Perfluoroalkyl substances (PFASs) are a classic environmental endocrine disruptor with carcinogenic risk. Epidemiological studies have shown that PFASs contamination is associated with breast cancer development, but the mechanism remains largely unknown. This study first obtained complex biological information about PFASs-induced breast cancer through the comparative toxicogenomics database (CTD). The Protein-Protein Interaction (PPI) network, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis were utilized to investigate molecular pathways. The ESR1 and GPER expression levels at different pathological stages and the prognosis of Breast Cancer patients were confirmed using the Cancer Genome Atlas (TCGA) database. Furthermore, we verified this by cellular experiments and the results showed breast cancer cell migration and invasion were promoted by PFOA. Two estrogen receptors (ER), ERα and G protein-coupled estrogen receptor (GPER), mediated the promoting effects of PFOA by activating MAPK/Erk and PI3K/Akt signaling pathways. These pathways were regulated by ERα and GPER in MCF-7 cells or independently by GPER in MDA-MB-231 cells. Overall, our study provides a better overview of the mechanisms associated with PFASs-induced breast cancer development and progression.

Polychlorinated biphenyls (PCBs) have been demonstrated as a kind of the persistent organic pollutants (POPs) that could exert complicated influences towards metabolism in human bodies. Since hydroxylated polychlorinated biphenyls (OH-PCBs) are important metabolites of PCBs, our study focuses on investigating the potential inhibitory capability of OH-PCBs on four human sulfotransferase (SULT) isoforms. P-nitrophenol (PNP) was utilized as nonselective probe substrate for this study, and recombinant SULT isoforms were utilized as the enzyme resources. Ultra-performance liquid chromatography (UPLC)-UV detecting system was used to analyze PNP and its metabolite PNP-sulfate. As result, 100 μM of most tested OH-PCBs significantly inhibited the activity of four SULT isoforms. Concentration-dependent inhibition of OH-PCBs towards SULTs was found, and half inhibition concentration values (IC50) of some inhibition processes were determined. Inhibition kinetics (inhibition kinetic type and parameters) were determined using 4'-OH-PCB106 as the representative OH-PCB, SULT1B1 and SULT1E1 as representative SULT isoforms. The inhibition kinetic parameters (Ki) were 1.73 μM and 1.81 μM for the inhibition of 4'-OH-PCB106 towards SULT1B1 and SULT1E1, respectively. In silico docking simulation was utilized to analyze the inhibition capability of 2'-OH-PCB5, 4'-OH-PCB9, 2'-OH-PCB12 towards SULT1A3.All these results obtained in this study are helpful for further understanding the toxicity of PCBs.

Mesenchymal stem cells (MSCs) have been investigated in preventing and treating allergic asthma in many reports. Recently, MSC-derived exosomes (MSC-Exo) were showed a promising alternative to stem cell-based therapy in many kinds of diseases. However, the effect of MSC-Exo on allergic asthma has not been investigated thoroughly thus far. Here, we aimed to investigate the immunomodulation effect of MSC-Exo in a murine model of asthma and explore the underlying mechanisms. BALB/c mice were sensitized and challenged by OVA to establish asthma model. MSC-Exo were intranasally delivered before or during challenge and the protective effect were assessed after the last OVA challenge. Allergic airway inflammation elicited by OVA were significantly attenuated by intranasal delivery of MSC-Exo. To explore the protective mechanism of MSC-Exo, lung interstitial macrophages (IMs) and alveolar macrophages (AMs) were analyzed by flow cytometry and the origin of IMs were traced. Lung IMs ratios were significantly enhanced and high level of IL-10 was produced after MSC-Exo intranasal delivery. IMs ratios were not obviously affected by CCR2 inhibitor or Clodronate liposome administration, whereas significantly decreased in splenectomized mice. Cx3cr1+ cell specific IL-10 conditionally deficient mice were used to further examine the role of IL-10 producing IMs in allergic asthma. IMs-mediated protection was dependent on IL-10, given that the protection disappeared in Cx3cr1-IL-10-/-mice. In conclusion, intranasal delivery of MSC-Exo could substantially expand lung IL-10-producing IMs, which may originate from spleen, thus contribute to protection against allergic asthma in mice.

