Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.853
Filtrar
1.
Ecotoxicol Environ Saf ; 208: 111716, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396047

RESUMO

Although withdrawn from the market in the 1980s, polychlorinated biphenyls (PCBs) are still found ubiquitously in the aquatic environment and pose a serious risk to biota due to their teratogenic potential. In fish, early life-stages are often considered most sensitive with regard to their exposure to PCBs and other dioxin-like compounds. However, little is known about the molecular drivers of the frequently observed teratogenic effects. Therefore, the aims of our study were to: (1) characterize the baseline transcriptome profiles at different embryonic life-stages in zebrafish (Danio rerio); and (2) to identify the molecular response to PCB exposure and life-stage specific-effects of the chemical on associated processes. For both objectives, embryos were sampled at 12, 48, and 96 h post-fertilization (hpf) and subjected to Illumina sequence-by-synthesis and RNAseq analysis. Results revealed that with increasing age more genes and related pathways were upregulated both in terms of number and magnitude. Yet, other transcripts followed an opposite pattern with greater transcript abundance at the earlier time points. Additionally, embryos were exposed to PCB126, a potent agonist of the aryl hydrocarbon receptor (AHR). ClueGO network analysis revealed significant enrichment of genes associated with basic cell metabolism, communication, and homeostasis as well as eye development, muscle formation, and skeletal formation. We selected eight genes involved in the affected pathways for an in-depth characterization of their regulation throughout normal embryogenesis and after exposure to PCB126 by quantification of transcript abundances every 12 h until 118 hpf. Among these, fgf7 and c9 stood out because of their strong upregulation by PCB126 exposure at 48 and 96 hpf, respectively. Cyp2aa12 was upregulated from 84 hpf on. Fabp10ab, myhz1.1, col8a1a, sulf1, and opn1sw1 displayed specific regulation depending on the developmental stage. Overall, we demonstrate that (1) the developmental transcriptome of zebrafish is highly dynamic, and (2) dysregulation of gene expression by exposure to PCB126 was significant and in several cases not directly connected to AHR-signaling. Hence, this study improves the understanding of linkages between molecular events and apical outcomes that are of regulatory relevance.


Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Bifenilos Policlorados/toxicidade , Teratogênios/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/embriologia , Animais , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Transcriptoma , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/antagonistas & inibidores
2.
PLoS One ; 15(9): e0239738, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32976529

RESUMO

The levels and activity of the enzyme paraoxonase 1 affect the vulnerability to the teratogenic effects of organophosphate pesticides. Mutant mice lacking the gene for paraoxonase1 (PON1-/-) are more susceptible to the toxic effects of chlorpyrifos, and were hypothesized to be more vulnerable to social behavior deficits induced by exposure to chlorpyrifos during gestation. Three experiments were performed comparing PON1-/- mice to PON1+/+ mice born to dams treated with 0.5 mg/kg chlorpyrifos or cornoil vehicle on gestational days 12-15. Chlofpyrifos-exposed male PON1-/- mouse pups had delayed development of reflexes in in the first experiment. In the second experiment, adult male and female PON1-/- mice and the female PON1+/+ mice all displayed lower social preference than the male vehicle-treated PON1+/+ mice. The PON1-/- mice and the female PON1+/+ mice displayed lower social preference compared to the PON1+/+ male mice. Male adult mice that had been exposed in utero to chlorpyrifos showed less conditioned social preference regardless of genotype. In the third study, the delayed reflex development was replicated in male and female PON1-/- mice, but chlorpyrifos did not augment this effect. Nest Odor Preference, a test of early social attachment to dam and siblings, was lower in PON1-/- mouse pups compared to PON1+/+ pups. This study shows for the first time that PON1-/- mice have a behavioral phenotype that indicates impaired reflex development and social behavior. Chlorpyrifos exposure during gestation tended to augment some of these effects.


