylor; Sled, John G.; Greene, Nicholas D.E.; Copp, Andrew J.; Serghides, Lena

doi:10.1016/j.ebiom.2023.104762

Cited by 3 publications

(9 citation statements)

References 43 publications

(88 reference statements)

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“…These abnormalities were rescued, although not completely, by FA supplementation. Our study then further supports previous evidence that DTG can interfere with FA pathways and also provides new insights regarding the mechanisms involved in the increased risk of DTG-associated fetal neurodevelopmental defects and adverse neurologic outcomes in children exposed in utero to DTG [8,[10][11][12]14,18,[25][26][27][28].…”

Section: Discussionsupporting

confidence: 88%

“…Survival rate was ameliorated and no gross morphological body deformities and, more interestingly, no gross brain malformations were found in both FA supplementation conditions in our model. All these findings are also coherent with the numerous observations in animal models and humans of a relationship among DTG exposure, sub-optimal folate levels and fetal defects, although the underlying mechanism of these evidences remain already mostly unclear [4,6,7,12,27]. Tukeman and colleagues [27] evaluated DTG developmental toxicity in fetuses from DTG-treated dams fed normal or low FA diet, finding NTD-affected fetuses (exencephaly) only with low FA diet.…”

Section: Discussionsupporting

confidence: 69%

“…Tukeman and colleagues [27] evaluated DTG developmental toxicity in fetuses from DTG-treated dams fed normal or low FA diet, finding NTD-affected fetuses (exencephaly) only with low FA diet. In a similar animal model, Mohan and colleagues [12,26] observed a higher rate of NTDs (exencephaly, encephalocele and spina bifida) and tail defects under folate-deficiency conditions, also together with severe left-right asymmetry, abdominal wall, limb and craniofacial anomalies, bleeding defects and severe edema. In our model, we as well observed the disruption of the AP axis and a strong reduction in ntl expression in the notochord after DTG exposure, both suggestive of NTDs, and the defects were rescued by FA supplementation, in agreement with what was previously observed in the murine model.…”

Section: Discussionmentioning

confidence: 89%

“…Recently, data from mouse pregnancy models showed that folate deficiency increases the incidence of DTG-associated fetal defects in tail, abdominal wall, limb and craniofacial structures with frequent bleeds [12], while normal FA levels during pregnancy ameliorate developmental defects that arise from DTG exposure, especially NTDs [27]. In concordance, in countries where maternal food is supplemented with FA, the risk of DTG-associated fetal malformations, including NTDs, is lower than those reported from the initial surveillance data in Botswana where there are no FA fortification public programs [4,7].…”

Section: Discussionmentioning

confidence: 99%

“…In pregnant mice, DTG administration was associated with an increase in both placental RFC and PCFT mRNA expression, and folate-deficient dietary conditions are accompanied by a decrease in placental folate receptor α (FRα) mRNA [11]. Notwithstanding, a recent investigation described no differences on total fetal folate levels, according to DTG exposure in mice [12]. Secondly, DTG can inhibit the activity of the matrix metalloproteinases (MMPs), a class of Zn ++ -dependent enzymes involved in the developmental processes of the central nervous system (CNS) [13], and this mechanism was also suggested as involved in the DTG-induced fetal neurodevelopment defects [14].…”

Section: Introductionmentioning

confidence: 99%

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

Zizioli,

Quiros-Roldan,

Ferretti

et al. 2024

IJMS

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Dolutegravir (DTG) is one of the most prescribed antiretroviral drugs for treating people with HIV infection, including women of child-bearing potential or pregnant. Nonetheless, neuropsychiatric symptoms are frequently reported. Early reports suggested that, probably in relation to folic acid (FA) shortage, DTG may induce neural tube defects in infants born to women taking the drug during pregnancy. Subsequent reports did not definitively confirm these findings. Recent studies in animal models have highlighted the association between DTG exposure in utero and congenital anomalies, and an increased risk of neurologic abnormalities in children exposed during in utero life has been reported. Underlying mechanisms for DTG-related neurologic symptoms and congenital anomalies are not fully understood. We aimed to deepen our knowledge on the neurodevelopmental effects of DTG exposure and further explore the protective role of FA by the use of zebrafish embryos. We treated embryos at 4 and up to 144 h post fertilization (hpf) with a subtherapeutic DTG concentration (1 μM) and observed the disruption of the anterior–posterior axis and several morphological malformations in the developing brain that were both prevented by pre-exposure (2 hpf) and rescued by post-exposure (10 hpf) with FA. By whole-mount in situ hybridization with riboprobes for genes that are crucial during the early phases of neurodevelopment (ntl, pax2a, ngn1, neurod1) and by in vivo visualization of the transgenic Tg(ngn1:EGFP) zebrafish line, we found that DTG induced severe neurodevelopmental defects over time in most regions of the nervous system (notochord, midbrain–hindbrain boundary, eye, forebrain, midbrain, hindbrain, spinal cord) that were mostly but not completely rescued by FA supplementation. Of note, we observed the disruption of ngn1 expression in the dopaminergic regions of the developing forebrain, spinal cord neurons and spinal motor neuron projections, with the depletion of the tyrosine hydroxylase (TH)+ dopaminergic neurons of the dorsal diencephalon and the strong reduction in larvae locomotion. Our study further supports previous evidence that DTG can interfere with FA pathways in the developing brain but also provides new insights regarding the mechanisms involved in the increased risk of DTG-associated fetal neurodevelopmental defects and adverse neurologic outcomes in in utero exposed children, suggesting the impairment of dopaminergic pathways.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Zizioli,

