Assuntos
Compostos Heterocíclicos com 3 Anéis , Defeitos do Tubo Neural , Oxazinas , Piperazinas , Piridonas , Defeitos do Tubo Neural/induzido quimicamente , Animais , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Camundongos , Piperazinas/efeitos adversos , Inibidores de Integrase de HIV/efeitos adversos , Ácido Fólico , FemininoRESUMO
The implementation of Zinc oxide nanoparticles (ZnO NPs) raises concerns regarding their potential toxic effects on human health. Although more and more researches have confirmed the toxic effects of ZnO NPs, limited attention has been given to their impact on the early embryonic nervous system. This study aimed to explore the impact of exposure to ZnO NPs on early neurogenesis and explore its underlying mechanisms. We conducted experiments here to confirm the hypothesis that exposure to ZnO NPs causes neural tube defects in early embryonic development. We first used mouse and chicken embryos to confirm that ZnO NPs and the Zn2+ they release are able to penetrate the placental barrier, influence fetal growth and result in incomplete neural tube closure. Using SH-SY5Y cells, we determined that ZnO NPs-induced incomplete neural tube closure was caused by activation of various cell death modes, including ferroptosis, apoptosis and autophagy. Moreover, dissolved Zn2+ played a role in triggering widespread cell death. ZnO NPs were accumulated within mitochondria after entering cells, damaging mitochondrial function and resulting in the over production of reactive oxygen species, ultimately inducing cellular oxidative stress. The N-acetylcysteine (NAC) exhibits significant efficacy in mitigating cellular oxidative stress, thereby alleviating the cytotoxicity and neurotoxicity brought about by ZnO NPs. These findings indicated that the exposure of ZnO NPs in early embryonic development can induce cell death through oxidative stress, resulting in a reduced number of cells involved in early neural tube closure and ultimately resulting in incomplete neural tube closure during embryo development. The findings of this study could raise public awareness regarding the potential risks associated with the exposure and use of ZnO NPs in early pregnancy.
Assuntos
Desenvolvimento Embrionário , Defeitos do Tubo Neural , Tubo Neural , Estresse Oxidativo , Espécies Reativas de Oxigênio , Óxido de Zinco , Óxido de Zinco/toxicidade , Animais , Estresse Oxidativo/efeitos dos fármacos , Embrião de Galinha , Desenvolvimento Embrionário/efeitos dos fármacos , Camundongos , Tubo Neural/efeitos dos fármacos , Tubo Neural/embriologia , Tubo Neural/metabolismo , Humanos , Defeitos do Tubo Neural/induzido quimicamente , Defeitos do Tubo Neural/metabolismo , Defeitos do Tubo Neural/embriologia , Defeitos do Tubo Neural/patologia , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Feminino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Nanopartículas Metálicas/toxicidade , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Nanopartículas/toxicidadeRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: jinkui Shenqi Pill (JSP) is a classic traditional Chinese medicine used to treat "Kidney Yang Deficiency" disease. Previous studies indicate a protective effect of JSP on apoptosis in mouse neurons. AIM OF THE STUDY: This research, combining network pharmacology with in vivo experiments, explores the mechanism of JSP in preventing neural tube defects (NTDs) in mice. MATERIALS AND METHODS: Network pharmacology analyzed JSP components and targets, identifying common genes with NTDs and exploring potential pathways. Molecular docking assessed interactions between key JSP components and pathway proteins. In an all-trans retinoic acid (atRA)-induced NTDs mouse model, histopathological changes were observed using HE staining, neuronal apoptosis was detected using TUNEL, and Western Blot assessed changes in the PI3K/AKT signaling pathway and apoptosis-related proteins. RESULTS: Different concentrations of JSP led to varying degrees of reduction in the occurrence of neural tube defects in mouse embryos, with the highest dose showing the most significant decrease. Furthermore, it showed a better reduction in NTDs rates compared to folic acid (FA). Network pharmacology constructed a Drug-Active Ingredient-Gene Target network, suggesting key active ingredients such as Quercetin, Wogonin, Beta-Sitosterol, Kaempferol, and Stigmasterol, possibly acting on the PI3K/Akt signaling pathway. Molecular docking confirmed stable binding structures. Western Blot analysis demonstrated increased expression of p-PI3K, p-Akt, p-Akt1, p-Akt2, p-Akt3, downregulation of cleaved caspase-3 and Bax, and upregulation of Bcl-2, indicating prevention of NTDs through anti-apoptotic effects. CONCLUSION: We have identified an effective dosage of JSP for preventing NTDs, revealing its potential by activating the PI3K/Akt signaling pathway and inhibiting cell apoptosis in atRA-induced mouse embryonic NTDs.
