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Cadmium exposure induces osteoporosis through cellular senescence, associated with activation of NF-κB pathway and mitochondrial dysfunction
2021
Luo, Huigen | Gu, Renjie | Ouyang, Huiya | Wang, Lihong | Shi, Shanwei | Ji, Yuna | Bao, Baicheng | Liao, Guiqing | Xu, Baoshan
Cadmium (Cd) is a heavy metal toxicant as a common pollutant derived from many agricultural and industrial sources. The absorption of Cd takes place primarily through Cd-contaminated food and water and, to a significant extent, via inhalation of Cd-contaminated air and cigarette smoking. Epidemiological data suggest that occupational or environmental exposure to Cd increases the health risk for osteoporosis and spontaneous fracture such as itai-itai disease. However, the direct effects and underlying mechanism(s) of Cd exposure on bone damage are largely unknown. We used primary bone marrow-derived mesenchymal stromal cells (BMMSCs) and found that Cd significantly induced BMMSC cellular senescence through over-activation of NF-κB signaling pathway. Increased cell senescence was determined by production of senescence-associated secretory phenotype (SASP), cell cycle arrest and upregulation of p21/p53/p16ᴵᴺᴷ⁴ᵃ protein expression. Additionally, Cd impaired osteogenic differentiation and increased adipogenesis of BMMSCs, and significantly induced cellular senescence-associated defects such as mitochondrial dysfunction and DNA damage. Sprague-Dawley (SD) rats were chronically exposed to Cd to verify that Cd significantly increased adipocyte number, and decreased mineralization tissues of bone marrow in vivo. Interestingly, we observed that Cd exposure remarkably retarded bone repair and regeneration after operation of skull defect. Notably, pretreatment of melatonin is able to partially prevent Cd-induced some senescence-associated defects of BMMSCs including mitochondrial dysfunction and DNA damage. Although Cd activated mammalian target of rapamycin (mTOR) pathway, rapamycin only partially ameliorated Cd-induced cell apoptosis rather than cellular senescence phenotypes of BMMSCs. In addition, a selective NF-κB inhibitor moderately alleviated Cd-caused the senescence-related defects of the BMMSCs. The study shed light on the action and mechanism of Cd on osteoporosis and bone ageing, and may provide a novel option to ameliorate the harmful effects of Cd exposure.
Mostrar más [+] Menos [-]β-catenin mediates fluoride-induced aberrant osteoblasts activity and osteogenesis
2020
Chu, Yanru | Gao, Yanhui | Yang, Yanmei | Liu, Yang | Guo, Zining | Wang, Limei | Huang, Wei | Wu, Liaowei | Sun, Dianjun | Gu, Weikuan
Excess fluoride in drinking water is an environmental issue of increasing worldwide concern, because of its adverse effect on human health. Skeletal fluorosis caused by chronic exposure to excessive fluoride is a metabolic bone disease characterized by accelerated bone turnover accompanied by aberrant activation of osteoblasts. It is not clear whether Wnt/β-catenin signaling, an important signaling pathway regulating the function of osteoblasts, mediates the pathogenesis of skeletal fluorosis. A cross-sectional case-control study was conducted in Tongyu County, Jilin Province, China showed that fluoride stimulated the levels of OCN and OPG, resulting in accelerated bone turnover in patients with skeletal fluorosis. To investigate the influence of fluoride on Wnt/β-catenin signaling pathway, 64 male BALB/c mice were allotted randomly to four groups and treated with deionized water containing 0, 55, 110 and 221 mg/L NaF for 3 months, respectively. The results demonstrated that fluoride significantly increased mouse cancellous bone formation and the protein expression of Wnt3a, phospho-GSK3β (ser 9) and Runx2. Moreover, partial correlation analysis indicated that there was no significant correlation between fluoride exposure and Runx2 protein levels, after adjusting for β-catenin, suggesting that β-catenin might play a crucial role in fluoride-induced aberrant osteogenesis. In vivo, viability of SaoS2 cells was significantly facilitated by 4 mg/L NaF, and fluoride could induce the abnormal activation of Wnt/β-catenin signaling, the expression of its target gene Runx2 and significantly increased Tcf/Lef reporter activity. Importantly, inhibition of β-catenin suppressed fluoride-induced Runx2 protein expression and the osteogenic phenotypes. Taken together, the present study provided in vivo and in vitro evidence reveals a potential mechanism for fluoride-induced aberrant osteoblast activation and indicates that β-catenin is the pivot molecule mediating viability and differentiation of osteoblasts and might be a therapeutic target for skeletal fluorosis.