Assuntos
Arildialquilfosfatase/genética , Clorpirifos/toxicidade , Inibidores da Colinesterase/toxicidade , Deficiências do Desenvolvimento/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Comportamento Social , Teratogênios/toxicidade , Animais , Arildialquilfosfatase/deficiência , Feminino , Masculino , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Reflexo
3.
Chemosphere ; 254: 126900, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32957295

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous pollutants in marine environments and have arouse great concern since they pose adverse effects to marine ecosystem. To determine the potential impacts of environmentally relevant PAHs on early life stages of marine fish, this study exposed embryos of marine medaka (Oryzias melastigma) to 0, 2, 10, 50, and 250 µg/L of phenanthrene (Phe), one of the most abundant PAHs. The results demonstrated that Phe exposure decreased hatching rates, delayed hatching time of embryos, and increased deformity rate of newly-hatched larvae. Exposure to 10 and 50 µg/L Phe decreased the survival rate of marine medaka larvae at 28 days post-fertilization (dpf), and no embryo successfully hatched in 250 µg/L Phe exposure group. Morphology results showed that 10, 50, and 250 µg/L Phe exposure significantly retarded the development of embryos, and 2, 10, and 50 µg/L caused yolk sac edema and pericardial edema in newly-hatched larvae, indicating that low concentrations of Phe could induce developmental cardiac toxicity. Furthermore, the changes in the expression of heart development-related genes were determined, and the results showed that Phe-induced cardiac malformation might be related with fgf8, bmp4, smyd1, ATPase and gata4 genes. Overall, environmentally relevant PAHs could disrupt heart morphogenesis and hatching process of marine medaka, which might have profound consequences for sustainability of fish population.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Oryzias/crescimento & desenvolvimento , Fenantrenos/toxicidade , Teratogênios/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Ecossistema , Embrião não Mamífero/anormalidades , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/embriologia , Larva/efeitos dos fármacos , Larva/genética , Oryzias/genética , Fenantrenos/análise , Teratogênios/análise , Poluentes Químicos da Água/análise
4.
Ecotoxicol Environ Saf ; 202: 110909, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800244

RESUMO

The presence of mycotoxins in food has created concern. Mycotoxin prevalence in our environment has changed in the last few years maybe due to climatic and other environmental changes. Evidence has emerged from in vitro and in vivo models: some mycotoxins have been found to be potentially carcinogenic, embryogenically harmful, teratogenic, and to generate nephrotoxicity. The risk assessment of exposures to mycotoxins at early life stages became mandatory. In this regard, the effects of toxic compounds on zebrafish have been widely studied, and more recently, mycotoxins have been tested with respect to their effects on developmental and teratogenic effects in this model system, which offers several advantages as it is an inexpensive and an accessible vertebrate model to study developmental toxicity. External post-fertilization and quick maturation make it sensitive to environmental effects and facilitate the detection of endpoints such as morphological deformities, time of hatching, and behavioral responses. Therefore, there is a potential for larval zebrafish to provide new insights into the toxicological effects of mycotoxins. We provide an overview of recent mycotoxin toxicological research in zebrafish embryos and larvae, highlighting its usefulness to toxicology and discuss the strengths and limitations of this model system.


Assuntos
Micotoxinas/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Animais , Embrião não Mamífero/efeitos dos fármacos , Larva/efeitos dos fármacos , Teratogênios/toxicidade
5.
Toxicol Lett ; 333: 71-79, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32768651

RESUMO

All vitamin K antagonist active substances used as rodenticides were reclassified in 2016 by the European authorities as active substances "toxic for reproduction", using a "read-across" alternative method based on warfarin, a human vitamin K antagonist drug. Recent study suggested that all vitamin K antagonist active substances are not all teratogenic. Using a neonatal exposure protocol, warfarin evokes skeletal deformities in rats, while bromadiolone, a widely used second-generation anticoagulant rodenticide, failed to cause such effects. Herein, using a rat model we investigated the mechanisms that may explain teratogenicity differences between warfarin and bromadiolone, despite their similar vitamin K antagonist mechanism of action. This study also included coumatetralyl, a first-generation active substance rodenticide. Pharmacokinetic studies were conducted in rats to evaluate a potential difference in the transfer of vitamin K antagonists from mother to fetus. The data clearly demonstrate that warfarin is highly transferred from the mother to the fetus during gestation or lactation. In contrast, bromadiolone transfer from dam to the fetus is modest (5% compared to warfarin). This difference appears to be associated to almost complete uptake of bromadiolone by mother's liver, resulting in very low exposure in plasma and eventually in other peripheric tissues. This study suggests that the pharmacokinetic properties of vitamin K antagonists are not identical and could challenge the classification of such active substances as "toxic for reproduction".