Assuntos
Apoptose , Medicamentos de Ervas Chinesas , Simulação de Acoplamento Molecular , Farmacologia em Rede , Defeitos do Tubo Neural , Animais , Defeitos do Tubo Neural/prevenção & controle , Defeitos do Tubo Neural/induzido quimicamente , Medicamentos de Ervas Chinesas/farmacologia , Camundongos , Apoptose/efeitos dos fármacos , Feminino , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Tretinoína/farmacologia , Modelos Animais de Doenças , GravidezRESUMO
Neural tube defects (NTDs), which are caused by impaired embryonic neural tube closure, are one of the most serious and common birth defects. Peptidyl-prolyl cis/trans isomerase 1 (Pin1) is a prolyl isomerase that uniquely regulates cell signaling by manipulating protein conformation following phosphorylation, although its involvement in neuronal development remains unknown. In this study, we explored the involvement of Pin1 in NTDs and its potential mechanisms both in vitro and in vivo. The levels of Pin1 expression were reduced in NTD models induced by all-trans retinoic acid (Atra). Pin1 plays a significant role in regulating the apoptosis, proliferation, differentiation, and migration of neurons. Moreover, Pin1 knockdown significantly was found to exacerbate oxidative stress (OS) and endoplasmic reticulum stress (ERs) in neuronal cells. Further studies showed that the Notch1-Nrf2 signaling pathway may participate in Pin1 regulation of NTDs, as evidenced by the inhibition and overexpression of the Notch1-Nrf2 pathway. In addition, immunofluorescence (IF), co-immunoprecipitation (Co-IP), and GST pull-down experiments also showed that Pin1 interacts directly with Notch1 and Nrf2. Thus, our study suggested that the knocking down of Pin1 promotes NTD progression by inhibiting the activation of the Notch1-Nrf2 signaling pathway, and it is possible that this effect is achieved by disrupting the interaction of Pin1 with Notch1 and Nrf2, affecting their proteostasis. Our research identified that the regulation of Pin1 by retinoic acid (RA) and its involvement in the development of NTDs through the Notch1-Nrf2 axis could enhance our comprehension of the mechanism behind RA-induced brain abnormalities.
Assuntos
Peptidilprolil Isomerase de Interação com NIMA , Defeitos do Tubo Neural , Tretinoína , Animais , Feminino , Humanos , Camundongos , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Tubo Neural/metabolismo , Tubo Neural/efeitos dos fármacos , Defeitos do Tubo Neural/metabolismo , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/induzido quimicamente , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Peptidilprolil Isomerase de Interação com NIMA/genética , Estresse Oxidativo/efeitos dos fármacos , Receptor Notch1/metabolismo , Receptor Notch1/genética , Transdução de Sinais/efeitos dos fármacos , Tretinoína/metabolismo , Tretinoína/farmacologiaRESUMO
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.
Assuntos
Ácido Fólico , Compostos Heterocíclicos com 3 Anéis , Oxazinas , Piperazinas , Piridonas , Peixe-Zebra , Animais , Compostos Heterocíclicos com 3 Anéis/farmacologia , Ácido Fólico/metabolismo , Oxazinas/farmacologia , Piridonas/farmacologia , Piperazinas/farmacologia , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Defeitos do Tubo Neural/induzido quimicamente , Neurogênese/efeitos dos fármacos , FemininoRESUMO
Neural tube defects (NTDs) represent a prevalent and severe category of congenital anomalies in humans. Cadmium (Cd) is an environmental teratogen known to cause fetal NTDs. However, its underlying mechanisms remain elusive. This study aims to investigate the therapeutic potential of lipophagy in the treatment of NTDs, providing valuable insights for future strategies targeting lipophagy activation as a means to mitigate NTDs.We successfully modeled NTDs by Cd exposure during pregnancy. RNA sequencing was employed to investigate the transcriptomic alterations and functional enrichment of differentially expressed genes in NTD placental tissues. Subsequently, pharmacological/genetic (Atg5-/- placentas) experiments confirmed that inducing placental lipophagy can alleviate Cd induced-NTDs. We found that Cd exposure caused NTDs. Further analyzed transcriptomic data from the placentas with NTDs which revealed significant downregulation of low-density lipoprotein receptor associated protein 1(Lrp1) gene expression responsible for positive regulation of low-density lipoprotein cholesterol (LDL-C) transport. Correspondingly, there was an increase in maternal serum/placenta/amniotic fluid LDL-C content. Subsequently, we have discovered that Cd exposure activated placental lipophagy. Pharmacological/genetic (Atg5-/- placentas) experiments confirmed that inducing placental lipophagy can alleviate Cd induced-NTDs. Furthermore, our findings demonstrate that activation of placental lipophagy effectively counteracts the Cd-induced elevation in LDL-C levels. Lipophagy serves to mitigate Cd-induced NTDs by reducing LDL-C levels within mouse placentas.