Mostrar más [+] Menos [-]Disturbance in transcriptomic profile, proliferation and multipotency in human mesenchymal stem cells caused by hexafluoropropylene oxides
2022
Pan, Yifan | Qin, Hui | Zheng, Lu | Guo, Yong | Liu, Wei
As alternatives to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide dimer acid (HFPO-DA) and hexafluoropropylene oxide trimer acid (HFPO-TA) have raised concerns of their potential health risks. Human bone marrow mesenchymal stem cell was employed as an in vitro model to investigate the molecular targets and the adverse effects of HFPOs in stem cells in concentrations range starting at human relevant levels. Unsupervised transcriptomic analysis identified 1794 and 1429 DEGs affected by HFPO-TA and HFPO-DA, respectively. Cell cycle-associated biological processes were commonly altered by both chemicals. 18 and 35 KEGG pathways were enriched in HFPO-TA and HFPO-DA treatment group, respectively, among which multiple pathways were related to cancer and pluripotency. Few genes in PPAR signalling pathway were disturbed by HFPOs suggesting the involvement of PPAR-independent toxic mechanism. HFPO-TA promoted cell proliferation with significance at 1 μM mRNA levels of CDK and MYC were down-regulated by HFPOs, suggesting the negative feedback regulation to the abnormal cell proliferation. Decreased expression of CD44 protein, and ENG and THY1 mRNA levels demonstrated HFPOs-caused changes of hBMSCs phenotype. The osteogenic differentiation was also inhibited by HFPOs with reduced formation of calcium deposition. Furthermore, gene and protein expression of core pluripotency regulators NANOG was enhanced by HFPO-TA. The present study provides human relevant mechanistic evidence for health risk assessment of HFPOs, prioritizing comprehensive carcinogenicity assessment of this type of PFOA alternatives.
Mostrar más [+] Menos [-]Low-dose cadmium exposure acts on rat mesenchymal stem cells via RANKL/OPG and downregulate osteogenic differentiation genes
2019
Lv, Ying-Jian | Wei, Qin-Zhi | Zhang, Yang-Cong | Huang, Rui | Li, Bai-Sheng | Tan, Jian-Bin | Wang, Jing | Ling, Hai-Tuan | Wu, Shi-Xuan | Yang, Xing-Fen
Chronic cadmium (Cd) toxicity is a significant health concern, and the mechanism of long-term low-dose Cd exposure on bone has not been fully elucidated till date. This study aimed to assess the association between rat mesenchymal stem cells (MSCs) and long-term Cd exposure through 38-week intake of CdCl2 at 1 and 2 mg/kg body weight (bw). Increased gene expression of receptor activator of NF-κB ligand (RANKL) and decreased gene expression of osteoprotegerin (OPG) were observed. Fold change of RANKL gene expression (fold change = 1.97) and OPG gene expression (fold change = 1.72) showed statistically significant differences at dose 2 mg/kg bw. Decreased expression of key genes was observed during the early osteogenic differentiation of MSCs. The gene expression of Osterix in 1 mg/kg bw group was decreased by 3.70-fold, and the gene expressions of Osterix, Osteopontin, collagen type I alpha 2 chain (COL1a2) and runt-related transcription factor 2 (RUNX2) in 2 mg/kg bw group were decreased by 1.79, 1.67, 1.45 and 1.35-folds, respectively. Exposure to CdCl2 induced an increase in the renal Cd load, but only an adaptive response was observed, including increased expression of autophagy-related proteins LC3B and Beclin-1, autophagy receptor p62, and heme oxygenase 1 (HO-1), which is an inducible isoform that releases in response to stress. There were no significant changes in the urinary low molecular weight proteins including N-acetyl-b-D-glucosaminidase (NAG), β2-microglobulin and albumin (U-Alb). Urinary calcium (Ca) excretion showed no increase, and no obvious renal histological changes. Taken together, these results indicated that the chronic CdCl2 exposure directly act on MSCs through RANKL/OPG pathway and downregulate the key genes involved in osteogenic differentiation of MSCs. The toxic effect of Cd on bone may occur in parallel to nephrotoxicity.