Quiros-Roldan,

Ferretti

et al. 2024

IJMS

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Characterizing neuroinflammation and identifying prenatal diagnostic markers for neural tube defects through integrated multi-omics analysis

Wang,

Ji,

Dong

et al. 2024

J Transl Med

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Background Neural Tube Defects (NTDs) are congenital malformations of the central nervous system resulting from the incomplete closure of the neural tube during early embryonic development. Neuroinflammation refers to the inflammatory response in the nervous system, typically resulting from damage to neural tissue. Immune-related processes have been identified in NTDs, however, the detailed relationship and underlying mechanisms between neuroinflammation and NTDs remain largely unclear. In this study, we utilized integrated multi-omics analysis to explore the role of neuroinflammation in NTDs and identify potential prenatal diagnostic markers using a murine model. Methods Nine public datasets from Gene Expression Omnibus (GEO) and ArrayExpress were mined using integrated multi-omics analysis to characterize the molecular landscape associated with neuroinflammation in NTDs. Special attention was given to the involvement of macrophages in neuroinflammation within amniotic fluid, as well as the dynamics of macrophage polarization and their interactions with neural cells at single-cell resolution. We also used qPCR assay to validate the key TFs and candidate prenatal diagnostic genes identified through the integrated analysis in a retinoic acid-induced NTDs mouse model. Results Our analysis indicated that neuroinflammation is a critical pathological feature of NTDs, regulated both transcriptionally and epigenetically within central nervous system tissues. Key alterations in gene expression and pathways highlighted the crucial role of STATs molecules in the JAK-STAT signaling pathway in regulating NTDs-associated neuroinflammation. Furthermore, single-cell resolution analysis revealed significant polarization of macrophages and their interaction with neural cells in amniotic fluid, underscoring their central role in mediating neuroinflammation associated with NTDs. Finally, we identified a set of six potential prenatal diagnostic genes, including FABP7, CRMP1, SCG3, SLC16A10, RNASE6 and RNASE1, which were subsequently validated in a murine NTDs model, indicating their promise as prospective markers for prenatal diagnosis of NTDs. Conclusions Our study emphasizes the pivotal role of neuroinflammation in the progression of NTDs and underlines the potential of specific inflammatory and neural markers as novel prenatal diagnostic tools. These findings provide important clues for further understanding the underlying mechanisms between neuroinflammation and NTDs, and offer valuable insights for the future development of prenatal diagnostics.

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Dolutegravir induces FOLR1 expression during brain organoid development

Caiaffa,

Tukeman,

Delgado

et al. 2024

Front. Mol. Neurosci.

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During the first month of pregnancy, the brain and spinal cord are formed through a process called neurulation. However, this process can be altered by low serum levels of folic acid, environmental factors, or genetic predispositions. In 2018, a surveillance study in Botswana, a country with a high incidence of human immunodeficiency virus (HIV) and lacking mandatory food folate fortification programs, found that newborns whose mothers were taking dolutegravir (DTG) during the first trimester of pregnancy had an increased risk of neural tube defects (NTDs). As a result, the World Health Organization and the U.S. Food and Drug Administration have issued guidelines emphasizing the potential risks associated with the use of DTG-based antiretroviral therapies during pregnancy. To elucidate the potential mechanisms underlying the DTG-induced NTDs, we sought to assess the potential neurotoxicity of DTG in stem cell-derived brain organoids. The gene expression of brain organoids developed in the presence of DTG was analyzed by RNA sequencing, Optical Coherence Tomography (OCT), Optical Coherence Elastography (OCE), and Brillouin microscopy. The sequencing data shows that DTG induces the expression of the folate receptor (FOLR1) and modifies the expression of genes required for neurogenesis. The Brillouin frequency shift observed at the surface of DTG-exposed brain organoids indicates an increase in superficial tissue stiffness. In contrast, reverberant OCE measurements indicate decreased organoid volumes and internal stiffness.

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Folate deficiency increases the incidence of dolutegravir-associated foetal defects in a mouse pregnancy model

Cited by 3 publications

References 43 publications

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

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

Characterizing neuroinflammation and identifying prenatal diagnostic markers for neural tube defects through integrated multi-omics analysis

Dolutegravir induces FOLR1 expression during brain organoid development

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