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1.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360880

RESUMO

To prevent congenital defects arising from maternal exposure, safety regulations require pre-market developmental toxicity screens for industrial chemicals and pharmaceuticals. Traditional embryotoxicity approaches depend heavily on the use of low-throughput animal models which may not adequately predict human risk. The validated embryonic stem cell test (EST) developed in murine embryonic stem cells addressed the former problem over 15 years ago. Here, we present a proof-of-concept study to address the latter challenge by updating all three endpoints of the classic mouse EST with endpoints derived from human induced pluripotent stem cells (hiPSCs) and human fibroblasts. Exposure of hiPSCs to selected test chemicals inhibited differentiation at lower concentrations than observed in the mouse EST. The hiPSC-EST also discerned adverse developmental outcomes driven by novel environmental toxicants. Evaluation of the early cardiac gene TBX5 yielded similar toxicity patterns as the full-length hiPSC-EST. Together, these findings support the further development of hiPSCs and early molecular endpoints as a biologically relevant embryotoxicity screening approach for individual chemicals and mixtures.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Fluoruracila/toxicidade , Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/citologia , Penicilina G/farmacologia , Teratógenos/farmacologia , Testes de Toxicidade/métodos , Tretinoína/toxicidade , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Anormalidades Congênitas/prevenção & controle , Desenvolvimento Embrionário/efeitos dos fármacos , Fibroblastos/citologia , Humanos , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Miócitos Cardíacos/efeitos dos fármacos , Proteínas com Domínio T
2.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298908

RESUMO

Elevated molecular stress in women is known to have negative impacts on the reproductive development of oocytes and the embryos prior to implantation. In recent years, the prevalence of cannabis use among women of reproductive age has risen due to its ability to relieve psychological stress and nausea, which are mediated by its psychoactive component, ∆-9-tetrahydrocannabinol (THC). Although cannabis is the most popular recreational drug of the 21st century, much is unknown about its influence on molecular stress in reproductive tissues. The current literature has demonstrated that THC causes dose- and time-dependent alterations in glucocorticoid signaling, which have the potential to compromise morphology, development, and quality of oocytes and embryos. However, there are inconsistencies across studies regarding the mechanisms for THC-dependent changes in stress hormones and how either compounds may drive or arrest development. Factors such as variability between animal models, physiologically relevant doses, and undiscovered downstream gene targets of both glucocorticoids and THC could account for such inconsistencies. This review evaluates the results of studies which have investigated the effects of glucocorticoids on reproductive development and how THC may alter stress signaling in relevant tissues.


Assuntos
Dronabinol/farmacocinética , Desenvolvimento Embrionário/efeitos dos fármacos , Glucocorticoides/metabolismo , Animais , Cannabis/química , Humanos , Náusea/tratamento farmacológico , Náusea/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo
3.
Chem Biol Interact ; 346: 109578, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34265256

RESUMO

Current organophosphate (OP) toxicity research now considers potential non-cholinergic mechanisms for these compounds, since the inhibition of acetylcholinesterase (AChE) cannot completely explain all the adverse biological effects of OP. Thanks to the development of new strategies for OP detection, some potential molecular targets have been identified. Among these molecules are several cytoskeletal proteins, including actin, tubulin, intermediate filament proteins, and associated proteins, such as motor proteins, microtubule-associated proteins (MAPs), and cofilin. in vitro, ex vivo, and some in vivo reports have identified alterations in the cytoskeleton following OP exposure, including cell morphology defects, cells detachments, intracellular transport disruption, aberrant mitotic spindle formation, modification of cell motility, and reduced phagocytic capability, which implicate the cytoskeleton in OP toxicity. Here, we reviewed the evidence indicating the cytoskeletal targets of OP compounds, including their strategies, the potential effects of their alterations, and their possible participation in neurotoxicity, embryonic development, cell division, and immunotoxicity related to OP compounds exposure.