Assuntos
4-Hidroxicumarinas/toxicidade , Efeitos Tardios da Exposição Pré-Natal/sangue , Rodenticidas/toxicidade , Teratogênese/efeitos dos fármacos , Teratogênios/toxicidade , Vitamina K/antagonistas & inibidores , Varfarina/toxicidade , 4-Hidroxicumarinas/farmacocinética , Administração Oral , Animais , Animais Recém-Nascidos , Animais Lactentes , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/embriologia , Fígado/metabolismo , Masculino , Exposição Materna , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Rodenticidas/farmacocinética , Teratogênios/farmacocinética , Varfarina/farmacocinética
6.
Ecotoxicol Environ Saf ; 202: 110936, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800219

RESUMO

Developmental toxicity refers to the occurrence of adverse effects on a developing organism as a consequence of exposure to hazardous chemicals. The assessment of developmental toxicity has become relevant to the safety assessment process of chemicals. The zebrafish embryo developmental toxicology assay is an emerging test used to screen the teratogenic potential of chemicals and it is proposed as a promising test to replace teratogenic assays with animals. Supported by the increased availability of data from this test, the developmental toxicity assay with zebrafish has become an interesting endpoint for the in silico modelling. The purpose of this study was to build up quantitative structure-activity relationship (QSAR) models. In this work, new in silico models for the evaluation of developmental toxicity were built using a well-defined set of data from the ToxCastTM Phase I chemical library on the zebrafish embryo. Categorical and continuous QSAR models were built by gradient boosting machine learning and the Monte Carlo technique respectively, in accordance with Organization for Economic Co-operation and Development principles and their statistical quality was satisfactory. The classification model reached balanced accuracy 0.89 and Matthews correlation coefficient 0.77 on the test set. The regression model reached correlation coefficient R2 0.70 in external validation and leave-one-out cross-validated Q2 0.73 in internal validation.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Testes de Toxicidade/métodos , Poluentes Químicos da Água/toxicidade , Animais , Simulação por Computador , Substâncias Perigosas , Aprendizado de Máquina , Relação Quantitativa Estrutura-Atividade , Teratogênios , Peixe-Zebra/embriologia
7.
Pediatrics ; 146(Suppl 1): S93-S98, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32737240

RESUMO

A central tension in pediatric research ethics arises from our desire to protect children from harm while also allowing progress toward discoveries that could improve child health. A prime example of this tension is research on a controversial yet increasingly common practice: the use of cannabis by women to treat nausea and vomiting of pregnancy. Studies of cannabis use in pregnancy face a combination of ethical hurdles because of the inclusion of pregnant women and involvement of a schedule I controlled substance. Given the growing need for research on the safety and efficacy of cannabis for nausea and vomiting of pregnancy, we reflect on the multiple historical contexts that have contributed to the challenge of studying cannabis use during pregnancy and make a case for the ethical rationale for such research.


Assuntos
Ética em Pesquisa , Maconha Medicinal/uso terapêutico , Êmese Gravídica/terapia , Pediatria/ética , Gestantes , Sujeitos da Pesquisa , Antieméticos/efeitos adversos , Diciclomina/uso terapêutico , Doxilamina/uso terapêutico , Aprovação de Drogas , Combinação de Medicamentos , Feminino , Humanos , Maconha Medicinal/efeitos adversos , Ondansetron/uso terapêutico , Gravidez , Piridoxina/uso terapêutico , Teratogênios , Talidomida/efeitos adversos
8.
Proc Natl Acad Sci U S A ; 117(37): 23106-23112, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32848052