Assuntos
Cádmio , LDL-Colesterol , Defeitos do Tubo Neural , Placenta , Feminino , Animais , Gravidez , Placenta/metabolismo , Placenta/efeitos dos fármacos , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/induzido quimicamente , Defeitos do Tubo Neural/metabolismo , Camundongos , Cádmio/toxicidade , LDL-Colesterol/sangue , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Human exposure to chromium (Cr) is common but little is known about its adverse effects on pregnancy outcomes. This study aimed to explore the association between Cr exposure and the risk of neural tube defects (NTDs) and the underlying mechanisms of Cr-induced NTDs. 593 controls and 408 NTD cases with placentas were included in this study. Chromium trichloride (Cr(III)) and potassium dichromate (Cr(VI)) were intragastrically administered to pregnant mice and the number of NTDs was recorded. The odds ratio for total NTDs in the highest exposure group in placenta was 4.18 (95% confidence interval (CI), 1.97-8.84). The incidence of fetal NTDs in mice administered with Cr(III) showed a dose-response relationship. Cr(VI) didn't show teratogenicity of NTDs whereas increased the stillbirth rate. Prenatal exposure to Cr(III) increased levels of oxidative stress and apoptosis in fetal mice. RNA-sequencing results indicated significant enrichment of the MAPK pathway. RT-qPCR and Western blot analysis revealed that Cr(III) induced increased expression of p-JNK, p-P38, and Casp3. Toxicological effects can be partly antagonized by antioxidant supplementation. High chromium exposure was associated with increased human NTD risks. Excessive Cr(III) exposure can induce NTDs in fetal mice by increasing apoptosis through upgrading oxidative stress and then activating JNK/P38 MAPK signaling pathway.
Assuntos
Cromo , Defeitos do Tubo Neural , Placenta , Feminino , Defeitos do Tubo Neural/induzido quimicamente , Animais , Gravidez , Cromo/toxicidade , Camundongos , Placenta/metabolismo , Placenta/efeitos dos fármacos , Humanos , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Exposição MaternaRESUMO
BACKGROUND: As emerging environmental contaminants, antibiotics pose potential threats to human health, in particular to pregnant women and infants. However, the potential harm of inadvertent antibiotic exposure (IAE) is often disregarded in light of the focus on intentional antibiotic use during pregnancy. Currently, little is known about the effects of IAE during pregnancy on fetal neural tube development. METHODS: In this case-control study, we used questionnaire data from 855 subjects to investigate the effects of intentional antibiotic use in early pregnancy on neural tube defects (NTDs). Then we tested for placental antibiotics in mothers who had not intentionally used antibiotics, and the compounds were detected in 379 subjects; these were considered IAE cases. We assessed the association between IAE during pregnancy and fetal NTDs using both multivariable logistic and multi-pollutant exposure models. We also analyzed the correlation between maternal dietary habits and placental antibiotics to explore possible sources of IAE. RESULTS: Only 50 of 855 participants (5.8%) intentionally used antibiotics and such use showed no significant association with NTD risk (odds ratio [OR] = 1.92, confidence interval [95%CI] = [0.66, 5.59]). However, 14 of 15 placental antibiotics were detected in 378 of 379 subjects (99.7%) and multivariable logistic analysis indicated that high levels of placental macrolides were significantly associated with increased NTD risk (4.42 [2.01-10.45]). Multi-pollutant exposure analysis suggested an increase in NTD risk with an increase in exposure to a mixture of placental antibiotics, among which macrolides were the most important contributor. In addition, the level of placental macrolides was positively correlated with the intake frequency of milk. Finally, mothers who drank river, well, or pond water had higher levels of placental macrolides than those who drank only tap water. CONCLUSIONS: Intentional antibiotic use during early pregnancy may not be associated with NTDs, while IAE during pregnancy is associated with higher NTD risk in offspring. Macrolides are crucial risk factors. Milk, and river, well, or pond water may be important sources of IAE.
