RESUMO
Thalidomide is a drug used worldwide for several indications, but the molecular mechanisms of its teratogenic property are not fully understood. Studies in animal models suggest the oxidative stress, the inhibition of angiogenesis, and the binding to E3-ubiquitin ligase complex as mechanisms by which thalidomide can change the expression of genes important to embryonic development. In this study, seven polymorphisms in genes related to development (FGF8, FGF10, BMP4, SHH, TP53, TP63, and TP73) were analyzed in people with thalidomide embryopathy (TE) and compared to people without malformations. The sample consisted of 36 people with TE and 135 unrelated and nonsyndromic people who had their DNA genotyped by PCR real-time. Although no allelic or genotypic differences were observed between the groups, we hypothesized that other regions in these genes and related genes may play an important role in thalidomide teratogenesis, which is known to have a genetic contribution. Identifying such molecular mechanisms is essential for the development of a molecule that will be analogue to thalidomide but safe enough to avoid the emergence of new cases of TE.
Assuntos
Anormalidades Induzidas por Medicamentos/genética , Predisposição Genética para Doença , Genótipo , Polimorfismo Genético , Talidomida/efeitos adversos , Feminino , Humanos , Recém-Nascido , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Talidomida/administração & dosagemRESUMO
Thalidomide causes Thalidomide Embryopathy (TE), but is largely used to treat several conditions. Investigations with Cereblon, a thalidomide target protein encoded by CRBN gene, have helped to understand thalidomide therapeutic and teratogenic properties. We sequenced CRBN-thalidomide binding region in 38 TE individuals and 136 Brazilians without congenital anomalies, and performed in silico analyses. Eight variants were identified, seven intronic and one in 3'UTR. TE individuals had rare variants in higher frequency than the non-affected group (p=0.04). The genotype rs1620675 CC was related to neurological anomalies in TE individuals (p=0.004). Bioinformatics analysis suggested this genotype leads to potential alterations in splicing sites and binding to transcription factors. Comparison of the Cereblon-thalidomide binding domains in mammals demonstrated that CRBN is highly conserved across species. All the variants require evaluation in functional assays in order to understand their role in Cereblon-thalidomide binding and complex interactions that lead to TE.
Assuntos
Anormalidades Induzidas por Medicamentos/genética , Anormalidades Múltiplas/genética , Doenças Fetais/genética , Peptídeo Hidrolases/genética , Teratogênicos/toxicidade , Talidomida/toxicidade , Anormalidades Induzidas por Medicamentos/etiologia , Anormalidades Múltiplas/induzido quimicamente , Proteínas Adaptadoras de Transdução de Sinal , Sítios de Ligação , Brasil , Simulação por Computador , Doenças Fetais/induzido quimicamente , Genômica , Humanos , Ubiquitina-Proteína LigasesRESUMO
BACKGROUND: Orofacial clefts (OFCs) are common birth defects, which include a range of disorders with a complex etiology affecting formation of craniofacial structures. Some forms of syndromic OFCs are produced by defects in the cholesterol pathway. The principal enzyme of the cholesterol pathway is the 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR). Our aim is to study whether defects of HMGCR function would produce orofacial malformation similar to those found in disorders of cholesterol synthesis. METHODS: We used zebrafish hmgcrb mutants and HMGCR inhibition assay using atorvastatin during early and late stages of orofacial morphogenesis in zebrafish. To describe craniofacial phenotypes, we stained cartilage and bone and performed in situ hybridization using known craniofacial markers. Also, we visualized neural crest cell migration in a transgenic fish. RESULTS: Our results showed that mutants displayed loss of cartilage and diminished orofacial outgrowth, and in some cases palatal cleft. Late treatments with statin show a similar phenotype. Affected-siblings displayed a moderate phenotype, whereas early-treated embryos had a minor cleft. We found reduced expression of the downstream component of Sonic Hedgehog-signaling gli1 in ventral brain, oral ectoderm, and pharyngeal endoderm in mutants and in late atorvastatin-treated embryos. CONCLUSION: Our results suggest that HMGCR loss-of-function primarily affects postmigratory cranial neural crest cells through abnormal Sonic Hedgehog signaling, probably induced by reduction in metabolites of the cholesterol pathway. Malformation severity correlates with the grade of HMGCR inhibition, developmental stage of its disruption, and probably with availability of maternal lipids. Together, our results might help to understand the spectrum of orofacial phenotypes found in cholesterol synthesis disorders. Birth Defects Research (Part A) 106:814-830, 2016. © 2016 Wiley Periodicals, Inc.