Endocrine disrupting chemicals may disrupt developing neuroendocrine systems, especially when the exposure occurs during a critical period. This study aimed to investigate whether prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a major component of plasticizers used worldwide, disrupted the development of a network of genes important for neuroendocrine function in male rats. Pregnant rats were treated with corn oil (vehicle control), 2, 10 or 50 mg/kg DEHP by gavage from gestational day 14 to 19. The neuroendocrine gene expressions were quantified using a 48-gene Taqman qPCR array in the whole hypothalamus of neonatal rats (postnatal day 1) and in the anteroventral periventricular nucleus (AVPV), medial preoptic nucleus (MPN) and arcuate nucleus (ARC) of adult rats (postnatal day 70). Immunofluorescent signals of ERα and CYP19 were detected using the confocal microscopy in adult AVPV, MPN and ARC. The results showed that prenatal DEHP exposure perturbed somatic and reproductive development of offspring. Eleven genes were down-regulated in neonatal hypothalamus and showed non-monotonic dose–response relationships, that the 10 mg/kg DEHP dosage was associated with the greatest number of gene expression changes. Different from this, 14 genes were altered in adult AVPV, MPN and ARC and most of alterations were found in the 50 mg/kg DEHP group. Also, 50 mg/kg DEHP reduced ERα expression in the ARC, but no alterations were observed in CYP19 expression. These results indicated that prenatal DEHP exposure may perturb hypothalamic gene programming and the influences are permanent. The effects showed dependence on developmental stages and nuclei region.

1.Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) and has been clinically utilized to prevent the rejection of organ transplants. This study aims to determine the inhibition of everolimus on the activity of phase-II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs).2.The results showed that 100 M of everolimus exerted more than 80% inhibition toward UGT1A1, UGT-1A3 and UGT-2B7. UGT1A3 and UGT2B7 were selected to elucidate the inhibition mechanism, and in silico docking showed that hydrogen bonds and hydrophobic interactions mainly contributed to the strong binding of everolimus toward the activity cavity of UGT1A3 and UGT2B7. Inhibition kinetic-type analysis using Lineweaver-Burk plot showed competitive inhibition toward all these UGT isoforms. The inhibition kinetic parameters (K-i) were calculated to be 2.3, 0.07 and 4.4 M for the inhibition of everolimus toward UGT1A1, UGT-1A3 and UGT-2B7, respectively.3.In vitro-in vivo extrapolation (IVIVE) showed that [I]/K-i value was calculated to be 0.004, 0.14 and 0.002 for UGT1A1, UGT-1A3 and UGT-2B7, respectively. Therefore, high DDI potential existed between everolimus and clinical drugs mainly undergoing UGT1A3-catalyzed glucuronidation.

1. UDP-glucuronosyltransferases (UGTs) are important drug-metabolizing enzymes (DMEs) catalyzing the glucuronidation elimination of various xenobiotics and endogenous substances. Endogenous substances are important regulators for the activity of various UGT isoforms. Triiodothyronine (T3) and thyroxine (T4) are important thyroid hormones essential for normal cellular differentiation and growth. The present study aims to elucidate the inhibition behavior of T3 and T4 on the activity of UGT isoforms. 2. In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was used to screen the inhibition potential of T3 and T4 on the activity of various UGT isoforms. Initial screening results showed that T4 exerted stronger inhibition potential than T3 on the activity of various UGT isoforms at 100 μM. Inhibition kinetics was determined for the inhibition of T4 on the representative UGT isoforms, including UGT1A1, -1A3, -1A7, -1A8, -1A10 and -2B7. The results showed that T4 competitively inhibited the activity of UGT1A1, -1A3, -1A7, 1A10 and -2B7, and noncompetitively inhibited the activity of UGT1A8. The inhibition kinetic parameters were calculated to be 1.5, 2.4, 11, 9.6, 4.8 and 3.0 μM for UGT1A1, -1A3, -1A7, -1A8, -1A10 and -2B7, respectively. In silico docking method was employed to demonstrate why T4 exerted stronger inhibition than T3 towards UGT1A1. Stronger hydrogen bonds and hydrophobic interaction between T4 and activity cavity of UGT1A1 than T3 contributed to stronger inhibition of T4 towards UGT1A1. 3. In conclusion, more clinical monitoring should be given for the patients with the elevation of T4 level due to stronger inhibition of UGT isoforms-catalyzed metabolism of drugs or endogenous substances by T4.