Assuntos
Poluentes Ambientais , Defeitos do Tubo Neural , Lactente , Humanos , Feminino , Gravidez , Estudos de Casos e Controles , Antibacterianos/efeitos adversos , Placenta , Defeitos do Tubo Neural/induzido quimicamente , Defeitos do Tubo Neural/epidemiologia , Fatores de Risco , Macrolídeos/efeitos adversos , ÁguaRESUMO
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.
Assuntos
Multiômica , Defeitos do Tubo Neural , Gravidez , Feminino , Animais , Camundongos , Doenças Neuroinflamatórias , Estudos Prospectivos , Defeitos do Tubo Neural/diagnóstico , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/induzido quimicamente , Sistema Nervoso Central/patologiaRESUMO
Arsenic exposure is a significant risk factor for folate-resistant neural tube defects (NTDs), but the potential mechanism is unclear. In this study, a mouse model of arsenic-induced NTDs was established to investigate how arsenic affects early neurogenesis leading to malformations. The results showed that in utero exposure to arsenic caused a decline in the normal embryos, an elevated embryo resorption, and a higher incidence of malformed embryos. Cranial and spinal deformities were the main malformation phenotypes observed. Meanwhile, arsenic-induced NTDs were accompanied by an oxidant/antioxidant imbalance manifested by elevated levels of reactive oxygen species (ROS) and decreased antioxidant activities. In addition, changes in the expression of autophagy-related genes and proteins (ULK1, Atg5, LC3B, p62) as well as an increase in autophagosomes were observed in arsenic-induced aberrant brain vesicles. Also, the components of the upstream pathway regulating autophagy (AMPK, PKB, mTOR, Raptor) were altered accordingly after arsenic exposure. Collectively, our findings propose a mechanism for arsenic-induced NTDs involving AMPK/PKB-mTORC1-mediated autophagy. Blocking autophagic cell death due to excessive autophagy provides a novel strategy for the prevention of folate-resistant NTDs, especially for arsenic-exposed populations.
Assuntos
Arsênio , Defeitos do Tubo Neural , Camundongos , Animais , Arsênio/toxicidade , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Antioxidantes , Tubo Neural/metabolismo , Autofagia/fisiologia , Ácido Fólico/efeitos adversos , Defeitos do Tubo Neural/induzido quimicamenteRESUMO
Primary cilia are crucial for neurogenesis, and cilium-related genes are involved in the closure of neural tubes. Inositol polyphosphate-5-phosphatase (Inpp5e) was enriched in primary cilia and closely related to the occurrence of neural tube defects (NTDs). However, the role of Inpp5e in the development of NTDs is not well-known. To investigate whether Inpp5e gene is associated with the neural tube closure, we established a mouse model of NTDs by 5-fluorouracil (5-FU) exposure at gestational day 7.5 (GD7.5). The Inpp5e knockdown (Inpp5e-/-) mouse embryonic stem cells (mESCs) were produced by CRISPR/Cas9 system. The expressions of Inpp5e and other cilium-related genes including intraflagellar transport 80 (Ift80), McKusick-Kaufman syndrome (Mkks), and Kirsten rat sarcoma viral oncogene homolog (Kras) were determined, utilizing quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), western blot, PCR array, and immunofluorescence staining. The result showed that the incidence of NTDs was 37.10% (23 NTDs/62 total embryos) and significantly higher than that in the control group (P < 0.001). The neuroepithelial cells of neural tubes were obviously disarranged in NTD embryos. The mRNA and protein levels of Inpp5e, Ift80, Mkks, and Kras were significantly decreased in NTD embryonic brain tissues, compared to the control (P < 0.05). Knockdown of the Inpp5e (Inpp5e-/-) reduced the expressions of Ift80, Mkks, and Kras in mESCs. Furthermore, the levels of α-tubulin were significantly reduced in NTD embryonic neural tissue and Inpp5e-/- mESCs. These results suggested that maternal 5-FU exposure inhibited the expression of Inpp5e, which resulted in the downregulation of cilium-related genes (Ift80, Mkks, and Kras), leading to the impairment of primary cilium development, and ultimately disrupted the neural tube closure.