Mostrar más [+] Menos [-]Molecular pathology of skeletal growth anomalies in the brain coral Platygyra carnosa: A meta-transcriptomic analysis
2017
Zhang, Yu | Sun, Jin | Mu, Huawei | Lun, Janice C.Y. | Qiu, Jian-Wen
Coral skeletal growth anomaly (GA) is a common coral disease. Although extensive ecological characterizations of coral GA have been performed, the molecular pathology of this disease remains largely unknown. We compared the meta-transcriptome of normal and GA-affected polyps of Platygyra carnosa using RNA-Seq. Approximately 50 million sequences were generated from four pairs of normal and GA-affected tissue samples. There were 109 differentially expressed genes (DEGs) in P. carnosa and 31 DEGs in the coral symbiont Symbiodinium sp. These differentially expressed host genes were enriched in GO terms related to osteogenesis and oncogenesis. There were several differentially expressed immune genes, indicating the presence of both bacteria and viruses in GA-affected tissues. The differentially expressed Symbiodinium genes were enriched in reproduction, nitrogen metabolism and pigment formation, indicating that GA affects the physiology of the symbiont. Our results have provided new insights into the molecular pathology of coral GA.
Mostrar más [+] Menos [-]Mapping elements distribution in carapace of Caretta caretta: A strategy for biomonitoring contamination in sea turtles?
2015
Mattei, D. | Veschetti, E. | D’Ilio, S. | Blasi, M.F.
This study analyzed the carapace distribution of Ca, Cd, Cr, Cu, Mg, Mn, Pb, Sb, U, V and Zn by GF-AAS and ICP-AES in one specimen of Caretta caretta from Mediterranean Sea. Calcium, Mg, Mn, Pb, U, Zn were mainly distributed in the central area while Cd, Cr, Cu, Sb, V in lateral areas. Cadmium, Cr, Mg, Mn, Sb, U and V were different between lateral areas.The different distribution may be related to several exposures during lifetime and/or the shell ossification during growth. Carapace may be a suitable matrix for metal biomonitoring, however, further studies are required to confirm these findings.
Mostrar más [+] Menos [-]Aloe vera protects against fluoride-induced teratogenic effects during pre- and postnatal development in mice
2022
Pregnancy and feto-gestational toxicities on exposure to fluoride and its possible amelioration on co-administration with aloe vera were studied in pregnant Swiss albino mice. Once the confirmed pregnancy was tested, animals were equally divided into four groups as follows: group I was given no treatment and served as control, and groups II and III were administered with 100 and 300 ppm sodium fluoride, respectively, while group IV was co- administered aloe vera (300 mg/kg bw) along with sodium fluoride (300 ppm) daily for 14 days prior to gestation and continued till the 18th day of gestation. Animals were sacrificed on the 19th day of gestation for prenatal observations. Maternal body weight, the gravid uterine weight, number of corpora lutea in both the ovaries, number of implantations and resorptions, number of live (mature and immature) fetuses, and number of dead fetuses were examined in each dam. The treatment continued in another set of animals till the completion of the weaning period to observe postnatal changes due to test substances on the mother and pups. Sodium fluoride–treated animals showed morphometric and skeletal changes which were more pronounced in the high-dose group showing significantly decreased body weight gain in pregnant mothers and dead/immature fetuses. Morphometric changes included open eyelids, limb defects, wrinkles on the whole body, anophthalmia, pulmonary edema, enlarged esophagus, and decreased body weight of fetuses and pups. Alizarin-prepared skeletal structures of fetuses of such female mice showed delayed ossification or bending in the number of bones of skull, thoracic, and limb regions. However, concomitant exposure to sodium fluoride and aloe vera in treated animals led to a marked improvement in all the prenatal and postnatal variables. The study suggests that sodium fluoride at high concentrations may be teratogenic while co-administration of aloe vera during fluoride exposure might be beneficial in reducing these toxic effects. The use of aloe vera as a preventive agent or as a complimentary agent is thus recommended following fluoride exposure through the oral route.
Mostrar más [+] Menos [-]Induction of fetal abnormalities and genotoxicity by molybdenum nanoparticles in pregnant female mice and fetuses
2020
Mohamed, Hanan RH | El-Atawy, Radwa H. | Ghoneim, Ahmed M. | El-Ghor, Akmal A.