The present study was performed to evaluate the insulin-like effects of zinc in normal L6 myotubes as well as its ability to alleviate insulin resistance. Glucose consumption was measured in both normal and insulin-resistant L6 myotubes. Western blotting and immunofluorescence revealed that zinc exhibited insulin-like glucose transporting effects by activating key markers that are involved in the insulin signaling cascade (including Akt, GLUT4 and GSK3β), and downregulating members of the insulin signaling feedback cascade such as mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase (S6K1). In normal L6 myotubes, zinc enhanced glucose consumption via a mechanism that might involve the activation of Akt phosphorylation, glucose transporter 4 (GLUT4) translocation and GSK3β phosphorylation. In contrast, zinc exerted insulin-mimetic effects in insulin-resistant L6 myotubes by upregulating Akt phosphorylation, GLUT4 translocation and GSK3β phosphorylation, and downregulating the expression of mTOR and S6K1. In conclusion, zinc might enhance glucose consumption by modulating insulin signaling pathways including Akt–GLUT4, GSK3β, mTOR and S6K1.

目的 探讨出生前邻苯二甲酸二(2-乙基己基)酯(DEHP)暴露对成年后SD大鼠生殖腺促性腺激素释放激素(GnRH)、促性腺激素释放激素受体(GnRHR)mRNA表达水平的影响.方法 将32只健康SD孕鼠随机分为0(溶剂对照组)和2、10、50 mg/kg DEHP染毒组,每组8只.于妊娠第14～19天,采用灌胃方式进行染毒,染毒容量为10 ml/kg,每天1次.仔鼠出生后正常饲养10周,采用实时荧光定量PCR检测卵巢和睾丸GnRH及GnRHR mRNA的表达水平.结果 与对照组相比,仅2 mg/kg DEHP染毒组成年雌性仔鼠卵巢组织内的GnRH mRNA表达水平升高,差异有统计学意义(P＜0.05);而各剂量DEHP染毒组成年雌性仔鼠卵巢组织内GnRHR mRNA的表达水平均无明显改变.各剂量DEHP染毒组成年雄性仔鼠睾丸组织GnRH及GnRHR mRNA的表达水平与对照组相比,差异均无统计学意义(P＞0.05).结论 出生前低剂量DEHP暴露可能通过上调成年后子代雌鼠卵巢GnRH基因表达水平,干扰雌性生殖内分泌调控功能,且可能存在低剂量效应.

<span id="ChDivSummary" name="ChDivSummary" class="abstract-text">目的探讨锌对胰岛素抵抗靶细胞活力和葡萄糖消耗量的影响。方法建成Hep G2细胞、3T3-L1细胞和L6成肌细胞胰岛素抵抗模型后,用10-7mol/L胰岛素和不同浓度锌（0、20、50、100、200、400μmol/L）孵育细胞,通过MTT法和葡萄糖氧化酶法测定基础状态和胰岛素刺激状态下3种胰岛素抵抗细胞葡萄糖的消耗量。结果不同剂量的锌孵育3种细胞3 h后,200、400μmol/L的锌可明显抑制各组细胞的活力（P&lt;0.05）;50¹00μmol/L的锌干预3 h能在不同程度上提高Hep G2、3T3-L1正常细胞和胰岛素抵抗细胞的葡萄糖消耗量,但其作用效果明显低于胰岛素;其中100μmol/L的锌与胰岛素共同作用的效果分别优于胰岛素或锌单独作用的效果（P&lt;0.05）;对于L6肌细胞,20、50和100μmol/L锌均能明显提高基础状态下正常细胞和胰岛素抵抗细胞的葡萄糖消耗量（P&lt;0.05）;仅有20μmol/L锌和胰岛素共同作用的效果优于胰岛素或锌单独作用的效果（P&lt;0.05）。结论不同浓度的锌可以在一定程度上提高3种胰岛素抵抗的靶细胞葡萄糖摄取量,且不同的细胞具有不同的适宜作用剂量。</span>