Assuntos
Citoesqueleto/metabolismo , Compostos Organofosforados/metabolismo , Actinas/metabolismo , Animais , Carcinogênese , Divisão Celular/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Compostos Organofosforados/química , Compostos Organofosforados/toxicidade , Tubulina (Proteína)/metabolismo
4.
Toxicology ; 458: 152844, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34214637

RESUMO

Aflatoxin B1 (AFB1), a naturally occurring mycotoxin, is present in human placenta and cord blood. AFB1 at concentrations found in contaminated food commodities (0.25 and 0.5 µM) did not alter the spontaneous movement, heart rate, hatchability, or morphology of embryonic zebrafish. However, around 86 % of 0.25 µM AFB1-treated embryos had livers of reduced size, and AFB1 disrupted the hepatocyte structures, according to histological analysis. Additionally, AFB1 treatment that begins at any stage before 72 h post-fertilization (hpf) effectively reduced the size of embryonic livers. In hepatic areas, AFB1 suppressed the expression of Hhex and Prox1, which are two critical transcriptional factors for initiating hepatoblast specification. KEGG analysis based on transcriptome profiling indicated that p53 signaling and apoptosis are the only observed pathways in AFB1-treated embryos. AFB1 at 0.5 µM significantly activated the expression of tp53, mdm2, puma, noxa, pidd1, and gadd45aa genes that are related to the p53 pathway and also that of baxa, casp 8 and casp 3a in the apoptotic process. TUNEL staining demonstrated that AFB1 triggered the apoptosis of embryonic hepatocytes in a dose-dependent manner. These results indicate that the deficiency of both hhex and prox1 as well as hepatocyte apoptosis via the p53-Puma/Noxa-Bax axis may contribute to the embryonic liver shrinkage that is caused by AFB1.


Assuntos
Aflatoxina B1/toxicidade , Apoptose/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/embriologia , Transdução de Sinais/efeitos dos fármacos , Teratógenos/toxicidade , Proteína Supressora de Tumor p53/efeitos dos fármacos , Peixe-Zebra/fisiologia , Animais , Proteínas Reguladoras de Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Fígado/patologia , MicroRNAs/biossíntese , MicroRNAs/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética
5.
Int J Mol Sci ; 22(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299380

RESUMO

Artificial activation of oocytes is an important step for successful parthenogenesis and somatic cell nuclear transfer (SCNT). Here, we investigated the initiation of DNA synthesis and in vivo development of canine PA embryos and cloned embryos produced by treatment with 1.9 mM 6-dimethylaminopurine (6-DMAP) for different lengths of time. For experiments, oocytes for parthenogenesis and SCNT oocytes were cultured for 4 min in 10 µM calcium ionophore, and then divided into 2 groups: (1) culture for 2 h in 6-DMAP (DMAP-2h group); (2) culture for 4 h in DMAP (DMAP-4h group). DNA synthesis was clearly detected in all parthenogenetic (PA) embryos and cloned embryos incorporated BrdU 4 h after activation in DMAP-2h and DMAP-4h groups. In vivo development of canine parthenogenetic fetuses was observed after embryo transfer and the implantation rates of PA embryos in DMAP-2h were 34%, which was significantly higher than those in DMAP-4h (6.5%, p < 0.05). However, in SCNT, there was no significant difference in pregnancy rate (DMAP-2h: 41.6% vs. DMAP-4h: 33.3%) and implantation rates (DMAP-2h: 4.94% vs. DMAP-4h: 3.19%) between DMAP-2h and DMAP-4h. In conclusion, the use of DMAP-2h for canine oocyte activation may be ideal for the in vivo development of PA zygotes, but it was not more effective in in vivo development of canine reconstructed SCNT oocytes. The present study demonstrated that DMAP-2h treatment on activation of canine parthenogenesis and SCNT could effectively induce the onset of DNA synthesis during the first cell cycle.


Assuntos
Adenina/análogos & derivados , Replicação do DNA/efeitos dos fármacos , DNA/efeitos dos fármacos , Embrião de Mamíferos/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Adenina/farmacologia , Animais , Clonagem de Organismos/métodos , Cães , Transferência Embrionária/métodos , Feminino , Técnicas de Transferência Nuclear , Oócitos/efeitos dos fármacos , Partenogênese/efeitos dos fármacos , Gravidez
6.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072880

