宫内暴露氟他胺对子鼠子宫和卵巢发育及氧化应激的影响

doi:10.3969/j.issn.1004-616x.2018.05.011

Abstract

Abstract: OBJECTIVE:To investigate the effects of flutamide exposure in pregnant mice on their uterus and ovarian development,and on oxidative stress among offspring,and to provide mechanistic understanding of reproductive system malformation. METHODS:40 eight-week-old conceived ICR females mice were randomly assigned into treatment and the control groups. Flutamide was orally administered to pregnant mice at 300 mg/(kg·d) during gestation days 12-18,while the control group was treated with equal volume of soybean oil. More than 7 weeks after birth,the appearance of female offspring was observed. The body weights, uterine weight, ovarian weight were collected to calculate the organ coefficient. The uterus and ovarian tissues were taken for sectioning,and the pathological changes were observed. Follicles of each level were counted and their pathological changes observed. Then 12 animals were randomly taken out for measuring the superoxide dismutase (SOD),glutathioneperoxidase (GSH-Px) and malonaldehyde (MDA) of the uterus and ovary in each dose group,and their abundance of Nox1,Sod1 and Gpx1 was detected by qPCR. RESULTS:Compared to the control group,there was no significant difference in the appearance of the female offspring in the treatment group,but the body weight was lower than control(P < 0.05),the visceral coefficients of uterus and ovary had no statistical difference from the control group(P > 0.05). The results of follicle count showed that the numbers of primordial follicles and mature follicles in the experimental group were less than control(P < 0.05). The SOD activity and GSH-Px level in the uterus of the treatment female mice were lower than those in the control group,and the MDA level was higher(P < 0.05). In the ovary of the treatment group,the SOD activity and GSH-Px level were lower(P < 0.05),and the MDA level had no significantly difference(P > 0.05). The mRNA abundance of Noxo1 in the uterus of the experimental group was increased,while the abundance of Sod1 mRNA was decreased (P < 0.05),and the abundance of Gpx1 mRNA was not statistically different from the control(P > 0.05). The mRNA abundance of Noxo1 was increased and the abundance of Gpx1 in the ovary of the treatment group were decreased (P < 0.05),and the mRNA abundance of Sod1 has no statistically difference from the control group(P > 0.05). CONCLUSION:Data from our study show that pregnant mice exposed to flutamide caused abnormal uterus and ovarian development in their offspring and demonstrated anti-oxidative stress.

Key words: flutamide, female offspring, uterus, ovary, oxidative stress

CLC Number:

R994.6

ZHOU Xiaoqing, WEN Kexin, YIN Hongping, YANG Jinru, ZHU Yongfei. Effects of intrauterine flutamide exposure on uterus and ovary development and on oxidative stress among female offspring[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2018, 30(5): 384-388,394.

References

[1] GUO C,YEH S,NIU Y,et al. Targeting androgen receptor versus targeting androgens to suppress castration resistant prostate cancer[J]. Cancer Lett,2017,397(1):133-143.
[2] SINCLAIR A W,CAO M,PASK A,et al. Flutamide-induced hypospadias in rats:A critical assessment[J]. Differentiation, 2017,94(1):37-57.
[3] DURLEJ M,KOPERA I,KNAPCZYK-STWORA K,et al. Connexin 43 gene expression in male and female gonads of porcine offspring following in utero exposure to an anti-androgen,flutamide[J]. Acta Histochem,2011,113(1):6-12.
[4] MENEZO Y J,SILVESTRIS E,DALE B,et al. Oxidative stress and alterations in DNA methylation:two sides of the same coin in reproduction[J]. Reprod Biomed Online,2016,33(6):668-683.
[5] AL MARUF A,O'BRIEN P. Flutamide-induced cytotoxicity and oxidative stress in an in vitro rat hepatocyte system[J]. Oxid Med Cell Longev,2014,2014:398285.
[6] 唐家泷,贺明,何梦如,等. 氟他胺致小鼠阴茎组织中sHsps表达改变的研究[J]. 湖南师范大学学报(医学版), 2017,14(2):26-29.
[7] 袁耀美,张茨,白晨,等. 胰岛素样因子3在氟他胺诱导的小鼠隐睾模型中的表达和意义[J]. 中华男科学杂志,2013, 29(11):968-971.
[8] 周小青,文可欣,何梦如,等. 氟他胺致小鼠生殖器官畸形模型的建立[C]//中国环境诱变剂学会第七届全国会员代表大会暨第十七次学术大会论文集. 上海,2017:96.
[9] HOFFMAN G E, LE W W, ENTEZAM A, et al. Ovarian abnormalities in a mouse model of fragile X primary ovarian insufficiency[J]. J Histochem Cytochem,2012,60(6):439-456.
[10] 孙秀红. AMH和INS在PCOS大鼠卵泡生长发育中的作用及相关性研究[D]. 广州:暨南大学,2011.
[11] KNAPCZYK-STWORA K, GRZESIAK M, CIERESZKO R E,et al. The impact of sex steroid agonists and antagonists on folliculogenesis in the neonatal porcine ovary via cell proliferation and apoptosis[J]. Theriogenology,2018,113(1):19-26.
[12] 陈恒禧,黄薇. 子宫内膜蜕膜化调节机制的研究现状[J]. 现代妇产科进展,2018,27(3):218-221.
[13] HILLEBRAND A C,PIZZOLATO L S,BRANCHINI G,et al. Androgenic modulation of AR-Vs[J]. Endocrine,2018. DOI:10.1007/s12020-018-1682-5.
[14] CHENG G, LAMBETH J D. NOXO1, regulation of lipid binding, localization, and activation of Nox1 by the Phox homology (PX) domain[J]. J Biol Chem,2004,279(6):4737-4742.
[15] CHENG G,RITSICK D,LAMBETH J D. Nox3 regulation by NOXO1, p47phox, and p67phox[J]. J Biol Chem, 2004, 279(33):34250-34255.
[16] JOO J H,OH H,KIM M,et al. NADPH oxidase 1 activity and ROS generation are regulated by Grb2/Cbl-mediated proteasomal degradation of Noxo1 in colon cancer cells[J]. Cancer Res,2016,76(4):855-865.
[17] SCHATZMAN S S,CULOTTA V C. Chemical warfare at the microorganismal level:A closer look at the superoxide dismutase enzymes of pathogens[J]. ACS Infect Dis, 2018, 4(6):893-903.
[18] ZHANG L,GUO J. Flutamide induces hepatic cell death and mitochondrial dysfunction via inhibition of Nrf2-mediated heme oxygenase-1[J]. Oxid Med Cell Longev, 2018, 2018:8017073.
[19] CARVALHO A A, FAUSTINO L R, SILVA C M, et al. Catalase addition to vitrification solutions maintains goat ovarian preantral follicles stability[J]. Res Vet Sci,2014,97(1):140-147.
[20] PAJARES M, CUADRADO A. The role of free radicals in autophagy regulation:implications for ageing[J].Oxid Med Cell Longev,2018,2018:2450748

Effects of intrauterine flutamide exposure on uterus and ovary development and on oxidative stress among female offspring

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