目的 探讨邻苯二甲酸-单-乙基己基酯[mono-(2-ethylhexyl)phthalate,MEHP]对新生大鼠海马神经元细胞活性和凋亡率的影响.方法 取出生24h内清洁级SD大鼠海马组织神经元原代培养8d后,分别加入含终浓度0(溶剂对照)～100 μmol/L MEHP的培养液暴露12、24 h.采用MTT法检测细胞活性,采用Hoechst 33258染色法检测神经元的凋亡情况.结果 随着MEHP暴露剂量的升高,新生大鼠海马神经元的存活率、凋亡率均呈先上升后下降的趋势.结论 MEHP可抑制新生大鼠海马神经元细胞活性,促进神经元凋亡.提示MEHP对新生大鼠的海马神经元具有毒性作用.

目的 探讨妊娠期邻苯二甲酸(2-乙基己基)酯(DEHP)暴露对成年后子代大鼠精子的致突变作用.方法 将32只健康SPF级SD孕鼠随机分为4组,分别为对照(玉米油)组和2、10、50 mg/kg DEHP染毒组,每组8只.自GD13至GD19,采用灌胃方式进行,每天1次.每窝随机选取1只初生雄性仔鼠,观察其生殖器的发育情况;于70日龄时,观察精子的畸形情况.结果 妊娠期DEHP暴露雄性仔鼠的体重、肛殖距系数(AGI)及主要生殖器(睾丸、附睾、精囊腺)的脏器系数与对照组比较,差异无统计学意义(P＞0.05);主要生殖器未见畸形.2 mg/kg及50 mg/kg DEHP染毒组子代雄性大鼠精子的头部畸形率和总畸形率均高于对照组,差异有统计学意义(P＜0.05);而各剂量DEHP染毒组子代雄性大鼠的尾部畸形率与对照组比较,差异均无统计学意义(P＞0.05).结论 在本实验条件下,妊娠期较低(2 mg/kg)及较高(50 mg/kg)剂量DEHP暴露对子代雄鼠的精子均具有遗传毒性作用.

Numerous research have begun to reveal the importance of maternal nutrition in offspring brain development. Particularly, the maternal obesity or exposure to high-fat diet has been strongly suggested to exert irreversible impact on the structure and function of offspring's brain. However, it remains obscure about whether neonatal neural stem cells (NSCs) in offspring's brain are susceptible to maternal exposure to high-fat diet. Here we focused on the alternation in the Notch signaling in NSCs derived from neonatal mice, which had been given birth by female mice with a high-fat diet and found that, in fact, the high-fat diet administration imposed effects on not only maternal mice, indicated by the accumulation of viscera fat as well as the increase in body weight and serum total cholesterol, but also NSCs in the offspring's brain, where significant increase was observed in the expression of genes, either downstream of Notch signaling or regulating this pathway, which have been shown essential for the maturation of NSCs. Therefore, our data provided the first evidence for the potential effect of maternal exposure to the high-fat diet on the Notch signaling pathway in offspring's NSCs, indicating this altered signaling response might contribute to a profound change in offspring's brains as a result of maternal high-fat diet prior to and during gestation.