RESUMO

The segregation of trophectoderm (TE) and inner cell mass in early embryos is driven primarily by the transcription factor CDX2. The signals that trigger CDX2 activation are, however, less clear. In mouse embryos, the Hippo-YAP signaling pathway is important for the activation of CDX2 expression; it is less clear whether this relationship is conserved in other mammals. Lysophosphatidic acid (LPA) has been reported to increase YAP levels by inhibiting its degradation. In this study, we cultured bovine embryos in the presence of LPA and examined changes in gene and protein expression. LPA was found to accelerate the onset of blastocyst formation on days 5 and 6, without changing the TE/inner cell mass ratio. We further observed that the expression of TAZ and TEAD4 was up-regulated, and YAP was overexpressed, in LPA-treated day 6 embryos. However, LPA-induced up-regulation of CDX2 expression was only evident in day 8 embryos. Overall, our data suggest that the Hippo signaling pathway is involved in the initiation of bovine blastocyst formation, but does not affect the cell lineage constitution of blastocysts.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Blastocisto/efeitos dos fármacos , Fator de Transcrição CDX2/genética , Lisofosfolipídeos/farmacologia , Proteínas Serina-Treonina Quinases/genética , Aciltransferases/genética , Animais , Massa Celular Interna do Blastocisto/efeitos dos fármacos , Bovinos , Linhagem da Célula/genética , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Camundongos , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/genética , Trofoblastos/efeitos dos fármacos
7.
Int J Mol Sci ; 22(9)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063734

RESUMO

In this study, we report the effects of caffeine on angiogenesis in zebrafish embryos both during normal development and after exposure to Fibroblast Growth Factor 2 (FGF2). As markers of angiogenesis, we measured the length and width of intersegmental vessels (ISVs), performed whole-mount in situ hybridization with fli1 and cadh5 vascular markers, and counted the number of interconnecting vessels (ICVs) in sub-intestinal venous plexus (SIVP). In addition, we measured angiogenesis after performing zebrafish yolk membrane (ZFYM) assay with microinjection of fibroblast growth factor 2 (FGF2) and perivitelline tumor xenograft assay with microinjection of tumorigenic FGF2-overexpressing endothelial (FGF2-T-MAE) cells. The results showed that caffeine treatment causes a shortening and thinning of ISVs along with a decreased expression of the vascular marker genes and a decrease in the number of ICVs in the SIVP. Caffeine was also able to block angiogenesis induced by exogenous FGF2 or FGF2-producing cells. Overall, our results are suggestive of the inhibitory effect of caffeine in both direct and indirect angiogenesis.


Assuntos
Cafeína/farmacologia , Fator 2 de Crescimento de Fibroblastos/genética , Neovascularização Patológica/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Embrião não Mamífero , Desenvolvimento Embrionário/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Xenoenxertos , Humanos , Hibridização In Situ , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Neovascularização Fisiológica/genética , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
8.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070944

RESUMO

Embryogenesis is a complex multi-stage process regulated by various signaling molecules including pineal and extrapineal melatonin (MT). Extrapineal MT is found in the placenta and ovaries, where it carries out local hormonal regulation. MT is necessary for normal development of oocytes, fertilization and subsequent development of human, animal and avian embryos. This review discusses the role of MT as a regulator of preimplantation development of the embryo and its implantation into endometrial tissue, followed by histo-, morpho- and organogenesis. MT possesses pronounced antioxidant properties and helps to protect the embryo from oxidative stress by regulating the expression of the NFE2L2, SOD1, and GPX1 genes. MT activates the expression of the ErbB1, ErbB4, GJA1, POU5F1, and Nanog genes which are necessary for embryo implantation and blastocyst growth. MT induces the expression of vascular endothelial growth factor (VEGF) and its type 1 receptor (VEGF-R1) in the ovaries, activating angiogenesis. Given the increased difficulties in successful fertilization and embryogenesis with age, it is of note that MT slows down ovarian aging by increasing the transcription of sirtuins. MT administration to patients suffering from infertility demonstrates an increase in the effectiveness of in vitro fertilization. Thus, MT may be viewed as a key factor in embryogenesis regulation, including having utility in the management of infertility.