RESUMO

Thalidomide exerts its teratogenic and immunomodulatory effects by binding to cereblon (CRBN) and thereby inhibiting/modifying the CRBN-mediated ubiquitination pathway consisting of the Cullin4-DDB1-ROC1 E3 ligase complex. The mechanism of thalidomide's classical hypnotic effect remains largely unexplored, however. Here we examined whether CRBN is involved in the hypnotic effect of thalidomide by generating mice harboring a thalidomide-resistant mutant allele of Crbn (Crbn YW/AA knock-in mice). Thalidomide increased non-REM sleep time in Crbn YW/AA knock-in homozygotes and heterozygotes to a similar degree as seen in wild-type littermates. Thalidomide similarly depressed excitatory synaptic transmission in the cortical slices obtained from wild-type and Crbn YW/AA homozygous knock-in mice without affecting GABAergic inhibition. Thalidomide induced Fos expression in vasopressin-containing neurons of the supraoptic nucleus and reduced Fos expression in the tuberomammillary nuclei. Thus, thalidomide's hypnotic effect seems to share some downstream mechanisms with general anesthetics and GABAA-activating sedatives but does not involve the teratogenic CRBN-mediated ubiquitin/proteasome pathway.


Assuntos
Hipnóticos e Sedativos/farmacologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Teratogênios/metabolismo , Talidomida/farmacologia , Ubiquitinação/efeitos dos fármacos , Ubiquitinas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
10.
Arq. bras. med. vet. zootec. (Online) ; 72(3): 719-728, May-June, 2020. tab
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1128887

RESUMO

Este estudo investigou a toxicidade pré-natal do inseticida piriproxifeno em ratos Wistar, de forma a detectar possíveis alterações no desenvolvimento fetal da progênie exposta durante o período organogênico. Três doses de piriproxifeno (100, 300 e 500mg.kg-1) foram administradas por via oral às progenitoras, do sexto ao 15º dia de gestação. Os fetos foram submetidos à técnica de diafanização modificada descrita por Taylor e Van Dyke, para avaliação de malformações e alterações esqueléticas. Os resultados não demonstraram a ocorrência de toxicidade materna sistêmica ou alterações nos índices reprodutivos avaliados. Malformações ou alterações teratogênicas não foram detectadas, no entanto alterações esqueléticas sugestivas de retardo no desenvolvimento foram observadas especialmente nas doses mais altas testadas (300mg.kg-1 e 500mg.kg-1). Considerando-se a situação complexa de risco para a saúde humana, mostra-se importante a execução de investigações adicionais, de modo a contribuir para a adequada avaliação de risco do piriproxifeno em água potável.(AU)


This study investigated the prenatal toxicity of the insecticide pyriproxyfen in Wistar rats to detect the possible changes in the fetal development of the progeny exposed during the organogenic period. Three doses of pyriproxyfen (100, 300, and 500mg.kg-1) were administered orally to the progenitors, from day 6 to 15 of gestation. The fetuses were processed using the Taylor and Van Dyke modified diaphanization technique to evaluate malformations and skeletal changes. The results did not demonstrate the occurrence of systemic maternal toxicity or changes in the reproductive indexes evaluated. Malformations or teratogenic changes were not detected, however, skeletal changes suggestive of developmental delay were observed, especially in the highest doses tested (300 mg.kg-1 and 500 mg.kg-1). Owing to the potentially complex situation regarding its risk to human health, it is important that further studies be performed to contribute to the risk assessment of the addition of pyriproxyfen in drinking water.(AU)


Assuntos
Animais , Ratos , Praguicidas/efeitos adversos , Piridinas , Teratogênios/análise , Desenvolvimento Fetal/efeitos dos fármacos , Ratos Wistar/embriologia , Zika virus , Microcefalia/veterinária
11.
Epilepsia ; 61(6): 1291-1300, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32415786