DNA methylation is an important part of epigenetics. In this study, we examined the methylation state of two CpG islands in the promoter of the p16 gene in radiation-induced thymic lymphoma samples. The mRNA and protein levels of P16 were significantly reduced in radiation-induced thymic lymphoma tissue samples. Twenty-three CpG sites of the CpG islands in the p16 promoter region were detected, and the methylation percentages of -71, -63, -239, -29, -38, -40, -23, 46 CpG sites were significantly higher in radiation-induced thymic lymphoma tissue samples than those in matched non-irradiated thymus tissue samples. This study provides new evidence for the methylation state of p16 in the radiation-induced thymic lymphoma samples, which suggests that the methylation of these CpG sites in the p16 promoter may reduce its expression in the thymic lymphoma after irradiation.

BACKGROUND: Silicosis is a serious disease that harms human’s health. So far, there has been no effective treatment strategy. OBJECTIVE: To investigate the therapeutic effects of bone marrow mesenchymal stem cel transplantation on silicosis. METHODS: Thirty-six C57BL/6 mice were randomly divided into three groups. In the control group, mice received intrateacheal injection of physiological saline. Mice from the silicosis model group and bone marrow mesenchymal stem cel transplantation group received intrateacheal injection of silica crystals (SiO2) to establish silicosis mouse models. In the bone marrow mesenchymal stem cel transplantation group, bone marrow mesenchymal stem cells were transfused into the tail vein at 6 hours after silicosis induction. RESULTS AND CONCLUSION: Hydroxyproline content in lung parenchyma in the silicosis model group and bone marrow mesenchymal stem cel transplantation group were significantly higher compared to the control group (P <0.01). The hydrocyproline content in the bone marrow mesenchymal stem cel transplantation group was significantly higher than that in the silicosis model group (P < 0.01). The lung index in the silicosis model group and bone marrow mesenchymal stem cel transplantation group was significantly higher than that in the control group (P < 0.01), but the lung index was significantly lower in the bone marrow mesenchymal stem cel transplantation group than in the silicosis model group (P < 0.01). Interleukin-1β expression in the lung tissue was significantly higher in the silicosis model group and bone marrow mesenchymal stem cel transplantation group than that in the control group (P < 0.01), and interleukin-1β expression in the bone marrow mesenchymal stem cel transplantation group was significantly lower than that in the silicosis model group (P < 0.01). Transforming growth factor β1 expression in the lung tissue was significantly higher in the silicosis model group (P < 0.01) and bone marrow mesenchymal stem cel transplantation group (P < 0.05) than that in the control group, and transforming growth factor β1 expression was significantly lower in the bone marrow mesenchymal stem cel transplantation group was significantly lower than that in the silicosis model group (P < 0.01). These findings suggest that bone marrow mesenchymal stem cel transplantation can al eviate pulmonary inflammatory reaction and pulmonary fibrosis.

目的 检测Mda7基因联合放射线抑制前列腺癌PC-3细胞生长的作用.方法 PC-3细胞接受不同剂量X-射线照射,流式细胞术检测细胞凋亡；pcDNA-Mda7质粒转染PC-3细胞,流式细胞术检测细胞凋亡,集落形成法检测细胞生长；pcDNA-Mda7质粒与X-射线联合应用,流式细胞术检测细胞凋亡.结果 PC-3细胞凋亡率随X-射线照射剂量升高而增高,在10 Gy及以上剂量照射细胞凋亡率明显高于对照组(P＜0.01)；pcD-NA-Mda7质粒转染PC-3细胞,细胞凋亡率明显增高(P ＜0.001),集落形成百分数明显降低(P＜0.001)；pcDNA-Mda7质粒与X-射线联合应用效果明显好于单纯照射组和单纯转染组(P＜0.01).结论 PC-3细胞具有辐射抗性,pcDNA-Mda7质粒转染可以显著抑制PC-3细胞生长,pcDNA-Mda7质粒与X-射线联合应用效果好于单纯照射和单纯基因作用.