Assuntos
Implantação do Embrião/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Melatonina/uso terapêutico , Ovário/metabolismo , Placenta/metabolismo , Animais , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Feminino , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Humanos , Infertilidade Feminina/genética , Infertilidade Feminina/metabolismo , Infertilidade Feminina/patologia , Infertilidade Feminina/prevenção & controle , Melatonina/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ovário/crescimento & desenvolvimento , Glândula Pineal/crescimento & desenvolvimento , Glândula Pineal/metabolismo , Gravidez , Receptor ErbB-4/genética , Receptor ErbB-4/metabolismo , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
Cell Prolif ; 54(7): e13059, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34021643

RESUMO

OBJECTIVES: The genetic instability and DNA damage arise during transcription factor-mediated reprogramming of somatic cells, and its efficiency may be reduced due to abnormal chromatin remodelling. The efficiency in somatic cell nuclear transfer (SCNT)-mediated reprogramming is also very low, and it is caused by development arrest of most reconstituted embryos. MATERIALS AND METHODS: Whether the repair of genetic instability or double-strand breaks (DSBs) during SCNT reprogramming may play an important role in embryonic development, we observed and analysed the effect of Rad 51, a key modulator of DNA damage response (DDR) in SCNT-derived embryos. RESULTS: Here, we observed that the activity of Rad 51 is lower in SCNT eggs than in conventional IVF and found a significantly lower level of DSBs in SCNT embryos during reprogramming. To address this difference, supplementation with RS-1, an activator of Rad51, during the activation of SCNT embryos can increase RAD51 expression and DSB foci and thereby increased the efficiency of SCNT reprogramming. Through subsequent single-cell RNA-seq analysis, we observed the reactivation of a large number of genes that were not expressed in SCNT-2-cell embryos by the upregulation of DDR, which may be related to overcoming the developmental block. Additionally, there may be an independent pathway involving histone demethylase that can reduce reprograming-resistance regions. CONCLUSIONS: This technology can contribute to the production of comparable cell sources for regenerative medicine.


Assuntos
Benzamidas/farmacologia , Reprogramação Celular , Desenvolvimento Embrionário/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Reparo do DNA/efeitos dos fármacos , Embrião de Mamíferos/citologia , Embrião de Mamíferos/efeitos dos fármacos , Embrião de Mamíferos/metabolismo , Feminino , Instabilidade Genômica , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Técnicas de Transferência Nuclear , Rad51 Recombinase/metabolismo , Regulação para Cima/efeitos dos fármacos
10.
Turk Neurosurg ; 31(4): 594-600, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33978217

RESUMO

AIM: To investigate the effects of pregabalin on neural tube closure, and other potential effects on other organ systems in a chick embryo model. MATERIAL AND METHODS: Fertilized chicken eggs were divided into groups, and different doses of pregabalin was administered. All embryos were harvested in the 8th day of incubation, and investigated both macroscopically and microscopically against any developmental malformations caused by Pregabalin. RESULTS: Macroscopically not any malformations were detected but macrosomia was statistically significant in medium and high dose groups. Microscopically, vertebral lamina ossification was delayed in some embryos in high dose group but not interpreted as midline closure defect and also not statistically significant. Decrease in the number of renal glomerulus and increase in the tubular damage was statistically significant in medium and high dose groups. Cardiomegaly was also found in some embryos in middle and high dose groups but not statistically significant. CONCLUSION: The use of pregabalin does not cause neural tube closure defect in the embryo unless not exceed recommended maximum dose. Causing macrosomia instead of developmental retardation by Pregabalin is in conflict with the literature. This study revealed that Pregabalin causes fetal nephrotoxicity and macrosomia. These findings indicate that the use of Pregabalin in pregnancy still needs to be accounted as suspicious.


Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Tubo Neural/efeitos dos fármacos , Pregabalina/toxicidade , Teratogênese/efeitos dos fármacos , Animais , Embrião de Galinha , Galinhas/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Tubo Neural/embriologia , Tubo Neural/crescimento & desenvolvimento , Defeitos do Tubo Neural/induzido quimicamente , Pregabalina/farmacologia , Testes de Toxicidade
11.
Int J Mol Sci ; 22(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805345