RESUMO

OBJECTIVE: Sodium valproate (VPA), the most effective antiepileptic drug for patients with genetic generalized epilepsy (GGE), is a potent human teratogen that increases the risk of a range of congenital malformations, including spina bifida. The mechanisms underlying this teratogenicity are not known, but may involve genetic risk factors. This study aimed to develop an animal model of VPA-induced birth defects. METHODS: We used three different rat strains: inbred Genetic Absence Epilepsy Rats From Strasbourg (GAERS), a model of GGE with absence seizures; inbred Non-Epileptic Controls (NEC); and outbred nonepileptic Wistars. Female rats were fed standard chow or VPA (20 g/kg food) mixed in standard chow for 2 weeks prior to conception, and then mated with same-strain males. Treatment continued throughout pregnancy. Fetuses were extracted via C-section on gestational day 21 and examined for birth defects, including external assessment and spinal measurements. RESULTS: VPA-exposed pups showed significant reductions in weight, length, and whole-body development compared with controls of all three strains (P < .0001). Gestational VPA treatment altered intravertebral distances, and resulted in underdeveloped vertebral arches between thoracic region T11 and caudal region C2 in most pups (GAERS, 100%; NEC, 95%; Wistar, 80%), more frequently than in controls (9%, 13%, 19%). SIGNIFICANCE: Gestational VPA treatment results in similar developmental and morphological abnormalities in three rat strains, including one with GGE, indicating that the genetic underpinnings of epilepsy do not contribute markedly to VPA-induced birth defects. This model may be used in future studies to investigate mechanisms involved in the pathogenesis of antiepileptic drug-induced birth defects.


Assuntos
Anticonvulsivantes/toxicidade , Modelos Animais de Doenças , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/patologia , Teratogênios/toxicidade , Ácido Valproico/toxicidade , Anormalidades Induzidas por Medicamentos/patologia , Administração Oral , Animais , Feminino , Masculino , Gravidez , Ratos , Ratos Transgênicos , Ratos Wistar
12.
Sci Rep ; 10(1): 3905, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32127562

RESUMO

Nonhereditary factors play an important role in the occurrence of congenital heart disease (CHD). This study was to explore the possible parental nonhereditary exposure factors relevant to the occurrence of CHD in the northeastern Sichuan area. A total of 367 children with CHD and 367 children without congenital malformations aged 0 to 14 years old were recruited from the Affiliated Hospital of North Sichuan Medical College and Nanchong Central Hospital between March 2016 and November 2018. This study was designed as a case-control study with 1:1 frequency matching, in which the parents of cases and controls were interviewed with the same questionnaire according to the gestational age of the child, maternal age during pregnancy and the same maternal race/ethnicity. Then, 322 matched case-control pairs were analysed by SPSS 22. Thirty-one suspicious factors were entered into the binary logistic regression analysis after univariate regression analysis of 55 factors (alpha = 0.05). The analysis results showed that 7 factors were significantly associated with the occurrence of CHD. Thus, augmenting maternal mental healthcare, improving the quality of drinking water, obtaining adequate nutrition, maintaining a healthy physical condition during pregnancy, enhancing parents' level of knowledge and maintaining a healthy lifestyle may lower the occurrence of CHD.


Assuntos
Cardiopatias Congênitas/etiologia , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/etiologia , Teratogênios/toxicidade , Criança , Pré-Escolar , China , Feminino , Humanos , Lactente , Masculino , Gravidez , Fatores de Risco
13.
Environ Toxicol ; 35(7): 794-803, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32149475

RESUMO

The continued use of pesticides is one of the requirements of modern agriculture. Investigations have shown that pesticides can alter gene methylation and expression and subsequently may lead to abortion or birth of embryos with teratogenic disorders. In present study, 30 female NMRI mouse were divided in three experimental groups which in the CPF group, intraperitoneal chlorpyrifos was injected, in the sham group, DMSO was injected, and the control group without injection. The mice were mated and utinized 10 days' post gestation. The number of embryos in each fertilized female, maternal weight, and liver fibrosis was evaluated. The apoptosis pathway genes (caspase3, caspase9) and protein expressions (pro-caspase3, caspase3) of the embryos were evaluated with qRT-PCR and western blot, respectively. The DNA methylation of caspase3 and caspase9 were also assessed. The number of embryos and obtained maternal weight from the CPF group was significantly lower than other two groups. The mRNA expression of Caspase3 and Caspase9 were significantly higher in the CPF group. The protein expression evaluation confirmed the results achieved at the mRNA level. The percentage of Caspase9 DNA methylation in embryos collected from the CPF group was higher compared to the others. It can be considered that consumption of chlorpyrifos toxin can alter the DNA methylation and increase the expression of apoptotic genes. Therefore, continuous use of chlopyrifos may affect pregnancy by increasing the apoptosis pathway in the developing embryos which may lead to abortion or teratogenic disorders in newborn infants.


