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17β-estradiol at low concentrations attenuates the efficacy of tamoxifen in breast cancer therapy
2019
Xu, Zhixiang | Zheng, Xianyao | Xia, Xueshan | Wang, Xiaoxia | Luo, Nao | Huang, Bin | Pan, Xuejun
Tamoxifen has been applied widely in the treatment of estrogen receptor (ER)-positive breast cancer. The impact of low concentrations of 17β-estradiol (E2) (a pervasive environmental pollutant) on its effectiveness was studied in vitro using an MCF-7 cell line. Cell proliferation, migration, invasion, and apoptosis were studied along with cell cycle progression, reactive oxygen species generation and mitochondrial membrane potentials repression. The signaling pathways involved were identified. Typical concentrations of E2 in the environment (10⁻¹⁰ to 10⁻⁸ M) were observed to promote cell growth and protect MCF-7 cells from tamoxifen's cytotoxicity. Cell migration, invasion, cell cycle progression and apoptosis all involved in reducing tamoxifen's cytotoxicity. E2 at environmental concentrations induced PI3K/Akt and MAPK/ERK signal transduction through the estrogen receptor pathways to affect cell proliferation. Taken together, the results explain how E2 in the environment may attenuate the efficacy of tamoxifen in ER-positive breast cancer therapy. They provide considerable support for E2's adverse effects on human health and cancer management.
Show more [+] Less [-]High-throughput transcriptomics: Insights into the pathways involved in (nano) nickel toxicity in a key invertebrate test species
2019
Gomes, Susana I.L. | Roca, Carlos P. | Scott-Fordsmand, Janeck J. | Amorim, Mónica J.B.
Nickel nanoparticles (NiNPs) have an estimated production of ca. 20 tons per year in the US. Nickel has been risk-assessed for long in Europe, but not NiNPs, hence the concern for the environment. In the present study, we focused on investigating the mechanisms of toxicity of NiNPs and the comparison to NiNO3. The high-throughput microarray for the soil ecotox model Enchytraeus crypticus (Oligochaeta) was used. To anchor gene to phenotype effect level, organisms were exposed to reproduction effect concentrations EC20 and EC50, for 3 and 7 days. Results showed commonly affected pathways between NiNPs and NiNO3, including increase in proteolysis, apoptosis and inflammatory response, and interference with the nervous system. Mechanisms unique to NiNO3 were also observed (e.g. glutathione synthesis). No specific mechanisms for NiNPs were found, which could indicate that longer exposure period (>7 days) is required to capture the peak response to NiNPs. A mechanisms scheme is assembled, showing both common and unique mechanisms to NiNO3 and NiNPs, providing an important framework for further, more targeted, studies.
Show more [+] Less [-]Reprotoxicity of glyphosate-based formulation in Caenorhabditis elegans is not due to the active ingredient only
2019
Jacques, Mauricio Tavares | Bornhorst, Julia | Soares, Marcell Valandro | Schwerdtle, Tanja | Garcia, Solange | Ávila, Daiana Silva
Pesticides guarantee us high productivity in agriculture, but the long-term costs have proved too high. Acute and chronic intoxication of humans and animals, contamination of soil, water and food are the consequences of the current demand and sales of these products. In addition, pesticides such as glyphosate are sold in commercial formulations which have inert ingredients, substances with unknown composition and proportion. Facing this scenario, toxicological studies that investigate the interaction between the active principle and the inert ingredients are necessary. The following work proposed comparative toxicology studies between glyphosate and its commercial formulation using the alternative model Caenorhabditis elegans. Worms were exposed to different concentrations of the active ingredient (glyphosate in monoisopropylamine salt) and its commercial formulation. Reproductive capacity was evaluated through brood size, morphological analysis of oocytes and through the MD701 strain (bcIs39), which allows the visualization of germ cells in apoptosis. In addition, the metal composition in the commercial formulation was analyzed by ICP-MS. Only the commercial formulation of glyphosate showed significant negative effects on brood size, body length, oocyte size, and the number of apoptotic cells. Metal analysis showed the presence of Hg, Fe, Mn, Cu, Zn, As, Cd and Pb in the commercial formulation, which did not cause reprotoxicity at the concentrations found. However, metals can bioaccumulate in soil and water and cause environmental impacts. Finally, we demonstrated that the addition of inert ingredients increased the toxic profile of the active ingredient glyphosate in C. elegans, which reinforces the need of components description in the product labels.
