RESUMO
Cumulative human exposure to the environmental toxin, bisphenol A (BPA), has raised important health concerns in recent decades. However, the direct genomic regulation of BPA in skeletal muscles and its clinical significance are poorly understood. Therefore, we conducted a genome-wide transcriptome analysis after daily oral administration of BPA at the lowest observed adverse-effect level (LOAEL, 50 mg/kg) in male mice for six weeks to explore the gene-expression regulations in skeletal muscle induced by BPA. The primary Gene Ontology terms linked to BPA-dependent, differentially expressed genes at LOAEL comprised adaptive-immune response, positive regulation of T cell activation, and immune system process. The gene-set enrichment analysis disclosed increased complement-associated genes [complement components 3 (C3) and 4B, complement factor D, complement receptor 2, and immunoglobulin lambda constant 2] in the group administered with BPA, with a false-discovery rate of <0.05. Subsequent validation analysis conducted in BPA-fed animal skeletal muscle tissue and in vitro experiments confirmed that BPA induced immune activation, as evidenced by increased levels of C3 and C4α proteins in mice, C2C12 myoblasts, and mouse skeletal muscle cells. In addition, BPA markedly upregulated the transcription of tumor necrosis factor-α (Tnfα) in C2C12 myoblasts and mouse skeletal muscle cells, which was substantially inhibited by 5z-7-oxozeanol and parthenolide, providing further evidence of BPA-induced inflammation in muscle cells. Our bioinformatics and subsequent animal and in vitro validations demonstrate that BPA can activate inflammation in skeletal muscle, which could be a risk factor underlying chronic muscle weakness and wastage.
Assuntos
Compostos Benzidrílicos , Perfilação da Expressão Gênica , Músculo Esquelético , Fenóis , Compostos Benzidrílicos/toxicidade , Animais , Fenóis/toxicidade , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Transcriptoma/efeitos dos fármacos , Camundongos Endogâmicos C57BLRESUMO
Particulate matter (PM) generated by environmental and air pollution is known to have detrimental effects on human health. Among these, PM2.5 particles (diameter < 2.5 µm) can breach the alveolar-capillary barrier and disseminate to other organs, posing significant health risks. Numerous studies have shown that PMs can harm various organs, including the reproductive system. Therefore, this study aimed to investigate the harmful effects of PM2.5 on mouse GC-1 spermatogonia cells (GC-1 spg cells) and to verify the ameliorative effects of parthenolide (PTL) treatment on damaged GC-1 spg cells. We observed a significant dose-dependent reduction in cell proliferation after PM2.5 concentration of 2.5 µg/cm2. Additionally, treatment with 20 µg/cm2 PM2.5 concentration significantly increased the expression of autophagy-related proteins ATG7, the ratio of LC3-II/LC3-I, and decreased phosphorylation of PI3K and AKT. Furthermore, PM2.5 exposure augmented inflammation mediator gene expressions, the phosphorylation of the inflammation-related transcription factor NF-κB p65 at Ser536, and ubiquitination. Treatment of PM2.5-exposed GC-1 spg cells with PTL significantly reduced NF-κB p65 phosphorylation and the expression of autophagy-related proteins ATG7 and LC3-II, leading to a statistically significant recovery in cell proliferation. Together, our findings elucidated the detrimental effects of PM2.5 exposure on male germ cells, and the restorative properties of PTL against air pollutants.
Assuntos
NF-kappa B , Transdução de Sinais , Humanos , Masculino , Camundongos , Animais , NF-kappa B/metabolismo , Espermatogônias/metabolismo , Material Particulado/toxicidade , Autofagia , Inflamação/induzido quimicamente , Proteínas Relacionadas à AutofagiaRESUMO
Microparticulate systems have attracted a great deal of attention over the past few years as a carrier for the delivery of cells and proteins in the treatment of defective tissues. The composition of microparticulates is regarded as being of utmost importance for the successful recruitment of the cells involved in the tissue regeneration process. Collagen-apatite nanocomposites mimicking the extracellular bone matrix are thus considered to be a potential vector for bone regeneration, either directly or through the delivery of osteogenic cells. In this study, we developed microspheres constituted of collagen and apatite for the treatment of skeletal defects. The apatite-precipitated collagen solution (30% apatite) was formed into microspheres under a water-in-oil emulsion condition. Spherical particles with diameters of tens to hundreds of micrometers (average of approximately 166 microm) were successfully produced. The internal structure of the microspheres featured a typical nanocomposite wherein apatite nanocrystalline precipitates were organized evenly within the reconstituted collagen matrix. The nanocomposite microspheres were observed to recruit favorable adhesion and growth of rat bone marrow derived stem cells. The cells supported on the nanocomposite microspheres stimulated the expression of a series of bone-associated genes. The osteogenic marker, alkaline phosphatase, was secreted to a significantly higher level on the nanocomposite microspheres than on the pure collagen counterpart. The present finding suggests that the collagen-apatite nanocomposite microspheres have high osteogenic potential and are useful for tissue-engineering applications.