Assuntos
Apoptose/genética , Clorpirifos/toxicidade , Metilação de DNA/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Exposição Materna/efeitos adversos , Organogênese/genética , Animais , Apoptose/efeitos dos fármacos , Caspase 3/genética , Caspase 9/genética , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Camundongos , Organogênese/efeitos dos fármacos , Praguicidas/toxicidade , Gravidez , RNA Mensageiro/metabolismo , Teratogênios/toxicidade
14.
Ann Neurol ; 87(6): 897-906, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32215971

RESUMO

OBJECTIVE: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism that we investigated. METHODS: Whole exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and de novo copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in children exposed prenatally to AEDs (AED-exposed children) versus children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs versus those without BDs, adjusting for confounders. Fisher exact test was used to compare categorical data. RESULTS: Sixty-seven child-parent trios were included: 10 with AED-exposed children with BDs, 46 with AED-exposed unaffected children, and 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children (median dnSNV/indel number/child [range] = 3 [0-7] vs 3 [1-5], p = 0.50). Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9 of 67 (13%) children, none of whom had BDs. The proportion of cases harboring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. INTERPRETATION: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counseling. ANN NEUROL 2020;87:897-906.


Assuntos
Anormalidades Induzidas por Medicamentos/genética , Anticonvulsivantes/efeitos adversos , Carga Genética , Variação Genética/genética , Teratogênios , Anormalidades Induzidas por Medicamentos/epidemiologia , Adulto , DNA/genética , Variações do Número de Cópias de DNA/genética , Exoma/genética , Feminino , Humanos , Recém-Nascido , Masculino , Idade Paterna , Polimorfismo de Nucleotídeo Único/genética , Gravidez
15.
Chemosphere ; 250: 126124, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32092576

RESUMO

Toxic compounds from the mother's diet and medication in addition to genetic factors and infection during pregnancy remain risks for various congenital disorders and misbirth. To ensure the safety of food and drugs for pregnant women, establishment of an in vitro system that morphologically resembles human tissues has been long desired. In this study, we focused on dorsal mesoderm elongation, one of the critical early development events for trunk formation, and we established in vitro autonomous elongating tissues from human induced pluripotent stem cells (hiPSCs). This artificial tissue elongation is regulated by MYOSIN II and FGF signaling, and is diminished by methylmercury or retinoic acid (RA), similar to in vivo human developmental disabilities. Moreover, our method for differentiation of hiPSCs requires only a short culture period, and the elongation is cell number-independent. Therefore, our in vitro human tissue elongation system is a potential tool for risk assessment assays for identification of teratogenic chemicals via human tissue morphogenesis.


Assuntos
Teratogênios/toxicidade , Testes de Toxicidade/métodos , Diferenciação Celular , Humanos , Células-Tronco Pluripotentes Induzidas , Mesoderma , Morfogênese , Medição de Risco , Tretinoína
16.
Toxicon ; 176: 59-66, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32057833

