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1.
J Appl Toxicol ; 38(12): 1483-1491, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29952068

RESUMO

Few studies have investigated non-target effects of neonicotinoid insecticides on mammalian physiology. This is largely due to the widespread perception that their weak affinity for nicotinic acetylcholine receptor subtypes in vertebrates makes mammalian exposures unlikely to pose health risks. To the best of our knowledge, we describe the first investigation evaluating the interaction of seven principal neonicotinoid insecticides (thiamethoxam, imidacloprid, clothianidin, flupyradifurone, dinotefuran, nitenpyram, thiacloprid) with oestrogen and thyroid hormone receptors, as well as their adipogenic effects, in mammalian cell culture assay systems. An E-Screen with MCF-7 and T-Screen with GH3 cells respectively showed a lack of oestrogen and thyroid hormone receptor agonist effects for any of the neonicotinoids tested. Adipogenicity was assessed by the ability to stimulate lipid accumulation in adipocyte differentiated 3T3-L1 cells, with only imidacloprid scoring positive in this assay causing triglyceride accumulation from a concentration of 50 mg l-1 . Data mining of ToxCast high-throughput screening assays revealed that this adipogenic effect of imidacloprid is probably mediated via the pregnane X receptor.


Assuntos
Adipogenia/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Inseticidas/toxicidade , Lipogênese/efeitos dos fármacos , Neonicotinoides/toxicidade , Receptores de Estrogênio/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Técnicas de Cultura de Células , Humanos , Células MCF-7 , Camundongos
2.
Endocr Pathol ; 28(1): 41-48, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27704398

RESUMO

The REarranged during Transfection (RET) proto-oncogene is a receptor tyrosine kinase involved in growth and differentiation during embryogenesis and maintenance of the urogenital and nervous systems in mammals. Distinct mutations across hotspot RET exons can cause Multiple Endocrine Neoplasia Type 2A (MEN2A) characterised by development of medullary thyroid cancer (MTC), phaeochromocytoma (PCC) and primary hyperparathyroidism (PHPT), with a strong correlation between genotype and phenotype. Here, we report a 42-year-old man presented in the clinic with a unilateral PCC, with subsequent investigations revealing a nodular and cystic thyroid gland. He proceeded to thyroidectomy, which showed bilateral C-cell hyperplasia (CCH) without evidence of MTC. His brother had neonatal Hirschsprung disease (HSCR). Genetic testing revealed the presence of a heterozygous variant of unknown significance (VUS) in the cysteine-rich region of exon 10 in the RET gene (c.1846G>C, p.E616Q), in both affected siblings and their unaffected mother. Exon 10 RET mutations are known to be associated with HSCR and MEN2. Variants in the cysteine-rich region of the RET gene, outside of the key cysteine residues, may contribute to the development of MEN2 in a less aggressive manner, with a lower penetrance of MTC. Currently, a VUS in RET cannot be used to inform clinical management and direct future care. Analysis of RETE616Q reveals a gain of function mutant phenotype for this variant, which has not previously been reported, indicating that this VUS should be considered at risk for future clinical management.


Assuntos
Neoplasia Endócrina Múltipla Tipo 2a/genética , Proteínas Proto-Oncogênicas c-ret/genética , Adulto , Western Blotting , Feminino , Humanos , Masculino , Mutagênese Sítio-Dirigida , Mutação , Linhagem , Proto-Oncogene Mas
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