Show more [+] Less [-]Dibutyl phthalate exposure disrupts the progression of meiotic prophase I by interfering with homologous recombination in fetal mouse oocytes
2019
Tu, Zhihan | Mu, Xinyi | Chen, Xuemei | Geng, Yanqing | Zhang, Yan | Li, Qingying | Gao, Rufei | Liu, Taihang | Wang, Yingxiong | He, Junlin
Dibutyl phthalate (DBP), one of the most widely used plasticizers, is a known environmental endocrine disruptor that impairs male and female fertility. In this study, oral administration of DBP was given to pregnant mice on 14.5 days post coitus (dpc) for 3 days; and additionally, DBP was added into the culture of 14.5 dpc fetal ovaries for 3 days. DBP exposure during gestation disturbed the progression of meiotic prophase I of mouse oocytes, specifically from the zygotene to pachytene stages. Meanwhile, the DBP-exposed pachytene oocytes showed increased homologous recombination sites and unrepaired DNA damage. Furthermore, DBP caused DNA damage by increasing oxidative stress, decreased the expression of multiple critical meiotic regulators, and consequently induced oocyte apoptosis. Moreover, the effect of DBP on meiosis I prophase involved estrogen receptors α and β. Collectively, these results demonstrated a set of meiotic defects in DBP-exposed fetal oocytes. As aberrations in homologous recombination can result in aneuploid gametes and embryos, this study provides new support for the deleterious effects of phthalates.
Show more [+] Less [-]Activation of NF-κB pathways mediating the inflammation and pulmonary diseases associated with atmospheric methylamine exposure
2019
Li, Guiying | LIao, Yi | Hu, Junjie | Lu, Lirong | Zhang, Yanan | Li, Bing | An, Taicheng
The effects of methylamine on human health have been debated for several years, but the exact adverse outcomes and definite signaling cascades have not been elucidated yet. Herein, a NF-κB signal pathway, a positive regulator of inflammation was identified as the main pathway of methylamine exposure induced adverse effects in bronchial airway cells (16HBE) for the first time. The results indicated that methylamine could stimulate the overproduction of reactive oxygen species (ROS) in cytoplasm and mitochondria of 16HBE cells. Moreover, ROS accelerate the translocation and phosphorylation of NF-κB in nucleic and promote the expression of inflammatory, such as IL-8 and IL-6. As a result, methylamine was found to be increased ROS-mediated NF-κB activation in cells, leading to the production of inflammatory cytokine. Furthermore, the results also showed that methylamine could affect the expression of cytokines related genes, p53, STAT3, Bcl2, c-myc, Cyclin D, Hes1, Mcl-1, TGF-β2. The breakdown of those cell proliferation and apoptosis related genes were leading to a common toxic mechanism of cell death. In summary, our work uncovers a mechanism by which methylamine can induce the formation of inflammation response and demonstrates potential inflammation and carcinogenesis in human airway cell upon the methylamine inhaled.
Show more [+] Less [-]Aryl-phosphorus-containing flame retardants induce oxidative stress, the p53-dependent DNA damage response and mitochondrial impairment in A549 cells
2019
Yuan, Shengwu | Han, Yingnan | Ma, Mei | Rao, Kaifeng | Wang, Zijian | Yang, Rong | Liu, Yihong | Zhou, Xiaohong
Aryl phosphorus-containing flame retardants (aryl-PFRs) have been frequently detected with increasingly used worldwide as one of alternatives for brominated flame retardants. However, information on their adverse effects on human health and ecosystem is insufficient, with limited study on their molecular mode of action in vitro. In this study, the cytotoxicity, DNA damage, mitochondrial impairment and the involved molecular mechanisms of certain frequently detectable aryl-PFRs, including 2-ethylhexyldiphenyl phosphate (EHDPP), methyl diphenyl phosphate (MDPP), bisphenol-A bis (diphenyl phosphate) (BDP), isodecyl diphenyl phosphate (IDPP), cresyl diphenyl phosphate (CDP) and the structurally similar and widely used organophosphorus pesticide chlorpyrifos (CPF), were evaluated in A549 cells using high-content screening (HCS) system. Aryl-PFRs showed different lethal concentration 50 (LC50) values ranging from 97.94 to 546.85 μM in A549 cells using CCK-8 assay. EHDPP, IDPP, CDP, MDPP and CPF demonstrated an ability to induce DNA damage, evidenced by increased DNA content and S phase-reducing cell cycle arrest effect using fluorophore dye cocktail assay. Additionally, the selected aryl-PFRs induced mitochondrial impairment by the increasing mitochondrial mass and decreasing mitochondrial membrane potential. Moreover, BDP, MDPP, and CDP, which contain short alkyl chains showed their potential oxidative stress with intracellular ROS and mitochondrial superoxide overproduction from an initially relatively low concentration. Additionally, based on the promotion of firefly luminescence in p53-transfected A549 cells, p53 activation was found to be involved in aryl-PFRs-induced DNA damage. Further real-time PCR results showed that all selected aryl-PFRs triggered p53/p21/gadd45β-, and p53/p21/mdm2-mediated cell cycle pathways, and the p53/bax mediated apoptosis pathway to induce DNA damage and cytotoxic effects. These results suggest that aryl-PFRs (e.g., BDP, MDPP, CDP) cause oxidative stress-mediated DNA damage and mitochondrial impairment, and p53-dependent pathway was involved in the aryl-PFRs-induced DNA damage and cell cycle arrest. In conclusion, this study improves the understanding of PFRs-induced adverse outcomes and the involved molecular mechanism.