Assuntos
Anormalidades Induzidas por Medicamentos , Atorvastatina/efeitos adversos , Fenda Labial , Fissura Palatina , Hidroximetilglutaril-CoA Redutases , Mutação , Proteínas de Peixe-Zebra , Peixe-Zebra , Anormalidades Induzidas por Medicamentos/enzimologia , Anormalidades Induzidas por Medicamentos/genética , Animais , Atorvastatina/farmacologia , Fenda Labial/induzido quimicamente , Fenda Labial/enzimologia , Fenda Labial/genética , Fenda Labial/patologia , Fissura Palatina/induzido quimicamente , Fissura Palatina/enzimologia , Fissura Palatina/genética , Fissura Palatina/patologia , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
Warfarin is a synthetic oral anticoagulant that crosses the placenta and can lead to a number of congenital abnormalities known as fetal warfarin syndrome. Our aim is to report on the follow-up from birth to age 8 years of a patient with fetal warfarin syndrome. He presented significant respiratory dysfunction, as well as dental and speech and language complications. The patient was the second child of a mother who took warfarin during pregnancy due to a metallic heart valve. The patient had respiratory dysfunction at birth. On physical examination, he had a hypoplastic nose, pectus excavatum, and clubbing of the fingers. Nasal fibrobronchoscopy showed upper airway obstruction due to narrowing of the nasal cavities. He underwent surgical correction with Max Pereira graft, zetaplasty, and osteotomies for the piriform aperture. At dental evaluation, he had caries and delayed eruption of the upper incisors. Speech and language assessment revealed high palate, mouth breathing, little nasal patency, and shortened upper lip. Auditory long latency and cognitive-related potential to auditory stimuli demonstrated functional changes in the cortical auditory pathways. We believe that the frequency of certain findings observed in our patient may be higher in fetal warfarin syndrome than is appreciated, since a significant number result in abortions, stillbirths, or children evaluated in the first year of life without a follow-up. Thus, a multidisciplinary approach and long-term monitoring of these patients may be necessary.
Assuntos
Anormalidades Induzidas por Medicamentos/patologia , Transtornos da Percepção Auditiva/patologia , Osso Nasal/anormalidades , Obstrução Nasal/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Anormalidades Dentárias/patologia , Varfarina/efeitos adversos , Anormalidades Induzidas por Medicamentos/genética , Anormalidades Induzidas por Medicamentos/cirurgia , Transtornos da Percepção Auditiva/induzido quimicamente , Transtornos da Percepção Auditiva/genética , Transtornos da Percepção Auditiva/cirurgia , Criança , Feminino , Feto , Seguimentos , Humanos , Masculino , Mães , Osso Nasal/patologia , Osso Nasal/cirurgia , Obstrução Nasal/induzido quimicamente , Obstrução Nasal/genética , Obstrução Nasal/cirurgia , Osteotomia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/cirurgia , Anormalidades Dentárias/induzido quimicamente , Anormalidades Dentárias/genética , Anormalidades Dentárias/cirurgiaRESUMO
BACKGROUND: Congenital heart disease (CHD) is a serious threat to public health. Despite this, its etiology is poorly understood and few cardiac teratogens have been defined. The aim of the present study was to identify gestational and family risk factors for CHD in a sample of patients from a pediatric hospital in southern Brazil. METHODS: A prospective and consecutive sample from subjects with or without CHD, hospitalized at a pediatric intensive care unit, was enrolled. All patients with CHD underwent a GTG-banding karyotype. Chromosomal abnormalities were observed in 47 subjects (15.8%), and these were excluded from the study. The final sample consisted of 250 CHD subjects and 303 controls. RESULTS: After statistical analysis, using logistic regression, the variables age, rural location, gestational loss, use of anti-hypertensive medication, antibiotics and alcohol in the first trimester of pregnancy were all independently associated with CHD. These results were similar to those of some studies and different from others. It should be noted, however, that, for several variables, the data in the literature as well as the present study were insufficient to determine risk. CONCLUSIONS: Some differences found may be explained by genetic factors and sociocultural diversity. In contrast, because CHD consists of a heterogeneous group of lesions, the etiology may vary. The standardization of research data and classification of methods for future studies are essential.