RESUMO

Rhopalurus junceus is the most common scorpion in Cuba and the venom is often used as a natural product for anti-cancer therapy. Despite this, no study has been published concerning its toxicological profile. The aim of the study was characterizing the short-term, subchronic toxicity and the teratogenic potential of Rhopalurus junceus scorpion venom by oral route in mice. Short-term oral toxicity was test in both sexes NMRI mice that received 100 mg/kg/day of scorpion venom extract for 28 days. For the subchronic study, mice were administered with three doses (0.1, 10, and 100 mg/kg) by oral route for 90 days. Teratogenic potential was tested in pregnant mice administered from day 6-15 post conception. Significant differences were observed in body weight and food intake of animal treated for short-term and subchronic assays. Variations in serum urea and cholesterol were observed after 90 days oral treatment. Spontaneous findings not related to the treatment were reveal in histology evaluation. Exposure in pregnant mice did not produce maternal toxicity. Signs of embryo-fetal toxicity were not observed. The current study provides evidence that exposure to low or moderate dose of Rhopalurus junceus scorpion venom by oral route did not affect health of animals and has low impact on reproductive physiology.


Assuntos
Venenos de Escorpião/toxicidade , Teratogênios/toxicidade , Testes de Toxicidade Subcrônica , Administração Oral , Animais , Cuba , Feminino , Masculino , Camundongos , Escorpiões , Teratogênese
17.
Ecotoxicol Environ Saf ; 191: 110226, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31981955

RESUMO

Since 2006, harmful dinoflagellate blooms of Cochlodinium geminatum have infrequently occurred in the Pearl River Estuary, South China. During late October to early November in 2018, C. geminatum blooms occurred again in the region. To investigate the blooming mechanism in certain temporal conditions, we analysed the changes in the environmental parameters and phytoplankton community structure during and after the bloom. The results indicated that the water temperature and salinity had large impacts on the bloom. During the C. geminatum bloom, the phytoplankton community structure changed and the number of dominant species decreased. After the bloom, the species number and abundance of diatoms increased, as the species diversity was recovering. Retinal was detected in the field samples and cultured C. geminatum. It has been demonstrated to exist in some algae species (e.g. Cyanophyta, Chlorophyta, Bacillariophyta, and Euglenophyt), and our results indicates that such teratogens also exist in dinoflagellates. The highest concentration of retinal was detected during the bloom. This result indicates that the retinal content may accumulate during a bloom. Retinal has been demonstrated to be a teratogenic agent and may therefore present a potential risk to aquatic organisms during a bloom episode. This research provided more comprehensive information concerning the ecological influences of C. geminatum blooms.


Assuntos
Dinoflagelados/química , Dinoflagelados/crescimento & desenvolvimento , Estuários , Retinoides/análise , Teratogênios/análise , China , Clorófitas/química , Diatomáceas/isolamento & purificação , Fenômenos Ecológicos e Ambientais , Fitoplâncton/isolamento & purificação , Rios , Salinidade
18.
Artigo em Inglês | MEDLINE | ID: mdl-31936320

RESUMO

There are presently more than 18 known aflatoxins most of which have been insufficiently studied for their incidence, health-risk, and mechanisms of toxicity to allow effective intervention and control means that would significantly and sustainably reduce their incidence and adverse effects on health and economy. Among these, aflatoxin B1 (AFB1) has been by far the most studied; yet, many aspects of the range and mechanisms of the diseases it causes remain to be elucidated. Its mutagenicity, tumorigenicity, and carcinogenicity-which are the best known-still suffer from limitations regarding the relative contribution of the oxidative stress and the reactive epoxide derivative (Aflatoxin-exo 8,9-epoxide) in the induction of the diseases, as well as its metabolic and synthesis pathways. Additionally, despite the well-established additive effects for carcinogenicity between AFB1 and other risk factors, e.g., hepatitis viruses B and C, and the hepatotoxic algal microcystins, the mechanisms of this synergy remain unclear. This study reviews the most recent advances in the field of the mechanisms of toxicity of aflatoxins and the adverse health effects that they cause in humans and animals.