RESUMO

Acrylamide is a commonly used industrial chemical that is known to be neurotoxic to mammals. However, its developmental toxicity is rarely assessed in mammalian models because of the cost and complexity involved. We used zebrafish to assess the neurotoxicity, developmental and behavioral toxicity of acrylamide. At 6 h post fertilization, zebrafish embryos were exposed to four concentrations of acrylamide (10, 30, 100, or 300 mg/L) in a medium for 114 h. Acrylamide caused developmental toxicity characterized by yolk retention, scoliosis, swim bladder deficiency, and curvature of the body. Acrylamide also impaired locomotor activity, which was measured as swimming speed and distance traveled. In addition, treatment with 100 mg/L acrylamide shortened the width of the brain and spinal cord, indicating neuronal toxicity. In summary, acrylamide induces developmental toxicity and neurotoxicity in zebrafish. This can be used to study acrylamide neurotoxicity in a rapid and cost-efficient manner.


Assuntos
Acrilamida/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Síndromes Neurotóxicas/fisiopatologia , Peixe-Zebra/crescimento & desenvolvimento , Acrilamida/farmacologia , Sacos Aéreos/patologia , Animais , Animais Geneticamente Modificados , Modelos Animais de Doenças , Embrião não Mamífero/fisiopatologia , Desenvolvimento Embrionário/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Escoliose/etiologia , Natação , Peixe-Zebra/fisiologia
12.
BMC Pregnancy Childbirth ; 21(1): 187, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33676424

RESUMO

BACKGROUND: Zinc is an essential element for normal embryogenesis and embryonic and neonatal development. Therefore, we compared the birth weights of neonates born to mothers who consumed zinc supplement during pregnancy with that of neonates born to mothers who did not. METHODS: In a cross-sectional study, we divided 200 pregnant mothers into two groups: case group (mothers receiving zinc supplement during pregnancy) and control group (mothers not receiving zinc supplement during pregnancy) Then, the neonate's cord zinc level and mother's serum level were measured and neonate's growth charts (weight, height and head circumference)were completed. RESULTS: In this study, both groups of mothers were observed to have zinc deficiency; 35% of the mothers who consumed zinc supplements and 81% of the mothers who did not consume zinc supplements (P < 0.001). Based on the results, maternal serum of zinc (P < 0.001), neonatal birth weight (P = 0.008), maternal age (P < 0.001) and parity (P < 0.01) in zinc-supplemented group were higher. Neonatal birth weight was associated moderately with mother's zinc serum levels and poorly with neonatal serum zinc levels. CONCLUSION: Zinc consumption during pregnancy increases serum zinc level of mother and neonatal weight. Neonatal weight has a higher correlation to maternal serum zinc level.


Assuntos
Desenvolvimento Infantil/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Zinco/administração & dosagem , Adulto , Peso ao Nascer/efeitos dos fármacos , Estudos Transversais , Suplementos Nutricionais , Feminino , Gráficos de Crescimento , Humanos , Recém-Nascido , Idade Materna , Paridade , Gravidez , Oligoelementos/administração & dosagem , Oligoelementos/sangue , Resultado do Tratamento , Zinco/sangue
13.
PLoS One ; 16(3): e0247518, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33667248

RESUMO

This study aimed to evaluate the effect of scriptaid during pre-maturation (PIVM) and/or maturation (IVM) on developmental competence of bovine oocytes. Cumulus-oocyte complexes (COCs) were submitted to PIVM for 6 h in the presence or absence of scriptaid. COCs were distributed into five groups: T1-IVM for 22 h, T2-PIVM for 6 h and IVM for 22 h, T3-PIVM with scriptaid for 6 h and IVM for 22 h, T4-PIVM for 6 h and IVM with scriptaid for 22 h, and T5-PIVM with scriptaid for 6 h and IVM with scriptaid for 22 h. Nuclear maturation, gene expression, cumulus cells (CCs) expansion, and embryo development and quality were evaluated. At the end of maturation, all groups presented the majority of oocytes in MII (P>0.05). Only HAT1 gene was differentially expressed (P<0.01) in oocytes with different treatments. Regarding embryo development at D7, T4 (23%) and T5 (18%) had lower blastocyst rate (P<0.05) than the other treatments (T1 = 35%, T2 = 37% and T3 = 32%). No effect was observed when scriptaid in PIVM was used in less competent oocytes (P>0.05). In conclusion, presence of scriptaid in PIVM and/or IVM did not improve developmental competence or embryo quality.


Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Hidroxilaminas/farmacologia , Técnicas de Maturação in Vitro de Oócitos/veterinária , Oócitos/efeitos dos fármacos , Oogênese/efeitos dos fármacos , Quinolinas/farmacologia , Animais , Blastocisto/metabolismo , Bovinos , Células do Cúmulo/efeitos dos fármacos , Células do Cúmulo/fisiologia , Técnicas de Cultura Embrionária/veterinária , Feminino , Fertilização In Vitro/veterinária , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Histona Acetiltransferases/genética , Meiose/efeitos dos fármacos , Oócitos/fisiologia
14.
Aquat Toxicol ; 234: 105791, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33714762

RESUMO

Exposure to oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) at critical developmental time-points in fish models impairs red blood cell concentrations in a regioselective manner, with 2-hydroxychrysene being more potent than 6-hydroxychrysene. To better characterize this phenomenon, embryos of Japanese medaka (Oryzias latipes) were exposed to 2- or 6-hydroxychrysene (0.5, 2, or 5 µM) from 4 h-post-fertilization (hpf) to 7 d-post-fertilization. Following exposure, hemoglobin concentrations were quantified by staining fixed embryos with o-dianisidine (a hemoglobin-specific dye) and stained embryos were imaged using brightfield microscopy. Exposure to 2-hydroxychrysene resulted in a concentration-dependent decrease in hemoglobin relative to vehicle-exposed embryos, while only the highest concentration of 6-hydroxychrysene resulted in a significant decrease in hemoglobin. All tested concentrations of 2-hydroxychrysene also caused significant mortality (12.2 % ± 2.94, 38.9 % ± 14.4, 85.6 % ± 11.3), whereas mortality was not observed following exposure to 6-hydroxychrysene. Therefore, treatment of embryos with 2-hydroxychrysene at various developmental stages and durations was subsequently conducted to identify key developmental landmarks that may be targeted by 2-hydroxychrysene. A sensitive window of developmental toxicity to 2-hydroxychrysene was found between 52-100 hpf, with a 24 h exposure to 10 µM 2-hydroxychrysene resulting in significant anemia and mortality. Since exposure to 2-hydroxychrysene from 52 to 100 hpf, a window that includes liver morphogenesis in medaka, resulted in the highest magnitude of toxicity, liver development and function may have a role in 2-hydroxychrysene developmental toxicity.


Assuntos
Crisenos/toxicidade , Desenvolvimento Embrionário/efeitos dos fármacos , Oryzias/crescimento & desenvolvimento , Poluentes Químicos da Água/toxicidade , Animais , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Hemoglobinas/metabolismo , Estereoisomerismo
15.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673195

RESUMO

Different types of anxiety disorders have become the number one mental health issue in developed countries. The search for new, safer and effective drug-like molecules among naturally derived substances faces two difficulties: an efficient method of isolation compounds with a high-purity and high-throughput animal model for activity assay. Thus, the aim of the present study was to isolate by liquid-liquid chromatography high-purity rare coumarins from the fruits of Seseli devenyense Simonk. and evaluate their anxiolytic effect (defined as reversed thimotaxis) using a 5-days post-fertilization (dpf) Danio rerio larvae model. Liquid-liquid chromatography enabled the isolation of one simple hydroxycoumarin (devenyol) and four pyranocoumarins (cis-khellactone, d-laserpitin, isolaserpitin and octanoyllomatin). The anxiolytic effect was defined as a decrease in the time spent in the boundaries of the living space (also described as reversed thigmotaxis). Our results show that all isolated courmarins exerted a significant influence on the anxiety behavior (anxiolytic activity) in the zebrafish larvae model. According to our knowledge, this is the first report of anxiolytic activity of pyranocoumarins and devenyol.