Show more [+] Less [-]BDE-209 induces autophagy and apoptosis via IRE1α/Akt/mTOR signaling pathway in human umbilical vein endothelial cells
2019
Hou, Yun | Fu, Jiarong | Sun, Shitian | Jin, Yinchuan | Wang, Xifeng | Zhang, Lianshuang
Recently, the essentiality and fatalness of cardiovascular diseases is attracting much attention. Polybrominated diphenyl ethers (PBDEs) are persistent environmental pollutants, which could induce the toxic effect and have been implicated in the occurrence and development of cardiovascular diseases. However, it is unclear how autophagy and apoptosis induced by BDE-209 in endothelial cells are regulated. The aim of the present study was to investigate the effects of BDE-209 on human umbilical vein endothelial cells (HUVECs) and elucidate the mechanisms involved. HUVECs were treated with a wide range concentration of BDE-209 for 24 h. The appearance of autophagy was tested by the testing index such as outcomes of monodansylcadaverine (MDC) staining and lysotracker staining, observation of autophagosomes and conversion between autophagy marker light chain 3 (LC3)-I and LC3-II. Besides, the apoptotic cell rate was detected with flow cytometry. In addition, BDE-209 induced endoplasmic reticulum (ER) stress was detected by transmission electron microscopy (TEM). Our data suggest that the exposure of BDE-209 could induce autophagy, which was confirmed by MDC staining, transmission electron microscopy observation, lysotracker staining and LC3-I/LC3-II conversion. Besides, the ER stress-related inositol-requiring enzyme 1α (IRE1α)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway could be activated by reactive oxygen species (ROS) to regulate autophagy. Moreover, the apoptosis of endothelial cells was alleviated when autophagy was blocked by 3-Methyladenine (3-MA). The results demonstrated that BDE-209 could induce the production of ROS and ER stress, activate autophagy through IRE1α/AKT/mTOR signaling pathway and ultimately induce apoptosis of vascular endothelial cells. These findings indicate that exposure to PBDE is possible to be a potential risk factor for cardiovascular diseases.
Show more [+] Less [-]BDE-209 induces male reproductive toxicity via cell cycle arrest and apoptosis mediated by DNA damage response signaling pathways
2019
Decabromodiphenyl ether (BDE-209) is commonly used as a flame retardant, usually in products that were utilized in electronic equipment, plastics, furniture and textiles. To identify the impacts of BDE-209 on the male reproductive system and the underlying toxicological mechanisms, 40 male ICR mice were randomly divided into four groups, which were then exposed to BDE-209 at 0, 7.5, 25 and 75 mg kg−1 d−1 for four weeks, respectively. With regard to the in vitro study, GC-2spd cells were treated with BDE-209 at 0, 2, 8 and 32 μg mL−1 for 24 h, respectively. The results from the in vivo experiments showed that BDE-209 resulted in damage to the testis structure, led to cell apoptosis in testis and decreased sperm number and motility, while sperm malformation rates were significantly increased. Moreover, BDE-209 could induce oxidative stress with decreased testosterone levels, result in DNA damage and activate DNA damage response signaling pathways (ATM/Chk2, ATR/Chk1 and DNA-PKcs/XRCC4/DNA ligase Ⅳ). The data from the in vitro experiments showed that BDE-209 led to cytotoxicity by reducing cell viability and increasing LDH release as well. BDE-209 also induced DNA strand breaks, cell cycle arrest at G1 phase and elevated reactive oxygen species (ROS) level in GC-2 cells. These results suggested that BDE-209 could lead to male reproductive toxicity by inducing DNA damage and failure of DNA damage repair which resulted in cell cycle arrest and apoptosis of spermatogenic cell. The present study provided new evidence to elucidate the potential mechanism of male reproductive toxicity induced by BDE-209.