Assuntos
Cardiopatias Congênitas/etiologia , Anormalidades Induzidas por Medicamentos/epidemiologia , Anormalidades Induzidas por Medicamentos/genética , Adolescente , Brasil , Criança , Pré-Escolar , Saúde da Família , Feminino , Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Humanos , Lactente , Cariotipagem , Modelos Logísticos , Masculino , Gravidez , Estudos Prospectivos , Fatores de RiscoRESUMO
O objetivo deste trabalho é relatar um caso de reconstrução nasal precoce em um paciente com síndrome do Warfarin fetal, onde um paciente de 23 dias com apresentava hipoplasia nasal isolada. O ganho ponderal estava estagnado e não havia possibilidade de introdução de sonda nasoentérica devido à deformidade. Foi realizada rinoplastia aberta com incisão transcolumelar. Dois enxertos de cartilagem tragal foram confeccionados e introduzidos na região da ponta, porção cranial do septo cartilaginoso e alares. O paciente apresentou melhoria da permeabilidade ventilatória, diminuição do ruído inspiratório, ganho de peso e também da forma. Após um ano de seguimento o resultado continuava satisfatório. Concluímos que a intervenção precoce é satisfatória e pode minimizar ou mesmo prevenir procedimentos futuros.
The aim of this work is to report a case of early nasal reconstruction in a 23-day-old patient with fetal Warfarin syndrome and isolated nasal hypoplasia. Weight gain was arrested and the deformity precluded the use of a nasogastric tube. An open rhinoplasty with transcolumellar incision was performed. Two grafts of tragal cartilage were made and introduced in the tip area, cranial portion of the cartilaginous septum, and alar cartilages. The patient presented improved ventilatory permeability, decrease of inspiratory noise, and weight and shape gains. At the one-year follow-up the result was still satisfactory. We concluded that early intervention is satisfactory and may minimize or even prevent future procedures.
Assuntos
Humanos , Anormalidades Induzidas por Medicamentos/genética , Anormalidades Induzidas por Medicamentos/patologia , Rinoplastia , Varfarina , Varfarina/efeitos adversos , Anormalidades Maxilofaciais , Anticoagulantes/efeitos adversos , Doenças Fetais/cirurgia , Doenças Fetais/genética , Doenças Fetais/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/cirurgia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamenteRESUMO
Alterations that could lead to the cancer development may also be related to an adverse development of offspring in experimental animals. Some functional foods, which contain the polysaccharide beta-glucan, have been described as being effective in the prevention of clastogenic damage. Based on that finding, the aim of the present study was to determine the efficacy of this sugar polymer in the mutagenic and teratogenic damage control. Two sets of females, pregnant and non-pregnant, were evaluated. The results indicated that beta-glucan was effective in preventing clastogenic damage in pregnant as well as non-pregnant females. In addition, pregnant females were more susceptible to mutagenic damage. However, teratogenic effects were not prevented effectively, although there was a trend toward a reduction in level of malformations. Despite beta-glucan did not prevent malformations, it increased fetal viability and reduced number of post-implantation losses and resorption, thereby enhancing reproductive performance in females.