Increasing the uses of molybdenum (Mo) nanoparticles in a wide range of applications including food, industry, and medicine, resulted in increased human exposure and necessitated the study of their toxic effects. However, almost no studies are available on their genotoxic effects, especially on pregnant females and their fetuses. Therefore, this study was undertaken to estimate the possible induction of genotoxicity and fetal abnormalities, especially fetal malformations and skeletal abnormalities by Mo nanoparticle administration in mice. Oral administration of Mo nanoparticles resulted in significant decreases in the maternal body weight, the number and length of fetuses as well as skeletal abnormalities mainly less ossification and less chondrification. Administration of Mo nanoparticles also caused DNA damage induction which elevated the expression levels of p53, the vital gene in maintaining the genomic stability and cell differentiation in both maternal and fetus tissues. Similarly, the expression levels of E-Cad and N-Cad genes that control skeleton development have also been increased in the tissues of female mice administered Mo nanoparticles and their fetuses. Thus, we concluded that oral administration of Mo nanoparticles induced genotoxic effects and fetal abnormalities that necessitated further studies on the possible toxic effects of Mo nanoparticles.
Mostrar más [+] Menos [-]Evaluation of exposure to fluoride in child population of North Argentina
2017
Rocha, René Antonio | Calatayud, Marta | Devesa, Vicenta | Vélez, Dinoraz
Fluoride is an important element for humans. It inhibits initiation and progression of dental caries and stimulates bone formation. However, excessive intake may lead to the appearance of dental and/or skeletal fluorosis and a decrease in intellectual coefficient in child populations. This study evaluates exposure to fluoride in the child population of Chaco province (Argentina) by analysis of drinking water, food and its bioaccessible fraction (quantity of fluoride solubilised by gastrointestinal digestion and available for intestinal absorption) and urine as a biomarker of internal dose. The concentration of fluoride in drinking water varied between 0.050 and 4.6 mg L⁻¹, and 80% of the samples exceeded the WHO drinking-water guideline value (1.5 mg L⁻¹). Fluoride concentrations in food ranged between 0.80 and 3.0 mg kg⁻¹ fresh weight (fw), being lower in bioaccessible fraction (0.43–1.9 mg kg⁻¹, fw). On the basis of the consumption data declared for the young child population, fluoride intake varies between 4.1 and 6.5 mg day⁻¹, greater than the level recommended for this age group. Moreover, in some cases, concentrations of fluoride found in urine (0.62–8.9 mg L⁻¹) exceeded those reported in areas with declared fluorosis. All data obtained show the worrying situation of child population in this area of Argentina.
Mostrar más [+] Menos [-]Differential effects on adiposity and serum marker of bone formation by post-weaning exposure to methylparaben and butylparaben
2016
Hu, Pan | Kennedy, Rebekah C. | Chen, Xin | Zhang, Jia | Shen, Chwan-Li | Chen, Jiangang | Zhao, Ling
Paraben esters and their salts are widely used as preservatives in cosmetics, personal care products, pharmaceuticals, and foods. We and others have reported that parabens promote adipogenesis in vitro. Here, we investigated the effects of post-weaning exposure to parabens (methylparaben and butylparaben) on body weight, white adipose tissue mass, and obesity associated metabolic biomarkers in female obesity-prone C57BL/6J mice fed with a chow diet or a high fat diet. Methylparaben exposure by daily oral gavage (100 mg/kg/day) increased adiposity and serum leptin levels compared to the controls when fed the chow diet, but not the high fat diet. In contrast, butylparaben exposure did not induce such effects. Exposure to either paraben induced changes in gene expression related to adipocyte differentiation and lipogenesis in the white adipose tissue (WAT) and the liver, regardless of diet. Moreover, exposure to both parabens under the chow diet significantly decreased serum procollagen type 1 N-terminal propeptide (P1NP) but had no effects on C-terminal telopeptide of type I collagen (CTX-I) levels, suggesting that post-weaning exposure to paraben may negatively affect bone formation, but not bone resorption. Taken together, our results demonstrate that post-weaning exposure to paraben, methylparaben in particular, promotes adipogenesis but suppresses serum marker of bone formation in vivo. Our results add to the growing body of literature indicating potential negative health outcomes associated with paraben exposure. Further study of early life exposure to paraben on the development of fat and bone is warranted.
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