Show more [+] Less [-]Multi-generational impacts of organic contaminated stream water on Daphnia magna: A combined proteomics, epigenetics and ecotoxicity approach
2019
Chatterjee, Nivedita | Choi, Suhyon | Kwon, Oh Kwang | Lee, Sangkyu | Choi, Jinhee
The present study aimed to elucidate the mechanisms of organismal sensitivity and/or physiological adaptation in the contaminated water environment. Multigenerational cultures (F0, F1, F2) of Daphnia magna in collected stream water (OCSW), contaminated with high fecal coliform, altered the reproductive scenario (changes in first brood size timing, clutch numbers, clutch size etc.), compromised fitness (increase hemoglobin, alteration in behavior), and affected global DNA methylation (hypermethylation) without affecting survival. Using proteomics approach, we found 288 proteins in F0 and 139 proteins in F2 that were significantly differentially upregulated after OCSW exposure. The individual protein expressions, biological processes and molecular functions were mainly related to metabolic processes, development and reproduction, transport (protein/lipid/oxygen), antioxidant activity, increased globin and S-adenosylmethionine synthase protein level etc., which was further found to be connected to phenotype-dependent endpoints. The proteomics pathway analysis evoked proteasome, chaperone family proteins, neuronal disease pathways (such as, Parkinson's disease) and apoptosis signaling pathways in OCSW-F0, which might be the cause of behavioral and developmental alterations in OCSW-F0. Finally, chronic multigenerational exposure to OCSW exhibited slow physiological adaptation in most of the measured effects, including proteomics analysis, from the F0 to F2 generations. The common upregulated proteins in both generations (F0 & F2), such as, globin, vitellinogen, lipid transport proteins etc., were possibly play the pivotal role in the organism's physiological adaptation. Taken together, our results, obtained with a multilevel approach, provide new insight of the molecular mechanism in fecal coliform-induced phenotypic plasticity in Daphnia magna.
Show more [+] Less [-]Spermatogenesis disorder caused by T-2 toxin is associated with germ cell apoptosis mediated by oxidative stress
2019
Yang, Xu | Zhang, Xuliang | Zhang, Jian | Ji, Qiang | Huang, Wanyue | Zhang, Xueyan | Li, Yanfei
T-2 toxin is an unavoidable contaminant in human food, animal feeds, and agricultural products. T-2 toxin has been found to impair male reproductive function. But, few data is available that reveals the reproductive toxicity mechanism. In the study, male Kunming mice were orally administrated with T-2 toxin at the doses of 0, 0.5, 1 or 2 mg/kg body weight for 28 days. The body and reproductive organs weight, the concentration, malformation rate and ultrastructure of sperm in cauda epididymis were detected. Oxidative stress biomarkers and apoptosis were also measured in testes. Histological change of testes was performed by H&E and TUNEL staining. T-2 toxin down-regulated body and reproductive organs (testis, epididymis and seminal vesicle) weight, sperm concentration, increased sperm malformation rate and damaged the ultrastructure of sperm and structure of testes. T-2 toxin treatment increased the reactive oxygen species (ROS) and malondialdehyde content, while, decreased the total anti-oxidation capacity (T-AOC) and the superoxide dismutase activity in testes. T-2 toxin exposure increased the TUNEL-positive germ cells, the activities and mRNA expressions of caspase-3, caspase-8 and caspase-9, the mRNA expression of Bax, and inhibited the Bcl-2 mRNA expression. Furthermore, the expressions of caspase-3, caspase-8 caspase-9 and Bax were positively correlated with ROS level, but negatively correlated with T-AOC in testis. In summary, T-2 toxin caused spermatogenesis disorder associated with the germ cell apoptosis medicated by oxidative stress, impairing the male reproductive function.
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