Assuntos
Anormalidades Induzidas por Medicamentos/prevenção & controle , Antimutagênicos/uso terapêutico , Ciclofosfamida/toxicidade , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , beta-Glucanas/uso terapêutico , Anormalidades Induzidas por Medicamentos/embriologia , Anormalidades Induzidas por Medicamentos/etiologia , Anormalidades Induzidas por Medicamentos/genética , Animais , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Idade Gestacional , Masculino , Camundongos , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Micronúcleos com Defeito Cromossômico/embriologia , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/prevenção & controleRESUMO
The evidence presented here strengthens the argument that RA-induced truncation defects of the embryonic limb, and probably other teratogenic effects, are mediated by the nuclear retinoid receptors, particularly the RAR-beta 2 isoform. Although apoptotic cell death and an increased transglutaminase (tTG) activity accompany teratogenesis, it should be emphasized that the increased levels of RAR-beta 2 may influence additional events in limb development, e.g., modulation of connective tissue differentiation and an inhibition of chondrogenesis. Further work entails screening the effects of RA on genes targeted by the receptors.
Assuntos
Apoptose/efeitos dos fármacos , Deformidades Congênitas dos Membros , Tretinoína/toxicidade , Anormalidades Induzidas por Medicamentos/genética , Anormalidades Induzidas por Medicamentos/metabolismo , Anormalidades Induzidas por Medicamentos/patologia , Animais , Apoptose/genética , Extremidades/embriologia , Extremidades/patologia , Feminino , Troca Materno-Fetal , Mesoderma/efeitos dos fármacos , Mesoderma/patologia , Camundongos , Gravidez , Receptores do Ácido Retinoico/efeitos dos fármacos , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Transglutaminases/metabolismoRESUMO
The processes of cellular migration, cellular differentiation and cellular multiplication are studied, since these are the basic developmental processes upon which teratogenic agents act resulting in congenital malformations. We also carefully analyze the interactions between teratogen-embryo in order to establish adequate parameters for analysis of environmental teratogens, as well as experimental teratogenesis and epidemiology. Information on the pathogenesis of congenital malformations obtained from experimental teratology in an adequate biological model, can be extrapolated to the human. The etiology of congenital malformations resulting from environmental teratogens can only be elucidated through epidemiology, since there is species specificity. Such a study must fulfill the following prerequisites: diagnosis of the congenital malformation, ruling out genetic factors in the family tree and determination of the exact time of exposure to the possible teratogen during the pregnancy.
Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Poluentes Ambientais/efeitos adversos , Teratogênicos , Anormalidades Induzidas por Medicamentos/embriologia , Anormalidades Induzidas por Medicamentos/epidemiologia , Anormalidades Induzidas por Medicamentos/genética , Animais , Movimento Celular/efeitos dos fármacos , Indução Embrionária/efeitos dos fármacos , Idade Gestacional , Cardiopatias Congênitas/induzido quimicamente , Humanos , Modelos Biológicos , Morfogênese/efeitos dos fármacos , Projetos de Pesquisa , Teratogênicos/farmacologiaRESUMO
Sixty-two families with fetal diphenylhydantoin exposure were studied during two or more pregnancies. In 15 of these families at least one of the exposed children had some of the physical effects of DPH exposure ("affected" families); in the remaining 47 families no exposed child was affected ("unaffected" families). Review of 62 family histories and pedigrees was not helpful in differentiating these two groups for counseling purposes. However, mothers who had one affected child appeared to be at much higher risk for having subsequent affected children (9 of 10) if phenytoin use was continued through future pregnancies than were mothers whose first-born child was unaffected despite being exposed to phenytoin during the pregnancy (5 of 52 among all families, or 1 of 48 when only children exposed throughout the entire pregnancy were included). The difference between families with the first exposed child affected and first exposed child unaffected was highly statistically significant (p less than 0.0001). School and learning problems and developmental or mental retardation were present in both groups, and significantly more frequently in affected families. Physical and growth abnormalities were noted in both affected and unaffected family groups, also at a significantly higher rate in affected families.
Assuntos
Fenitoína/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal , Anormalidades Induzidas por Medicamentos/genética , Criança , Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Família , Pai , Feminino , Humanos , Masculino , Anamnese , Fenitoína/administração & dosagem , Gravidez , Fatores de Risco , SíndromeRESUMO
Four siblings exposed to phenytoin or primidone or both in utero are reported. Each has craniofacial features consistent with fetal hydantoin syndrome. Two of the siblings were exposed to primidone alone, indicating that phenytoin and primidone may have similar teratogenic effects.