RESUMO
A previous study using miRNA sequencing revealed that exposure to a mixture of phthalates during pregnancy and lactation dysregulated rno-miR-184 and rno-miR-141-3p in the ventral prostate (VP) of offspring. Here, rno-miR-184 and rno-miR-141-3 expressions were obtained by RT-qPCR in the VP of F1 males as well as in F2 offspring, aiming to establish a relationship with possible oncogenic targets through in silico analyses with multigenerational approach. Additionally, some targets were measured by western blots to highlight a possible relationship between the deregulated miRNAs and some of their targets. VP samples from rats exposed to a mixture of phthalates maternally during pregnancy and lactation (GD10 to PND21-F1) and VP from offspring (F2) were examined. The phthalate mixture at both concentrations (20 µg and 200 mg/kg/day) increased the expression of both miRNAs in the F1 (PND22 and 120) and F2 (descendants of F1-treated males) prostate. Target prediction analysis revealed that both microRNAs are responsible for modulating the expression and synthesis of 40 common targets. A phthalate target association analysis and the HPA database showed an interesting relationship among these possible miRNAs modulated targets with prostate adenocarcinoma and other oncogenic processes. Western blots showed alteration in P63, P53, WNT5, and STAT3 expression, which are targeted by the miRNAs, in the VP of F1/F2 males. The data draw attention to the epigenetic modulation in the prostate of descendants exposed to phthalates and adds to one of the few currently found in the literature to point to microRNAs signature as biomarkers of exposure to plasticizers.
Assuntos
MicroRNAs , Ácidos Ftálicos , Efeitos Tardios da Exposição Pré-Natal , Neoplasias da Próstata , MicroRNAs/genética , MicroRNAs/metabolismo , Masculino , Animais , Neoplasias da Próstata/induzido quimicamente , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Feminino , Ácidos Ftálicos/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/genética , Exposição Materna/efeitos adversos , Próstata/efeitos dos fármacos , Próstata/patologia , Ratos Wistar , Ratos , Simulação por ComputadorRESUMO
As the second leading cause of death for cancer among men worldwide, prostate cancer (PCa) prevention and detection remain a critical challenge. One aspect of PCa research is the identification of common environmental agents that may increase the risk of initiation and progression of PCa. Endocrine disrupting chemicals (EDCs) are strong candidates for risk factors, partially because they alter essential pathways for prostate gland development and oncogenesis. Phthalates correspond to a set of commercially used plasticizers that humans are exposed to ubiquitously. Here, we show that maternal exposure to a phthalate mixture interferes with the expression profile of mRNA and proteins in the ventral prostate of offspring and increases the susceptibility to prostate adenocarcinomas in aged animals. The data highlight Ubxn11, Aldoc, Kif5c, Tubb4a, Tubb3, Tubb2, Rab6b and Rab3b as differentially expressed targets in young and adult offspring descendants (PND22 and PND120). These phthalate-induced targets were enriched for pathways such as: dysregulation in post-translational protein modification (PTPM), cell homeostasis, HSP90 chaperone activity, gap junctions, and kinases. In addition, the Kif5c, Tubb3, Tubb2b and Tubb4a targets were enriched for impairment in cell cycle and GTPase activity. Furthermore, these targets showed strong relationships with 12 transcriptional factors (TF), which regulate the phosphorylation of eight protein kinases. The correlation of TF-kinases is associated with alterations in immune system, RAS/ErbB/VEGF/estrogen/HIF-1 signaling pathways, cellular senescence, cell cycle, autophagy, and apoptosis. Downregulation of KIF5C, TUBB3 and RAB6B targets is associated with poor prognosis in patients diagnosed with adenocarcinoma. Collectively, this integrative investigation establishes the post-transcriptional mechanisms in the prostate that are modulated by maternal exposure to phthalate mixture during gestation and lactation.
Assuntos
Neoplasias da Próstata , Proteoma , Animais , Humanos , Masculino , Gravidez , Ratos , Biomarcadores , Lactação , Neoplasias da Próstata/induzido quimicamente , Neoplasias da Próstata/genética , Transcriptoma , Feminino , Exposição Materna/efeitos adversosRESUMO
Western diet (WD), abundant in saturated fats and simple carbohydrates, has been associated with the development of prostate diseases. In addition, 2,4-dichlorophenoxyacetic acid (2,4-D), an herbicide used in agricultural and non-agricultural settings, may interfere with the endocrine system impacting reproductive health. The association of both factors is something common in everyday life, however, there are no relevant studies associating them as possible modulators of prostatic diseases. This study evaluated the action of the herbicide 2,4-D on the postnatal development of the prostate in mice fed with WD. Male C57Bl/6J mice received simultaneously a WD and 2,4-D at doses of 0.02, 2.0, or 20.0 mg/kg b.w./day for 6 months. The prolongated WD intake induced obesity and glucose intolerance, increasing body weight and fat. WD induced morphological changes and increased PCNA-positive epithelial cells in prostate. Additionally, the WD increased gene expression of AR, antioxidant targets, inflammation-related cytokines, cell repair and turnover, and targets related to methylation and miRNAs biosynthesis compared to the counterpart (basal diet). 2,4-D (0.02 and 2.0) changed prostate morphology and gene expression evoked by WD. In contrast, the WD group exposed to 20 mg/kg of 2,4-D reduced feed intake and body weight, and increased expression of androgen receptor and genes related to cell repair and DNA methylation compared to the negative control. Our results showed that 2,4-D was able to modulate the effects caused by WD, mainly at lower doses. However, further studies are needed to elucidate the mechanisms of 2,4-D on the obesogenic environment caused by the WD.
Assuntos
Dieta Ocidental , Herbicidas , Masculino , Camundongos , Animais , Próstata , Peso Corporal , Herbicidas/toxicidade , Ácido 2,4-Diclorofenoxiacético/toxicidade , Camundongos Endogâmicos C57BLRESUMO
A vectoeletronistagmografia (VENG) e otoneurologia clínica têm um ponto que deve ser sempre enfatizado: nenhum sinal clínico isolado tem um valor definitivo na localização da lesão. Por outro lado, a avaliação clínica do paciente junto com a audiometria de tronco cerebral (BERA), associada ao exame radiológico por imagem, ainda são as formas mais confiáveis de localizar uma lesão neurológica nas vias auditivas. No presente trabalho, avaliamos 05 indivíduos com diagnóstico de degeneração cerebelar autossômica dominante (ACAD), associadas ou não a lesão em tronco cerebral e vias supratentoriais. Os achados dos exames eletrofisiológicos (VENG e BERA), por imagem e estadiamento clínico são discutidos frente às várias síndromes labirínticas centrais. A tomografia computadorizada (TC) de crânio e a VENG mostraram-se alteradas em todos os pacientes, e o BERA mostrou-se alterado apenas nos pacientes com lesões do tronco. Pudemos observar vários sinais otoneurológicos como disritmia, decrutamento, dissociação cócleo-vestibular e rastreio tipo IV, entre outros. Concluímos que, apesar do estadiamento clínico BERA e TC serem mais precisos na localização da lesão, a VENG mostra alterações funcionais vestibulares centrais não identificadas na TC e bem mais precoces que o BERA, estando já presentes tanto nas doenças cerebelares isoladas como do tronco cerebral e vias supratentoriais.