Assuntos
Ansiolíticos , Cumarínicos , Embrião não Mamífero/embriologia , Desenvolvimento Embrionário/efeitos dos fármacos , Frutas/química , Plantas/química , Peixe-Zebra/embriologia , Animais , Ansiolíticos/química , Ansiolíticos/isolamento & purificação , Ansiolíticos/farmacologia , Cromatografia Líquida , Cumarínicos/química , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia
16.
FASEB J ; 35(4): e21280, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33710673

RESUMO

Ethylene glycol butyl ether (EGBE) is a ubiquitous environmental pollutant that is commonly used in maquillage, industrial, and household products. EGBE has been shown to cause blood toxicity, carcinogenicity, and organ malformations. However, little is known about the impact of EGBE on the female reproductive system, especially oocyte quality. Here, we reported that EGBE influenced oocyte quality by showing the disturbed oocyte meiotic capacity, fertilization potential, and early embryonic development competency. Specifically, EGBE exposure impaired spindle/chromosome structure, microtubule stability, and actin polymerization to result in the oocyte maturation arrest and aneuploidy. In addition, EGBE exposure compromised the dynamics of cortical granules and their component ovastacin, leading to the failure of sperm binding and fertilization. Last, single-cell transcriptome analysis revealed that EGBE-induced oocyte deterioration was caused by mitochondrial dysfunction, which led to the accumulation of ROS and occurrence of apoptosis. Altogether, our study illustrates that mitochondrial dysfunction and redox perturbation is the major cause of the poor quality of oocytes exposed to EGBE.


Assuntos
Etilenoglicóis/toxicidade , Oócitos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/fisiologia , Dano ao DNA , Desenvolvimento Embrionário/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Feminino , Meiose/efeitos dos fármacos , Camundongos , Organelas/efeitos dos fármacos , Organelas/fisiologia , Espécies Reativas de Oxigênio
17.
Aquat Toxicol ; 233: 105794, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33662880

RESUMO

Polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are environmental contaminants known to impact cardiac development, a key step in the embryonic development of most animals. To date, little is understood of the molecular mechanism driving the observed cardiac defects in exposed fishes. The literature shows PCB & TCDD derived cardiac defects are concurrent with, but not caused by, expression of cyp1A, due to activation of the aryl hydrocarbon receptor (AhR) gene activation pathway. However, in this study, detailed visualization of fish hearts exposed to PCBs and TCDD show that, in addition to a failure of cardiac looping in early heart development, the inner endocardial lining of the heart fails to maintain proper cell adhesion and tissue integrity. The resulting gap between the endocardium and myocardium in both zebrafish and Atlantic sturgeon suggested functional faults in endothelial adherens junction formation. Thus, we explored the molecular mechanism triggering cardiac defects using immunohistochemistry to identify the location and phosphorylation state of key regulatory and adhesion molecules. We hypothesized that PCB and TCDD activates AhR, phosphorylating Src, which then phosphorylates the endothelial adherens junction protein, VEcadherin. When phosphorylated, VEcadherin dimers, found in the endocardium and vasculature, separate, reducing tissue integrity. In zebrafish, treatment with PCB and TCDD contaminants leads to higher phosphorylation of VEcadherin in cardiac tissue suggesting that these cells have reduced connectivity. Small molecule inhibition of Src phosphorylation prevents contaminant stimulated phosphorylation of VEcadherin and rescues both cardiac function and gross morphology. Atlantic sturgeon hearts show parallels to contaminant exposed zebrafish cardiac phenotype at the tissue level. These data suggest that the mechanism for PCB and TCDD action in the heart is, in part, distinct from the canonical mechanism described in the literature and that cardiac defects are impacted by this nongenomic mechanism.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Coração/efeitos dos fármacos , Bifenilos Policlorados/toxicidade , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Animais , Sinergismo Farmacológico , Embrião não Mamífero/anormalidades , Embrião não Mamífero/metabolismo , Desenvolvimento Embrionário/efeitos dos fármacos , Coração/embriologia , Miocárdio/metabolismo , Peixe-Zebra/crescimento & desenvolvimento
18.
Toxicology ; 452: 152697, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33524428