In order to investigate the relation between kras gene and thymic lymphomas of mice induced by X-rays,we made the thymic lymphomas model of BALB/c mice exposed to X-rays,so as to extracte total RNA and synthesize cDNA and total protein from both of thymic lymphomas and normal thymus tissue.The mRNA and protein expression of kras gene in thymic lymphomas and normal thymus were detected by QRT-PCR and Western blot,respectively.The results show that mRNA expression of kras gene in thymic lymphomas(2.66 ± 1.51) is significantly higher(p0.05) than that of normal thymus tissue(0.93±0.30);and protein expression of kras gene in thymic lymphomas is higher than that of normal thymus tissue.The results suggest that kras gene might be relative to thymic lymphomas induced by X-rays,and it might be a susceptibility gene to radiation carcinogenesis.

Objective To investigate the differences of gene expression induced by ionizing radiation in thymic lym-phoma of mice.Methods BALB/c mice were subjected to whole body irradiation with 1.75Gy X-ray once a week for 4 weeks to induce thymic lymphoma.The difference of gene expression in thymic cell of mice was detected by Mouse WG-6 v2.0 Expression BeadChip.The real-time PCR was used to identify important genes.Results The chip depicted 3 063 genes with differential gene expressions including 1 591 up-regulation and 1 472 down-regulation genes.The genes re-lated to 145 pathways of KEGG database,76 pathways of BioCarta database and 218 pathways of GenMAPP database.The results of real-time PCR showed that the mRNA expression level of Bcl11b and Ikzf1 genes tended to be down-regulated.Conclusion The ionizing radiation may induce differential gene expression profile in thymic lymphoma of mice, and the process may involve many pathways.

Objective To investigate the association between thymic lymphoma induced by ionizing radiation and the polymorphism of Ikaros and p16 genes in mice.Methods Genomic DNA of thymic lymphoma cells was extracted by genomic DNA purification kit.PCR-restriction fragment length polymorphism(RFLP) was used to examine the single nucleotide polymorphisms(SNPs) of rs28185870(C/T) and rs28185923(C/T) of Ikaros gene and rs3695947(A/G) of p16 gene.Results The genotype of rs28185870 site in C57BL/6J and BALB/c was T/T and C/C.The genotype of rs28185923 site was C/C and T/T.The genotype of rs3695947 site was A/A and G/G.Conclusion The genotypes of rs28185870,rs28185923 and rs3695947 in C57BL/6J and BALB/c mice with different radiosusceptibility were different.It is suggested that there is an association between the polymorphism of Ikaros and p16 genes and thymic lymphoma induced by ionizing radiation.

Objective To study the change of c-myc gene expression in thymic lymphomas of mice induced by ionizing radiation and provide theoretical basis for mechanism of radiation carcinogenesis. Methods The thymic lymphomas models of BALB/c mice were made by X-ray(dose rate:0.287 Gy·min~(-1);total dose:7 Gy)exposuring,6 months later they were killed,then total RNA and total protein were extracted from thymic lymphomas and normal thymus tissue and cDNA was synthesized,the expressions of c-myc mRNA and protein in thymic lymphomas induced by ionizing radiation and normal thymus were detected by quantitative real-time PCR and Western blotting respectively.Results The expression of c-myc mRNA in thymic lyrnphomas(9.1 6±4.66)was higher than that in normal thymus tissue(1.16±0.54)(P<0.01).The expression of c-myc protein in thymic lymphomas was higher than that in normal thymus tissue.Conclusion There is relevance between c-myc gene and thymic lymphomas induced by ionizing radiation,c-myc gene might be susceptibility gene of radiation carcinogenesis.

随着人类基因组计划的完成,表观遗传学开始成为关注的热点.DNA甲基化是研究最早且较深入的表观遗传学标志之一.越来越多的研究表明,DNA甲基化在肿瘤的发生及演进过程中起着重要的作用.笔者着重综述了DNA甲基化及电离辐射诱导的DNA甲基化改变,探讨在辐射致癌表观遗传学机制研究中的作用.