Assuntos
Cílios , Fluoruracila , Defeitos do Tubo Neural , Animais , Fluoruracila/farmacologia , Fluoruracila/toxicidade , Cílios/metabolismo , Cílios/efeitos dos fármacos , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/induzido quimicamente , Feminino , Camundongos , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Gravidez , Células-Tronco Embrionárias Murinas/metabolismo , Células-Tronco Embrionárias Murinas/efeitos dos fármacosRESUMO
OBJECTIVES: In 2018, the Botswana Tsepamo Study reported a nine-fold increased risk of neural tube defects in infants whose mothers were treated with dolutegravir (DTG) from the time of conception. As maternal folate supplementation and status is a well known modifier of neural tube defect (NTD) risk, we sought to evaluate birth outcomes in mice fed normal and low folic acid diets treated with DTG during pregnancy. DESIGN: DTG was evaluated for developmental toxicity using pregnant mice fed normal or low folic acid diet. METHODS: CD-1 mice were provided diet with normal (3âmg/kg) or low (0.3âmg/kg) folic acid. They were treated with water, a human therapeutic-equivalent dose, or supratherapeutic dose of DTG from mouse embryonic day E6.5 to E12.5. Pregnant dams were sacrificed at term (E18.5) and fetuses were inspected for gross, internal, and skeletal defects. RESULTS: Fetuses with exencephaly, an NTD, were present in both therapeutic human equivalent and supratherapeutic exposures in dams fed low folic acid diet. Cleft palates were also found under both folate conditions. CONCLUSIONS: Recommended dietary folic acid levels during mouse pregnancy ameliorate developmental defects that arise from DTG exposure. Since low folate status in mice exposed to DTG increases the risk for NTDs, it is possible that DTG exposures in people living with HIV with low folate status during pregnancy may explain, at least in part, the elevated NTD risk signal observed in Botswana. Based on these results, future studies should consider folate status as a modifier for DTG-associated NTD risk.
Assuntos
Infecções por HIV , Defeitos do Tubo Neural , Oxazinas , Piperazinas , Piridonas , Humanos , Gravidez , Feminino , Animais , Camundongos , Ácido Fólico/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/complicações , Defeitos do Tubo Neural/induzido quimicamente , Defeitos do Tubo Neural/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/efeitos adversosRESUMO
Sugammadex is a new generation drug that has led to significant changes in the practice of anesthesia. However, its effects on fetal development are not yet fully known. The aim of this study is to investigate the teratogenic effects of sugammadex on neural tube and embryonic development in early chick embryos. In this study, 50 0-day fertile specific non-pathogenic (SPF) eggs were used. Fifty eggs were divided into 5 different groups, each consisting of 10 pieces. While no substance was given to the control group at the 28th hour of the study, 4 different doses of sugammadex were administered to the experimental groups, respectively 2, 4, 8, 16 mg/kg. Cranio-caudal lengths of embryos, somite numbers, average number of argyrophilic nucleolar regulatory regions (AgNOR) per nucleus, total AgNOR area/total nuclear area (TAA/NA) ratios, Caspase-3 H-Score results, and presence of neural tube defect were compared among the groups. While the mean cranio-caudal lengths, somite counts, TAA/NA ratios and AgNOR counts of the embryos were found to be statistically significantly lower than the control group, Caspase-3 H-Score mean results were found to be significantly higher (p < .05). In addition, it was observed that there was an increase in neural tube patency and developmental delay. As a result, sugammadex crossing the placenta was revealed to increase the release of proapopitotic molecules and disrupt the developmental stages of embryos. Thus, it was determined that sugammadex in increased developmental delay and incidence of neural tube defects in early chick embryos with increased dose dependent. Despite these results, the effects of sugammadex on fetal development in in vivo and in vitro environments should be studied with further studies. RESEARCH HIGHLIGHTS: Sugammadex is a new generation drug that has led to significant changes in the practice of anesthesia. However, its effects on fetal development are not yet fully known. It has been observed that different doses of sugammadex increase the risk of neural tube defect development on chick embryos and slow the embryo development in a dose-dependent manner.