RESUMO

Trichloroethylene (TCE), a prevalent environmental contaminant, has been shown to induce cardiac malformations. Resveratrol (RSV) is a natural polyphenolic compound exhibiting protective effects on heart development. To investigate if RSV could protect against TCE-induced heart defects, we exposed zebrafish embryos to TCE (10 ppb) in the presence or absence of RSV (1 µg/mL). Our results showed that RSV significantly attenuated TCE-induced heart defects in zebrafish embryos. The TCE-induced ROS (reactive oxygen species) generation, 8-OHdG (8-hydroxy-2`-deoxyguanosine) formation and cell proliferation were significantly counteracted by RSV. Moreover, RSV attenuated the TCE-induced changes in mRNA expression or activity of genes involved in AHR and Nrf2 signal pathways. We further showed that RSV might inhibit TCE-enhanced cell proliferation by rescuing the downregulation of the p53/p21 axis. In conclusion, our data demonstrates that RSV protects against the cardiac developmental toxicity of TCE by inhibiting AHR activity, oxidative stress and cell proliferation.


Assuntos
Cardiotônicos/farmacologia , Desenvolvimento Embrionário/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/embriologia , Resveratrol/farmacologia , Tricloroetileno/toxicidade , Animais , Desenvolvimento Embrionário/fisiologia , Solventes/toxicidade , Peixe-Zebra
19.
J Assist Reprod Genet ; 38(5): 1061-1068, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33619678

RESUMO

PURPOSE: When rescue artificial oocyte activation (ROA) is performed on the day after intracytoplasmic sperm injection (ICSI) or later, embryonic development is poor and seldom results in live births. The efficacy of an early ROA after ICSI is unclear. Is early ROA effective in rescuing unfertilized oocytes that have not undergone second polar body extrusion several hours after ICSI? METHODS: We performed retrospective cohort study between October 2016 and September 2019, targeting 2891 oocytes in 843 cycles when ICSI was performed. We performed ROA with calcium ionophore on 395 of the 475 oocytes with no second polar extrusion 2.5-6 h after ICSI. RESULTS: The normal fertilization rate of ROA oocytes was significantly higher than non-ROA oocytes (65.8% vs 6.7%, P < 0.001). The blastocyst development rate in ROA oocytes was significantly lower than spontaneously activated oocytes (48.9% vs 67.2%, P < 0.001). The ROA oocyte implantation rate did not significantly differ from the spontaneously activated oocytes (36.0% vs 41.2%). We observed no differences in the implantation rates and blastocyst development rates over the 2.5-6 h from ICSI until ROA. CONCLUSION: Early ROA is effective, and the optimal timing appears to be 2.5-6 h after ICSI.


Assuntos
Desenvolvimento Embrionário/genética , Fertilização In Vitro , Nascido Vivo/epidemiologia , Oócitos/crescimento & desenvolvimento , Blastocisto/efeitos dos fármacos , Ionóforos de Cálcio/farmacologia , Implantação do Embrião/genética , Transferência Embrionária/tendências , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Humanos , Masculino , Oócitos/efeitos dos fármacos , Corpos Polares/efeitos dos fármacos , Corpos Polares/metabolismo , Injeções de Esperma Intracitoplásmicas/tendências
20.
Artigo em Inglês | MEDLINE | ID: mdl-33529709

RESUMO

A dithiocarbamate (DTC) fungicide, propineb, affects thyroid function and exerts immunotoxicity, cytotoxicity, and neurotoxicity in humans. Long-term exposure to propineb is associated with carcinogenicity, teratogenicity, malfunction of the reproductive system, and abnormalities in vital signs during organ development. However, there is no evidence of acute toxicity attributable to propineb in zebrafish. Therefore, in the present study, we assessed the toxicity of propineb in zebrafish by studying its adverse effects on embryo development, angiogenesis, and notochord development. Embryos with propineb exposure developed morphological and physiological defects and in larvae, apoptosis and notochord defects were induced in the early development stage. Transgenic fli1:eGFP zebrafish exposed to propineb showed abnormal larval development with defects in angiogenesis and deformed vasculature. Propineb induced irreversible damage to the neural development of embryos and neurogenic defects in developing zebrafish in transgenic olig2:dsRED zebrafish. These results show that exposure to propineb triggers abnormalities in different organ systems of zebrafish and suggests the physiological complexity of the response to propineb.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Fungicidas Industriais/toxicidade , Peixe-Zebra/embriologia , Zineb/análogos & derivados , Animais , Neovascularização Fisiológica/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Notocorda/efeitos dos fármacos , Zineb/toxicidade
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