In silico investigation of the role of miRNAs in a possible developmental origin of prostate cancer in F1 and F2 offspring of mothers exposed to a phthalate mixture.

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.

Integrated transcriptome and proteome analysis indicates potential biomarkers of prostate cancer in offspring of pregnant rats exposed to a phthalate mixture during gestation and lactation.

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.

Topodiagnóstico nas síndromes vestibulares centrais / Topodiagnosis in the central vestibular syndromes

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.

Sustained microgravity reduces intrinsic wound healing and growth factor responses in the rat.

Spaceflight is known to diminish bone mass and reduce immune function, suggesting that repair of connective tissue might be impaired in a microgravity environment. Fisher 344 rats were used to test wound healing responses in the orbiting Space Shuttle Endeavour by preflight implantation of polyvinyl acetal sponge disks in which pellets were placed to release either platelet-derived growth factor (PDGF-BB), basic fibroblast growth factor (bFGF), or placebo. Control groups on the ground included a matched environment group in similar housing modules and temperature control groups in cages at 22 degreesC and 28 degreesC. After 12 days of implantation and 10 days in orbit, the removed sponges were analyzed for histological and biochemical responses. Growth factor responses were histologically evident after release of PDGF-BB and bFGF in ground controls, whereas only immediate-release bFGF and delayed-release PDGF-BB showed significant responses in microgravity. Biochemical data confirmed that cellularity was increased by both factors in ground sponges; however, this response was significantly blunted in flight sponges (P<0.005, ANOVA), irrespective timing of factor release. Collagen content was 62% lower in sponges from animals with 10 days of microgravity exposure (P<0.01, ANOVA) and further reduced by bFGF. These data suggest that orbital exposure retards the capacity of wounds to heal and respond to exogenous stimuli.

Monospecific antibodies implicate basic fibroblast growth factor in normal wound repair.

Exogenous polypeptide growth factors influence the rate of wound healing and other biological processes, but there is no direct evidence that these peptides have an intrinsic role. To test whether basic fibroblast growth factor is involved in wound repair, rats were implanted with subcutaneous polyvinyl alcohol sponges containing slow-release pellets releasing either a polyclonal neutralizing antiserum directed against basic fibroblast growth factor, preimmune IgG, or nothing. Histological and biochemical evaluation of the granulation tissue that infiltrated the sponges showed anti-basic fibroblast growth factor to cause significant reductions in DNA, protein, and collagen content when compared with either preimmune IgG or placebo at the early stages of wound repair.