The Role of Apoptosis Dysregulation in the Etiology of Anencephaly
Background: Anencephaly is a neural tube defect that results in the absence of the cranium with key aspects of the brain such as the cerebrum, cerebellum, and basal ganglia missing.1 It has a 100% fatality rate for fetuses or neonates.2 The cause is related to the failure of the neural tube to close anteriorly, resulting in exencephaly, the abnormal exposure of brain tissue to the amniotic fluid environment. The mechanism of neural tube closure involves closely regulated neural stem cell proliferation, differentiation, and apoptosis.3 The amniotic fluid breaks down the brain tissue, resulting in the lack of brain, or anencephaly in a fetus.4 Diagnosis is typically done via ultrasound, with a singular umbilical artery and translucent intracranial 3rd ventricle, choroid plexus, and thalamus being an indicator in the first trimester and exposed brain tissue resulting in 100% detection in the second trimester.2 Termination of pregnancy is an option that is discussed with pregnant patients upon detection of anencephaly.2 Folate supplementation during pregnancy is the primary way to prevent the occurrence of anencephaly and teratogenic environments and substances are correlated with increased occurrences of anencephaly.2 There are still knowledge gaps surrounding the etiology and mechanisms behind the development defects that lead to anencephaly.
Objective: In this study, we connected recent discoveries to find commonalities in the mechanisms through which teratogens impact the fetal development and lead to anencephaly.
Search Methods: A search on PubMed was conducted of publications between 2018 and 2023. Keywords in the search were: “Anencephaly”, “Chemically Induced”, “Diagnosis”, “Embryology”, “Epidemiology”, “Etiology”, “Pathology”, “Physiopathology”.
Results: An autosomal recessive mechanism linked to anencephaly is the NUAK autosomal recessive mutation, which impairs the NUAK2 gene that encodes for the SNF1/AMPK-related kinase, needed for activating the Hippo YAP/TAZ pathway required for nuclear translocation.5 Mutations in NUAK2 lead to unphosphorylated, inactive YAP that results increased apoptosis and has been associated with increased p53, an apoptotic molecular marker.6 The increased apoptosis that follows the detected impairment slows neuroepithelial growth and ultimately leads to delayed, inadequate neural tube closure and the development of neural tube defects like Anencephaly.5
Lithium, valproic acid, and okadaic acid have been identified as teratogens linked to the development of anencephaly. All three of these molecules interfere with the intrinsic mechanism of cell death involved in neural tube closure. Lithium carbonate has been linked to anencephaly development and decreases apoptosis through the inositol pathway through p53 and Caspase-3. Lithium exposure results in a decrease in the expression of apoptotic genes Bax, Bad, and Caspase-3.3 The cell apoptosis markers p53 and Caspase-3 were greatly reduced in lithium-treated subjects in conjunction with an increase in the cell proliferation marker PH3.3 This imbalance may be the mechanism that causes incomplete neural tube development, ultimately resulting in anencephaly. Valproic Acid has teratogenic effects due to its action as a histone deacetylase inhibitor that targets p53, increases reactive oxygen species development and causes oxidative shifts in organisms.7,8 Okadaic acid exposure leads to anencephaly by inhibiting serine/threonine protein phosphatase 1 and protein phosphatase 2A, which can cause decreased apoptosis while also inducing apoptosis in certain cell lines.9 Maternal exposure to okadaic acid can result in decreased Caspase-3 in embryos, as well as a significant decrease in apoptosis in neural tubes and an increase in reactive oxidative species.9 Increased reactive oxygen species cause DNA and cell damage that is typically mitigated through the p53 pathway. In these mechanisms, apoptosis dysregulation is seen through various pathways, resulting in defects in embryo development leading to Anencephaly.
Conclusions: Based on these findings, it suggests that dysregulated apoptosis, involving molecules such as p53 and Caspase-3, may contribute to the development of anencephaly. Teratogens like valproic acid and lithium inhibit p53, while impairments in signal transduction pathways caused by teratogens like lithium and okadaic acid inhibit Caspase-3. The presence of increased reactive oxygen species further disrupts neural tube development, leading to DNA and cell damage that is typically controlled by p53-mediated apoptotic pathways. The impaired folding of the neural tube may result from the persistence of damaged neuroepithelial cells that would normally be eliminated during proper neurulation.
- Society for Maternal-Fetal Medicine, Monteagudo A. Exencephaly-anencephaly Sequence. Am J Obstet Gynecol. 2020;223(6):B5-B8. doi:10.1016/j.ajog.2020.08.176
- Munteanu O, Cîrstoiu MM, Filipoiu FM, et al. The etiopathogenic and morphological spectrum of anencephaly: a comprehensive review of literature. Rom J Morphol Embryol. 2020;61(2):335-343. doi:10.47162/RJME.61.2.03
- Li S, Luo D, Yue H, et al. Neural tube defects: role of lithium carbonate exposure in embryonic neural development in a murine model. Pediatr Res. 2021;90(1):82-92. doi:10.1038/s41390-020-01244-1
- Bijok J, Dąbkowska S, Kucińska-Chahwan A, et al. Prenatal diagnosis of acrania/exencephaly/anencephaly sequence (AEAS): additional structural and genetic anomalies. Arch Gynecol Obstet. 2023;307(1):293-299. doi:10.1007/s00404-022-06584-3
- Bonnard C, Navaratnam N, Ghosh K, et al. A loss-of-function NUAK2 mutation in humans causes anencephaly due to impaired Hippo-YAP signaling. J Exp Med. 2020;217(12):e20191561. doi:10.1084/jem.20191561
- Raj N, Bam R. Reciprocal Crosstalk Between YAP1/Hippo Pathway and the p53 Family Proteins: Mechanisms and Outcomes in Cancer. Front Cell Dev Biol. 2019;7:159. Published 2019 Aug 9. doi:10.3389/fcell.2019.00159
- Piorczynski TB, Lapehn S, Ringer KP, et al. NRF2 activation inhibits valproic acid-induced neural tube defects in mice. Neurotoxicol Teratol. 2022;89:107039. doi:10.1016/j.ntt.2021.107039
- Guan Z, Liang Y, Wang X, et al. Unraveling the Mechanisms of Clinical Drugs-Induced Neural Tube Defects Based on Network Pharmacology and Molecular Docking Analysis. Neurochem Res. 2022;47(12):3709-3722. doi:10.1007/s11064-022-03717-7
- Jiao Y, Wang G, Li D, et al. Okadaic Acid Exposure Induced Neural Tube Defects in Chicken (Gallus gallus) Embryos. Mar Drugs. 2021;19(6):322. Published 2021 Jun 2. doi:10.3390/md19060322