Assuntos
Defeitos do Tubo Neural , Tubo Neural , Animais , Embrião de Galinha , Tubo Neural/patologia , Caspase 3 , Sugammadex/farmacologia , Defeitos do Tubo Neural/induzido quimicamente , Defeitos do Tubo Neural/patologia , Desenvolvimento EmbrionárioRESUMO
Neural tube defects (NTDs) represent a developmental disorder of the nervous system that can lead to significant disability in children and impose substantial social burdens. Valproic acid (VPA), a widely prescribed first-line antiepileptic drug for epilepsy and various neurological conditions, has been associated with a 4-fold increase in the risk of NTDs when used during pregnancy. Consequently, urgent efforts are required to identify innovative prevention and treatment approaches for VPA-induced NTDs. Studies have demonstrated that the disruption in the delicate balance between cell proliferation and apoptosis is a crucial factor contributing to NTDs induced by VPA. Encouragingly, our current data reveal that melatonin (MT) significantly inhibits apoptosis while promoting the restoration of neuroepithelial cell proliferation impaired by VPA. Moreover, further investigations demonstrate that MT substantially reduces the incidence of neural tube malformations resulted from VPA exposure, primarily by suppressing apoptosis through the modulation of intracellular reactive oxygen species levels. In addition, the Src/PI3K/ERK signaling pathway appears to play a pivotal role in VPA-induced NTDs, with significant inhibition observed in the affected samples. Notably, MT treatment successfully reinstates Src/PI3K/ERK signaling, thereby offering a potential underlying mechanism for the protective effects of MT against VPA-induced NTDs. In summary, our current study substantiates the considerable protective potential of MT in mitigating VPA-triggered NTDs, thereby offering valuable strategies for the clinical management of VPA-related birth defects.
Assuntos
Melatonina , Defeitos do Tubo Neural , Gravidez , Feminino , Criança , Humanos , Ácido Valproico , Melatonina/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Defeitos do Tubo Neural/induzido quimicamente , Defeitos do Tubo Neural/prevenção & controle , Estresse Oxidativo , Transdução de SinaisRESUMO
Birth defects have become a public health concern. The hazardous environmental factors exposure to embryos could increase the risk of birth defects. Cadmium, a toxic environmental factor, can cross the placental barrier during pregnancy. Pregnant woman may be subjected to cadmium before taking precautionary protective actions. However, the link between birth defects and cadmium remains obscure. Cadmium exposure can induce excessive apoptosis in neuroepithelium during embryonic development progresses. Cadmium exposure activated the p53 via enhancing the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and reactive oxygen species' (ROS) level. And cadmium decreases the level of Paired box 3 (Pax3) and murine double minute 2 (Mdm2), disrupting the process of p53 ubiquitylation. And p53 accumulation induced excessive apoptosis in neuroepithelium during embryonic development progresses. Excessive apoptosis led to the failure of neural tube closure. The study emphasizes that environmental materials may increase the health risk for embryos. Cadmium caused the failure of neural tube closure during early embryotic day. Pregnant women may be exposed by cadmium before taking precautionary protective actions, because of cadmium concentration-containing foods and environmental tobacco smoking. This suggests that prenatal cadmium exposure is a threatening risk factor for birth defects.
Assuntos
Defeitos do Tubo Neural , Feminino , Gravidez , Humanos , Animais , Camundongos , Defeitos do Tubo Neural/induzido quimicamente , Defeitos do Tubo Neural/metabolismo , Cádmio/toxicidade , Cádmio/metabolismo , Tubo Neural/metabolismo , Fator de Transcrição PAX3/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Placenta/metabolismo , ApoptoseRESUMO
Exposure to pesticides during pregnancy has been associated with several serious congenital malformations, such as neural tube defects, therefore, is a cause for concern in terms of human health. This review aims to gather information related to maternal exposure during pregnancy and the risk of triggering neural tube defects in the offspring. The search strategy for the studies followed the PRISMA guidelines. We conducted a systematic search in the Science Direct, PubMed, Cochrane Library, Embase, Scopus, and Web of Science databases for all epidemiological studies that sought to associate exposure to pesticides during embryonic development with the risk of neural tube defects (NTDs). The keywords used were "pesticide", "herbicide", "congenital" and "neural". Of the 229 articles, 8 eligible ones (7 case-control and 1 cross-sectional) evaluated pesticide exposure in pregnancy. Different methods were used, including analysis of biological samples and questionnaires. The pesticides studied included insecticides, herbicides, fungicides, and nematicides. Insecticides were the most studied, with variations in concentrations between tissues and studies. Distinct levels of pesticides have been detected in maternal serum, placenta, and umbilical cord. Models were statistically adjusted for confounding factors, such as smoking and dietary supplement intakes. Concentrations were measured in different exposure windows (periconception and prenatal), related to NTDs such as anencephaly and spina bifida. Different data collection techniques, types of biological samples, and exposure windows were used, which made comparison difficult. The main pesticides studied included DDT, DDE, HCH, and endosulfan. Maternal serum showed the highest concentrations of pesticides, but detection in placental tissue and umbilical cord confirms embryonic exposure. Confounding variables were adjusted for in the analysis of the articles, but they may still contribute to the risk of NTDs. All the studies analyzed pesticide exposure and the relationship with NTDs. However, a more standardized survey would be ideal for better comparisons.
Assuntos
Herbicidas , Inseticidas , Defeitos do Tubo Neural , Praguicidas , Feminino , Humanos , Gravidez , Praguicidas/toxicidade , Praguicidas/análise , Estudos Transversais , Placenta/química , Defeitos do Tubo Neural/induzido quimicamente , Defeitos do Tubo Neural/epidemiologia , Fatores de RiscoRESUMO
Neural tube defects are severe congenital disorders of the central nervous system that originate during embryonic development when the neural tube fails to close completely. It affects one to two infants per 1000 births. The aetiology is multifactorial with contributions from both genetic and environmental factors. Dysregulated epigenetic mechanisms, in particular the abnormal genome-wide methylation during embryogenesis, have been linked to developmental abnormalities including neural tube defects. The current study investigated the influence of decitabine (DCT), a DNA methylation inhibitor, on embryonic development in zebrafish, with a focus on neural tube formation. The developing zebrafish embryos were exposed to graded concentrations of decitabine (from 13.69 µM to 1 mM) before the onset of neurulation. The developmental process was monitored at regular time intervals post fertilization. At 120 h post fertilization, the developing embryos were inspected individually to determine the incidence and severity of neural tube defects. Using alizarin red staining, the cranial and caudal neural tube morphology was examined in formaldehyde fixed larvae. Anomalies in neural tube and somite development, as well as a delay in hatching, were discovered at an early stage of development. As development continued, neural tube defects became increasingly evident, and there was a concentration-dependent rise in the prevalence and severity of various neural tube defects. 90% of growing embryos in the group exposed to decitabine 1 mM had multiple neural tube malformations, and 10% had isolated neural tube defects. With several abnormalities, the caudal region of the neural tube was seriously compromised. The histopathological studies supported the malformations in neural tube. Our study revealed the harmful impact of decitabine on the development of the neural tube in growing zebrafish. Moreover, these findings support the hypothesis that the hypomethylation during embryonic development causes neural tube defects.
Assuntos
Defeitos do Tubo Neural , Peixe-Zebra , Humanos , Gravidez , Feminino , Animais , Decitabina/toxicidade , Defeitos do Tubo Neural/induzido quimicamente , Sistema Nervoso Central , Metilação de DNA , Tubo NeuralRESUMO
BACKGROUND: Sugammadex is a modified gamma-cyclodextrin that has been developed with the goal of reversing the steroidal neuromuscular blocking agents. The aim of the present study is to investigate the effects of different sugammadex doses on embryologic and neural tube development in an early-stage chick embryo model. METHODS: A total of 100 specific pathogen-free, fertilized domestic chicken eggs were randomly divided into five groups (n = 20, each), and placed in an automatic cycle incubator. The eggs in the "control (C)" group were incubated without administration of any drug till the end of the experiment. Sub-blastodermic administration of 0.9% NaCl as vehicle control (VC) and different doses of sugammadex solutions prepared with the latter [2 mg/mL (LD), 4 mg/mL (MD), 16 mg/mL (HD)] were performed at 30 hr of incubation. All embryos were removed from the eggs at 72 hr when they were expected to reach Hamburger-Hamilton (HH) stages 19-20, then they were fixed, and evaluated histo-morphologically. RESULTS: Embryonic development was not observed in 11 eggs (1 in C, 1 in VC; 3 in LD, 3 in MD, and 3 in HD). All the developed embryos were compatible with the HH stages 19-20. A neural tube closure defect was detected in one embryo in the HD group. No statistically significant difference was found between the groups in terms of embryonic and neural tube developments. CONCLUSIONS: No significant association was found between the drug and adverse outcomes; however, a trend with dosing was seen. Further studies are required before conclude on safety and extrapolate these results to human beings.
Assuntos
Defeitos do Tubo Neural , Tubo Neural , Sugammadex , Animais , Embrião de Galinha , Galinhas , Desenvolvimento Embrionário/efeitos dos fármacos , Tubo Neural/crescimento & desenvolvimento , Defeitos do Tubo Neural/induzido quimicamente , Sugammadex/efeitos adversosRESUMO
BACKGROUND: Neural tube defects (NTDs) affect >300,000 pregnancies worldwide annually. Few nongenetic factors, other than folate deficiency, have been identified that may provide intervenable solutions to reduce the burden of NTDs. Prenatal exposure to toxic metals [arsenic (As), cadmium (Cd), mercury (Hg), manganese (Mn) and lead (Pb)] may increase the risk of NTDs. Although a growing epidemiologic literature has examined associations, to our knowledge no systematic review has been conducted to date. OBJECTIVE: Through adaptation of the Navigation Guide systematic review methodology, we aimed to answer the question "does exposure to As, Cd, Hg, Mn, or Pb during gestation increase the risk of NTDs?" and to assess challenges to evaluating this question given the current evidence. METHODS: We selected available evidence on prenatal As, Cd, Hg, Mn, or Pb exposure and risk of specific NTDs (e.g., spina bifida, anencephaly) or all NTDs via a comprehensive search across MEDLINE, Embase, Web of Science, and TOXLINE databases and applied inclusion/exclusion criteria. We rated the quality and strength of the evidence for each metal. We applied a customized risk of bias protocol and evaluated the sufficiency of evidence of an effect of each metal on NTDs. RESULTS: We identified 30 studies that met our criteria. Risk of bias for confounding and selection was high in most studies, but low for missing data. We determined that, although the evidence was limited, the literature supported an association between prenatal exposure to Hg or Mn and increased risk of NTDs. For the remaining metals, the evidence was inadequate to establish or rule out an effect. CONCLUSION: The role of gestational As, Cd, or Pb exposure in the etiology of NTDs remains unclear and warrants further investigation in high-quality studies, with a particular focus on controlling confounding, mitigating selection bias, and improving exposure assessment. https://doi.org/10.1289/EHP11872.
Assuntos
Arsênio , Mercúrio , Defeitos do Tubo Neural , Efeitos Tardios da Exposição Pré-Natal , Feminino , Gravidez , Humanos , Cádmio , Chumbo/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Defeitos do Tubo Neural/induzido quimicamente , Defeitos do Tubo Neural/epidemiologia , ManganêsRESUMO
Bisphenol A (BPA) and its analogs such as bisphenol Z (BPZ) are widely used in the production of consumer products, but few studies have investigated the associations among BPA, its analogs, and chlorinated derivatives (collectively, BPs) and risk for NTDs. This study investigated the associations between concentrations of BPs in the placenta and risk for NTDs. This was a case-control study including 122 NTDs and 164 controls. BPs in the placenta were determined using liquid chromatography-tandem mass spectrometry. The associations between BPs and NTD risk were evaluated using conventional logistic regression and weighted quantile sum regression (WQS) models. In the logistic regression, exposure to higher levels of BPA and BPZ was associated with increased NTD risk (odds ratio [OR] = 3.17, 95 % confidence interval [CI], 1.22-8.22; OR = 3.11, 95 % CI, 1.20-8.09, respectively). Meanwhile, a significant dose-response relationship was found between BPA and BPZ concentrations and NTD risk. In the WQS model, a quartile increase in WQS index resulted in 4.34 (95 % CI: 1.69, 11.20) higher odds for NTDs, and BPA and BPZ accounted for most of the weight index in the joint effects of BPs. In conclusion, high levels of BPs in the placenta are associated with increased risk for NTDs, of which BPA and BPZ are important risk factors.