Assuntos
Aflatoxinas/toxicidade , Mutagênicos/toxicidade , Teratogênios/toxicidade , Animais , Doença Crônica , Humanos , Sistema Imunitário/efeitos dos fármacos , Neoplasias/induzido quimicamente
19.
J Pharmacol Exp Ther ; 373(1): 62-71, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31941719

RESUMO

The present study used human myeloid leukemia U937 cells, a versatile promonocytic cellular system that, based on its endoplasmic reticulum (ER)/mitochondria functional relationships, responds to low micromolar concentrations of arsenite with a single, defined mechanism of superoxide (O2 -.) formation. Under these conditions, we observe an initial Ca2+ mobilization from the ER associated with the mitochondrial accumulation of the cation, which is followed by Ca2+-dependent mitochondrial O2 -. (mitoO2 -.) formation. These events, which were barely detectable after 3 hours, were better appreciated at 6 hours. We found that markedly shorter exposure to arsenite and lower concentrations of arsenite are required to induce extensive O2 - formation in cells supplemented with inositol-1,4,5-trisphosphate receptor (IP3R) or ryanodine receptor (RyR) agonists. Indeed, nanomolar arsenite induced maximal O2 -. formation after only 10 minutes of exposure, and this response was uniquely dependent on the enforced mitochondrial Ca2+ accumulation. The dramatic anticipation of and sensitization to the effects of arsenite caused by the IP3R or RyR agonists were accompanied by a parallel significant genotoxic response in the absence of detectable mitochondrial dysfunction and cytotoxicity. We conclude that the prolonged, low-micromolar arsenite exposure paradigm resulting in mitoO2 -. formation is necessary to affect Ca2+ homeostasis and accumulate the cation in mitochondria. The arsenite requirements to promote mitoO2 -. formation in the presence of sufficient mitochondrial Ca2+ were instead remarkably lower in terms of both concentration and time of exposure. These conditions were associated with the induction of extensive DNA strand scission in the absence of detectable signs of toxicity. SIGNIFICANCE STATEMENT: In respiration-proficient cells, arsenite causes mitochondrial Ca2+ accumulation and Ca2+-dependent mitochondrial superoxide formation. We now report that the second event requires remarkably lower concentrations of and time of exposure to the metalloid than the former. Indeed, a brief exposure to nanomolar levels of arsenite produced maximal effects under conditions in which the mitochondrial Ca2+ concentration ([Ca2+]m) was increased by inositol-1,4,5-trisphosphate receptor or ryanodine receptor agonists. Hence, specific substances or conditions enhancing the [Ca2+]m may potentiate the deleterious effects of arsenite by selectively increasing mitochondrial superoxide formation.


Assuntos
Arsenitos/toxicidade , Retículo Endoplasmático/efeitos dos fármacos , Metaloides/toxicidade , Mitocôndrias/efeitos dos fármacos , Superóxidos , Teratogênios/toxicidade , Relação Dose-Resposta a Droga , Retículo Endoplasmático/metabolismo , Humanos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxidos/metabolismo , Fatores de Tempo , Células U937
20.
Odontology ; 108(1): 1-15, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31172336

RESUMO

The craniofacial complex develops mainly in the first trimester of pregnancy, but its final shaping and the development of the teeth extend into the second and third trimesters. It is intimately connected with the development of the brain because of the crucial role the cranial neural crest cells play and the fact that many signals which control craniofacial development originate in the brain and vice versa. As a result, malformations of one organ may affect the development of the other. Similarly, there are developmental connections between the craniofacial complex and the teeth. Craniofacial anomalies are either isolated, resulting from abnormal development of the first two embryonic pharyngeal arches, or part of multiple malformation syndromes affecting many other organs. They may stem from gene mutations, chromosomal aberrations or from environmental causes induced by teratogens. The craniofacial morphologic changes are generally cosmetic, but they often interfere with important functions such as chewing, swallowing and respiration. In addition, they may cause hearing or visual impairment. In this review we discussed only a small number of craniofacial malformations and barely touched upon related anomalies of dentition. Following a brief description of the craniofacial development, we discussed oral clefts, craniofacial microsomia, teratogens that may interfere with craniofacial development resulting in different malformations, the genetically determined craniosynostoses syndromes and few other relatively common syndromes that, in addition to the craniofacial complex, also affect other organs. The understanding of these malformations is important in dentistry as dentists play an integral role in their diagnosis and multidisciplinary treatment.


Assuntos
Encéfalo , Crista Neural , Feminino , Humanos , Gravidez , Síndrome , Teratogênios
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA