用户名: 密码: 验证码:
邻苯二甲酸二丁酯对青春期雌性大鼠生殖毒性及其作用机理的研究
详细信息    本馆镜像全文|  推荐本文 |  |   获取CNKI官网全文
摘要
目的:
     探讨邻苯二甲酸二丁酯(DBP)对青春期雌性大鼠生殖毒性作用及其作用机理。
     方法:
     21日龄SPF级雌性Sprague Dawley (SD)大鼠,按体重随机分为250mg/kg、500mg/kg、1000mg/kg三个剂量组和溶剂对照组(玉米油),连续8周灌胃染毒。当观察到大鼠阴道开口后,阴道脱落细胞学方法观察动情周期变化。染毒结束后,在动情前期股动脉取血,处死大鼠,称量子宫、卵巢湿重,计算脏器系数。放射免疫法检测血清中雌二醇(E2)、孕酮(P)、黄体生成素(LH)及促卵泡刺激素(FSH)的水平。取卵巢组织提取mRNA,实时荧光定量RT-PCR检测大鼠卵巢组织细胞色素P450芳香化酶(P450arom) mRNA、细胞色素P450胆固醇侧链裂解酶(P450scc) mRNA及过氧化物酶体增殖体激活受体γ(PPARy) mRNA表达水平。
     结果:
     (1)随着饲养时间的延长,大鼠体重逐渐增加,处理组之间大鼠体重变化有统计学差异(F=3.244,P<0.01),与对照组比较,500mg/kg剂量组大鼠体重高于对照组(P<0.05),250mg/kg及1000mg/kg剂量组大鼠体重与对照组无统计学差异(P>0.05),各剂量组间比较,500mg/kg剂量组大鼠体重高于1000mg/kg染毒组(P<0.05);(2)各处理组子宫及卵巢脏器系数均无统计学差异(P>0.05);(3)各处理组大鼠阴道开口时间无统计学差异(P>0.05)。各处理组大鼠动情周期总时间有统计学差异(F=25.599,P=0.001),与对照组比较,250mg/kg、500mg/kg、1000mg/kg剂量组大鼠动情周期总时间延长(P<0.05或P<0.01),各染毒剂量组之间动情周期总时间无统计学差异(P>0.05)。各处理组大鼠动情期时间有统计学差异(F=8.533,P=0.001),与对照组比较,250mg/kg、500mg/kg、1000mg/kg剂量组大鼠动情期时间延长(P<0.05或P<0.01),各染毒剂量组之间动情期时间无统计学差异(P>0.05)。各处理组大鼠动情前期、动情后期、动情间期时间无统计学差异(P>0.05);(4)各处理组大鼠血清E2水平有统计学差异(F=13.502,P=0.001),与对照组比较,250mg/kg、500mg/kg、1000mg/kg剂量组大鼠血清E2水平增高(P<0.05或P<0.01),各剂量组间比较,250mg/kg染毒组大鼠血清E2水平高于500mg/kg及1000mg/kg剂量组(P<0.05及P<0.01)。各处理组大鼠血清P水平有统计学差异(F=4.306,P=0.014),与对照组比较,1000mg/kg剂量组大鼠血清P水平降低(P<0.05),与对照组比较,250mg/kg及500mg/kg剂量大鼠血清P水平无统计学差异。各处理组大鼠血清LH及FSH水平均无统计学差异(P>0.05);(5)各处理组间大鼠卵巢P450arom mRNA表达水平有统计学差异(H=15.895,P<0.01),与对照组比较,250mg/kg、500mg/kg、1000mg/kg剂量组卵巢P450arom mRNA表达水平升高(P<0.01),各剂量组间卵巢P450arom mRNA表达水平无统计学差异(P>O.05)。各处理组间大鼠卵巢P450scc mRNA表达水平有统计学差异(H=15.591,P<0.01),与对照组比较,250mg/kg、500mg/kg、1000mg/kg剂量组大鼠卵巢P450scc mRNA表达水平降低(P<0.01),各剂量组间卵巢P450scc mRNA表达水平比较无统计学差异(P>0.05);(6)各处理组间大鼠卵巢PPARγmRNA表达水平有统计学差异(H=12.650,P<0.01),与对照组比较,500mg/kg及1000mg/kg剂量组大鼠卵巢PPARγmRNA表达水平升高(P<0.05及P<0.01),各剂量组间比较,250mg/kg及500mg/kg剂量组PPARγmRNA表达水平低于1000mg/kg剂量组(P<0.05)。
     结论:
     (1)DBP可干扰了青春期雌性大鼠生殖内分泌功能,使大鼠动情周期延长,血清E2水平升高,血清P水平降低。(2)DBP雌性生殖毒性的机理可能与增加卵巢甾体激素合成过程中的关键酶P450arom mRNA表达,抑制P450scc mRNA表达有关。DBP也可通过激活卵巢颗粒细胞PPARy mRNA表达,引起雌性大鼠的生殖毒性。
Objective:To study the reproductive toxicity and its related mechanisms of dibutyl phthalate (DBP) on puberty female rats.
     Methods:21-day-old Sprague Dawley (SD) female rats were randomly divided into 250mg/kg,500mg/kg and 1000mg/kg treatment groups and one control group(corn oil), the rats were administrated by gavage for 8 weeks. When observed vaginal opening, estrous cycles of rats were determined using vaginal exfoliative cytology examnation. By the end of 8 weeks' treatment of DBP blood samples were collected from femoral artery in proestrus and all animals were sacrificed,the wet weights of the uterus and ovaries were recorded and organ coefficients were calculated, respectively. The serum levels of estradiol (E2), progesterone (P), luteinizing hormone (LH), follicle stimulating hormone (FSH) were examined using radioimmunoassay. The mRNA levels of aromatase, cholesterol side-chain cleavage enzyme and peroxisome proliferator-activated receptor y of ovaries were detected by real-time fluorescent quantitative polymerase chain reaction (RT-PCR).
     Results:(1) The body weight (BW) among treatment and control groups was statistically different (F=3.244, P<0.01), compared with the control group, BW of 500mg/kg group was higher significantly (P<0.05), there were no significant difference of BW between 250mg/kg, 1000mg/kg group and control group (P>0.05), BW of 500mg/kg group was significantly higher than that of 1000mg/kg group (P<0.05); (2) There was no significant difference of uterus and ovary organ coefficients among treatment and control groups (P>0.05); (3) There was no significant difference of vaginal opening time among treatment and control groups (P>0.05). The difference of period of estrous cycles among treatment and control groups was statistically significant (F=25.599, P=0.001), compared with the control group, the periods of estrous cycles in 250mg/kg,500mg/kg and 1000mg/kg groups were significantly longer than that of the control group (P<0.05 or P<0.01), but there were no significant differences of estrous cycles among the three treatment groups (P>0.05). The difference of period of estrus between treatment and control groups was statistically significant (F=8.533, P=0.001), compared with the control group, the periods of estrous in 250mg/kg, 500mg/kg and 1000mg/kg groups were longer than that of the control group(P<0.05orP<0.01), but there were no significant differences of estrus among three treatment groups (P>0.05); (4) There was significant difference of serum estradiol levels among treatment and cotrol groups (F=13.502,P=0.001), compared with the control group, the levels of serum estradiol were elevated statistically in 250mg/kg,500mg/kg and 1000mg/kg does groups (P<0.05 or P<0.01), the serum estradiol levels was higher in 250mg/kg group than those of 500mg/kg and 1000mg/kg groups (P<0.05andP<0.01).There were statistically significant differences of serum progesterone levels among treatment and control groups(F=4.306, P=0.014), the serum progesterone level in 1000mg/kg does group was lower than that of the control group (P<0.05), while there was no significant difference of serum progesterone between 250mg/kg or 500mg/kg groups and the control group (P>0.05).The levels of serum LH and FSH between trestment and cotrol groups didn't change significantly(P>0.05); (5)The expression levels of P450arom mRNA in ovarian was statistically different in treatment and the control groups(H=15.895,P<0.05), compared with the control group, the expression levels of P450arom mRNA in ovarian increased in 250mg/kg,500mg/kg and 1000mg/kg does groups (P<0.01), while there were no significant differences of P450arom mRNA expression levels were observed among three treatment groups (P>0.05).The expression levels of P450scc mRNA in ovarian were significant different in treatment and the control groups(H=15.591 P<0.01), compared with the control group, the expression levels of P450scc mRNA in ovarian reduced in three treatment groups (P<0.01), but there were not significant differences in expression levels of P450scc mRNA among three treatment groups(P> 0.05); (6) The expression levels of PPARy mRNA in ovarian in 500mg/kg and 1000mg/kg does groups were significantly higher than that in the control group (P<0.05 and P<0.01), and the expression level of PPARy mRNA in 1000mg/kg does group was higher than those of 250mg/kg and 500mg/kg groups (P<0.05).
     Conclusion:(1) DBP has adverse effects on reproductive endocrine function of puberty female rats. The disrupting effects of DBP on reproductive endocrine functions of puberty female rats include:prolonged estrous cycle, increased the serum estradiol level and decreased serum progesterone level.(2)The possible mechanisms of female reproductive toxicity induced by DBP may be related to the increased expression of the key enzyme P450arom mRNA and the decreased expression of P450scc mRNA in ovary. The reproductive toxicity in puberty female rats of DBP may also be associated with the activating PPARy mRNA expression of granulosa cells in ovary.
引文
[1]Van WA,Van V,Post humus R,et al.Environmental risk limit s for two p ht halates,wit h special emp hasis on endocrine disruptive properties[J].Ecotoxico Environ Safety,2000,46:3205.
    [2]Moorman WJ,Ahlers HW,Chapin RE,et al.Prioritizatio of NTP reproductive taxicants for field studies[J].Reprod Toxicol,2000,14:293-301.
    [3]Susan M.NTP Center reports on phthalate concerns[J].Environ Health Perspect,2001,109:260-261.
    [4]陈济安,邱志群,舒为群,等.我国水环境中邻苯二甲酸酯污染现状及其生物降解研究进展[J].癌变崎变突变,2007,19(3):12-4.
    [5]Foster PM, Cattley RC, Mylehreest E.Effect of di-n-butyl Phthalate(DBP)on male Reproductive development in the rats:implications for hunman risk assessment.Food Chem Toxical JT—Food and chemical toxicology:an international journal Published for the British Industrial Biological Research Association,2000,38:(1)97-9.
    [6]俞力平,高光虎.我国增塑剂工业现状及发展[J].石油化工技术经济,1997,13(2):26-31.
    [7]胡雄星,韩中豪,刘必寅,等.邻苯二甲酸酯的毒性及其在环境中的分布[J].环境科学与管理,2007,32(1):37-40.
    [8]Silva MJ, Barr DB, Reidy JA, et al. Urinary levels of seven phthalate metabolites in the U.S. population from the National Health and Nutrition Examination Survey (NHANES) 1999-2000[J]. Environ Health Perspect,2004,112(3):331-8.
    [9]Hoppin JA,Brock JW,Davis BJ,et al.Reproducibility of urinary phthalate metabolites in first morning urine samples[J].Environ Health Perspect,2002,108:979-982.
    [10]刘慧杰,舒为群,李学奎等.人体内有机物分析及邻苯二甲酸酯含量测定[J].中国公共卫生,2004,20(3):318-9.
    [11]CMA.Comments of the Chemical Manufacturers Association phthalate esters panel in response to request for public input on seven phthalate esters [R].Washinngton DC:Chemical Manufactures Association,1999,FR DOC:99-9484.
    [12]Nair N,Bedwal S,Kumari D,et al. Effect on histological and sperm kinetics in DBP exposed wistar rats[J].J Environ Biol,2008,29(5):769-772.
    [13]Foster PM, Mylchreest E, Gaido KW,et al. Effects of phthalate esters on the developing reproductive tract of male rats [J].Hum Reprod Update,2001,7(3): 231-235.
    [14]张晓峰,李姿,郑晶等.邻苯二甲酸二丁酯抑制大鼠睾酮合成的影响机制[J].环境与健康杂志,2008,25(2):117-119.
    [15]王玉邦,宋玲,朱正平等.邻苯二甲酸二丁酯对睾酮合成的影响[J].中国公共卫生,2005,21(10):1168-1170.
    [16]Barlow NJ,Phillips SL,Wallace DG, et al.Quantitative changes in gene expression in fetal rat testes following exposure to di(n-butyl) phthalate[J]. Toxicol Sci 2003,73(2):431-41.
    [17]Wilson VS,Lambright C,Furr J,et al.Phthalate ester-induced gubernacular lesions are associated with reduced ins13 gene expression in the fetal rat testis[J]. Toxicol Lett,2004,146(3):207-215.
    [18]Shono T,Shima Y,Kondo T,et al. In utero exposure to mono-n-butyl phthalate impairs insulin-like factor 3 gene expression and the transabdominal phase of testicular descent in fetal rats[J].Pediatr Surg,2005,40:1861-1864.
    [19]Swan SH,Main KM,Liu F,et al.Decrease in anogenital distance among male infants with prenatal phthalate exposure[J].Environ Health Perspect,2005,113(8):1056-61.
    [20]Hauser R,Meeker JD,Duty S,et al. Altered semen quality in relation to urinary concentrations of phthalate monoester and oxidative metabolites[J]. Epidemiology, 2006,17(6):682-91.
    [21]Hauser R,Meeker JD,Singh NP,et al. DNA damage in human sperm is related to urinary levels of phthalate monoester and oxidative metabolites[J].Hum Reprod,2007,22(3):688-95.
    [22]Main KM, Mortensen GK, Kaleva MM, et al. Human breast milk contamination with phthalates and alterations of endogenous reproductive hormones in infants three months of age[J]. Environ Health Perspect,2006,114(2):270-6.
    [23]Pan G, Hanaoka T, Yoshimura M, et al. Decreased serum free testosterone in workers exposed to high levels of di-n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP):a cross-sectional study in China[J]. Environ Health Perspect,2006,114(11):1643-8.
    [24]Davis BJ,Maronpot RR,Heindel JJ. Di-(2-ethylhexyl)Phthalate suppresses estradiol and ovulation in cycling rats [J].Toxicol Appl Pharmaeol,1994,128(2): 216-223.
    [25]Gray LE, Jr., Laskey J, Ostby J. Chronic di-n-butyl phthalate exposure in rats reduces fertility and alters ovarian function during pregnancy in female Long Evans hooded rats[J]. Toxicol Sci,2006,93(1):189-95.
    [26]靳秋梅,孙增荣.邻苯二甲酸二丁酯对小鼠卵功能的影响[J].环境与健康杂志,2007,24(5):310-312.
    [27]Cobellis L,Latini G,De Felice C,et al.High plasma concentrations of di2(22ethylhexyl)2phthalate in women with endometriosis[J]. Hum Reprod,2003,18 (7):1512-1515
    [28]ColonI, Cam D, Bourdony CJ, et al Identification of phthalate esters in the serum of young Puerto Rican girls with premature breast development[J]. Environ Health Perspect,2000,108:895-900.
    [29]乔丽丽,郑力行,蔡德培.上海市女童血清中邻苯二甲酸二丁酯和邻苯二甲酸-2-乙基己酯水平与性早熟关系研究[J].卫生研究,2007,36(1):93-95.
    [30]李靖,李炫诚,吴云霞.确定小鼠动情周期的三种方法[J].实验动物科学,2007,24(3):63-66.
    [31]Livak KJ,Schmittgen TD.Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T))Method [J]. Methods,2001,25(4):402-408.
    [32]Rov JR,Chakraborty S,Chakraborty TR, et al.Estrogen-like endocrine disrupting chemicals affecting puberty in humans--a review[J].Med Sci Monit,2009,15(16):137-45.
    [33]Colborn T,vom Saal FS, Soto AM.Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environ[J].Health Perspect,1993,101:378-384.
    [34]Swan SH, Main KM, Liu F, et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure[J].Environmental Health Perspectives,2005,113:1056-1061.
    [35]余增丽,张立安,吴得生.一些化工原料的雌激素样效应[J].卫生研究,2003,32(1):10-12.
    [36]Kanno J,Onyon L,Haseman J,et al. The OECD program to validate the rat uterotrophic bioassay to screen compounds for in vivo estrogenic responses:phase 1[J].Environmental Health Perspectives,2001,109(8):785—794.
    [37]黄雅卿,张文昌,李煌元.镉对雌性大鼠体重变化和卵巢脏器系数的影响[J].职业与健康,2003,19(7):7-9.
    [38]Ge RS,Chen GR,Dong Q,et al.Biphasic effects of postnatal exposure to diethylhexylphthalate on the timing of puberty in male rats[J].J Androl,2007,28(4):513-20.
    [39]衷筱琴,蔡红平,万红萍等.邻苯二甲酸二(2-乙基己基)酯对大鼠不同脏器的损伤[J].环境与健康杂志,2009,26(3):212-214.
    [40]Newbold R, Padilla-Banks E, Snyder RJ, et al. Developmental exposure to endocrine disruptors and the obesity epidemic[J]. Reproductive Toxicology,2007,23:290-296.
    [41]Newbold RR,Padilla-Banks E,Snyder RJ,et al. Perinatal exposure to environmental estrogens and the development of obesity[J]. Molecular Nutrition& Food Research,2007,51:912-917.
    [42]Grun F, Blumberg B. Perturbed nuclear receptor signaling by environmental obesogens as emerging factors in the obesity crisis. Rev[J]. Endocr etab isord,2007, 8(2),161-171.
    [43]Robert M. Sargis, Daniel N. Johnson, Rashikh A. Choudhury, et al.Environmental Endocrine Disruptors Promote Adipogenesis in the 3T3-L1 Cell Line through Glucocorticoid Receptor Activation[J].Obesity,2009,19(11):1038.
    [44]Julie Boberga, Stine Metzdorff, Rasmus Wortzigera, et al. Impact of diisobutyl phthalate and other PPAR agonists on steroidogenesis and plasma insulin and leptin levels in fetal rats[J]. Toxicology,2008,250:75-81.
    [45]Vickers MH.Developmental programming and adult obesity:the role of leptin. Curr Opin Endocrinol Diabetes Obes,2007,14 (1):17-22.
    [46]李卫华,范奇元,申立军等.环境内分泌干扰物2-溴丙烷对大鼠睾丸毒性的研究[J].生殖与避孕,2001,21(3):157-161.
    [47]Kim HS, Kang TS,Kang IH,et al. Validation study of OECD rodent uterotrophic assay for the assessment of estrogenic activity in Sprague-Dawley immature female rats[J]. J Toxicol Environ Health A,2005 68(23-24):2249-62.
    [48]Tomonari Y, Kurata Y, David R, et al. Effect of di(2-ethylhexyl) phthalate (DEHP) on genital organs from juvenile common marmosets:I.Morphological And Biochemical Investigation In 65-Week Toxicity Study [J].Toxicol Environ Health,2006,69(17):1651-1672.
    [49]李海斌,李君,姚三巧.氯氰菊酯对雌性大鼠生殖器官的影响[J].环境与健康杂志,2008,25(8):708-710.
    [50]Simone Wichert Grande, Anderson JM Andrade, Chris E Talsness, et al.A Dose-Response Study Following In Utero and Lactational Exposure to Di(2-ethylhexyl)phthalate:Effects on Female Rat Reproductive Development[J]. Toxicological Sciences,2006,91(1),247-254.
    [51]Moore W, Rudy TA, Lin TM, et al. Abnormalities of sexual development in male rats with in utero and actational exposure to the antiandrogenic plasticizer di(2-ethylhexyl)phthalate[J]. Environ Health Perspect,2001,109:229-237.
    [52]Mylchreest E, Cattley RC, Foster PM,et al. Male reproductive tract malformations in rats following gestational and lactational exposure to di(nbutyl) phthalate:An antiandrogenic mechanism[J]? Toxicol Sci,1998,43:47-60.
    [53]Mylchreest E,Wallace DG,Cattley RC, et al. Dosedependent alterations in androgen-regulated male reproductive development in rats exposed to di(n-butyl) phthalate during late gestation[J]. Toxicol Sci,2000,55:143-151.
    [54]张森,王新,韦旭斌等.大鼠发情周期各阶段的阴道细胞变化观察[J].动物医学进展,2006,27(2):69-72.
    [55]王伟,唐明德,易义珍,等.甲醛对雌性小鼠动情周期及卵巢的影响[J].实用预防医学,2002,9(6):641-643.
    [56]张建江,舒为群,曹波,等.C市管网末梢水有机提取物对雌性小鼠性激素水平和动情周期的影响[J].环境与职业医学,2008,2(1):34-36.
    [57]Vickers MH.Developmental programming and adult obesity:the role of leptin[J]. Curr Opin Endocrinol Diabetes Obes,2007,14 (1):17-22.
    [58]张健如,主编1.生理学.第4版.北京:人民卫生出版社,1998.411-413.
    [59]张森,谭建华.大鼠发情周期中主要生殖激素的变化[J].动物医学进展[J].2005,26(12):1-6.
    [60]I Svechnikova, K Svechnikov, Soder. The influence of di-(2-ethylhexyl) phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats[J].Journal of Endocrinology,2007,194:603-609.
    [61]Lovekamp TN,Davis BJ.Mono-(2-ethylhexyl) phthalate suppresses aromatase transcript levels and estradiol production in cultured rat granulosa cells[J].Toxicology and Applied Pharmacology,2001,172:217-224.
    [62]David Gunnarsson, Per Leffler, Emelie Ekwurtzel, et al.Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes[J].Reproduction,2008,135:693-703.
    [63]常兵,刘德瑜,梁玉香.邻苯二甲酸二丁酯对青春期雄性大鼠的生殖毒性研究[J].中国自然医学杂志,2007,9(3):164-168.
    [64]Gurates B, Sebastian S, Yang S, et al. WT1 and DAX-1 inhibit aromatase P450 expression in human endometrial and endometriotic stromal cells[J].J Clin Endocrinol Metab,2002,87(9):4369-4377.
    [65]Deslypere GP,Verdonck L,Vermeulen A.Fat tissue:a steroid reservoir and site of steroid metabolism[J].Clin Endocrinol Metab,1985,61:564-570.
    [66]Harlow CR, Bradshaw AC, Rae MT, et al. Oestrogen formation and connective tissue growth factor expression in rat granulosa cells[J]. Endocrinology,2007,192(1): 41-52.
    [67]Mingyue Ma, Tomoko Kondo, Susumu Ban,et al. Exposure of Prepubertal Female Rats to Inhaled Di(2-ethylhexyl)phthalate Affects the Onset of Puberty and Postpubertal Reproductive Functions[J].Toxicological Sciences,2006,93(1):164-171.
    [68]Kim HS,Saito K,Ishizuka M, et al. Short period exposure to di-(2-ethylhexyl) phthalate regulates testosterone metabolism in testis of prepubertal rats[J].Arch Toxicol,2003,77(8):446-51.
    [69]Ju Young Ryu, Byung Mu Lee, Sam Kacew, et al.Identification of differentially expressed genes in the testis of Sprague-Dawley rats treated with di(n-butyl)Phthalate [J].Toxicology,2007,234(1-2):103-12.
    [70]Halkerston I,Eichhorn J,Hechter O.A requirement for reduced triphosphopyridine nucleotide for cholesterol side-chain cleavage by mitochondrial fractions of bovine adrenal cortex[J].J Biol Chem,1961,236:374.
    [71]Borch J,Metzdorff SB,Vinggaard AM,et al.Mechanisms underlying the anti-androgenic effects of diethylhexyl phthalate in fetal rat testis[J]. Toxicology,2006,223(1-2):144-55.
    [72]Ju Young Ryu, Byung Mu Lee, Sam Kacew, et al.Identification of differentially expressed genes in the testis of Sprague-Dawley rats treated with di(n-butyl)Phthalate [J].Toxicology,2007,234(1-2):103-12.
    [73]Ryu JY,Lee E,Kim TH,et al.Time-response effects of testicular gene expression profiles in Sprague-Dawley male rats treated with di(n-butyl) phthalate[J].J Toxicol Environ Health A,2008,71 (23):1542-9.
    [74]Gregoine FM, Sanas CM, SulHS, et al.Understanding adipocyte diferention[J]. PhysiolRev,1998,78:783-809.
    [75]Froment P,Gizard F,Defever D,et alPeroxisome proliferator-activated receptors in reproductive tissues:from gameto genesis to parturition[J]. Journal of Endocrinology,2006,189(2):199-209.
    [76]Komar CM, Braissant O, Wahli W, et al. Expression and localization of PPARs in the rat ovary during follicular development and the periovulatory period[J]. Endocrinology,2001,142:4831-4838.
    [77]Koeffler HP.Peroxisome prohferator-activated receptor and Cancers[J].Clin CancerRes,2003,9:1-9.
    [78]Corton JC,Anderson SP,Stauber A.Central role of peroxisomeProliferators-activated receptors in the actions of peroxisome proliferators[J]. Annu Rev Pharmacol Toxicol,2000,40:491-518.
    [79]Mu YM, Yanase T, Nishi Y, et al.Combined treatment with specific ligands for PPARγ:RXR nuclear receptor system markedly inhibits the expression ofcytochrome P450arom in human granulosa cancer cells[J].Mol Cell Endocrinol,2001,181:239-248.
    [80]Mu YM, Yanase T, Nishi Y, et al.Insulin sensitizer, troglitazone, directly inhibits aromatase activity in human ovarian granulosa cells[J].Biochem Biophys Res Commun,2000,271:710-713.
    [81]张顺财,刘斯青.肝炎后肝硬化的性激素变化及其意义.胃肠病学和肝病学杂,1995,4:184-185.
    [82]Deng JY,ShiD.Effect of estrogen on vascular endothelial cells and on the development of Buerger's disease.ZhongguoPutong Waike Zazhi,2002,11:746-748.
    [83]Cantrill E,Murray M,Mehta I, Downregulation of the male-specific hepatic microsomal steroid 16 alpha-hydroxy lase,cytochrome P-450UT-A,in rats with portal bypass.Relevance to estradiol accumulation and impaire drug metabolism in hepatic cirrhosis.J Clin Invest,1989,83:1211-1216.
    [84]O'Brien ML,Twaroski TP,Cunningham ML,et al.Effects of peroxisome proliferators on antioxidant enzymes and antioxidant vitamins in rats and hamsters[J]. Toxicol Sci,2001,60(2):271-8.
    [85]Ghisari M, Bonefeld-Jorgensen EC. Effects of plasticizers and their mixtures on estrogen receptor and thyroid hormone functions[J].Toxicol Lett,2009,189(1):67-77.
    [86]Vom Saal FS, Akingbemi BT, Belcher SM, et al. A Expert Panel Consensus Statement:integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure[J]. Reprod Toxicol,2007,24:131-138.
    [87]Andrade AJ, Grande SW, Talsness CE, et al.A dose response study following in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP):reproductive effects on adult male offspring rats[J].Toxicology,2006,228:85-97.
    [88]REN-SHAN GE, GUO-RONG CHEN, QIANG DONQet al.Biphasic Effects of Postnatal Exposure to Diethylhexylphthalate on the Timing of Puberty in Male Rats[J].Journal of Andrology,2007,28(4):531.
    [1]Van WA,Van V,Post humus R,et al.Environmental risk limit s for two p ht halates,wit h special emp hasis on endocrine disruptive properties[J].Ecotoxico Environ Safety,2000,46:3205.
    [2]Foster PM, Cattley RC, Mylehreest E.Effect of di-n-butyl Phthalate(DBP)on male Reproductive development in the rats:implications for hunman risk assessment..Food Chem Toxical JT—Food and chemical toxicology:an international journal Published for the British Industrial Biological Research Association,2000,38:(1)97-9.
    [3]胡雄星,韩中豪,刘必寅,等.邻苯二甲酸酯的毒性及其在环境中的分布[J].环境科学与管理,2007,32(1):37-40.
    [4]Silva MJ, Barr DB, Reidy JA, et al.Urinary levels of seven phthalate metabolites in the U.S. population from the National Health and Nutrition Examination Survey (NHANES) 1999-2000[J]. Environ Health Perspect,2004,112(3):331-8.
    [5]Hoppin JA,Brock JW,Davis BJ,et al.Reproducibility of urinary phthalate metabolites in first morning urine samples[J].Environ Health Perspect,2002,108:979-982.
    [6]刘慧杰,舒为群,李学奎等.人体内有机物分析及邻苯二甲酸酯含量测定[J].中国公共卫生,2004,20(3):318-9.
    [7]CMA.Comments of the Chemical Manufacturers Association phthalate esters panel in response to request for public input on seven phthalate esters [R].Washinngton DC:Chemical Manufactures Association,1999,FR DOC:99-9484.
    [8]McKee RH, Pavkov KL, Trimmer GW,et al.An assessment of the potential developmental and reproductivetoxicity of di-isoheptyl phthalate in rodents[J].Reproductive Toxicology,2006,21:241-252.
    [9]Kevin Marsee TJ,Woodruff DA,Axelrad AM,et al.Estimated Daily Phthalate Exposures in a Population of Mothers of Male Infants Exhibiting Reduced Anogenital Distance[J].Environmental Health Perspectives.2006,114(6):805-809
    [10]Heindel JJ.Animal models for probing the developmental basis of disease and dysfunction paradigm[J].Basic Clin Pharmacol Toxicol,2008,102(2):76-81.
    [11]常兵,刘德瑜,梁玉香.邻苯二甲酸二丁酯对青春期雄性大鼠的生殖毒性研究[J].中国自然医学杂志,2007,9(3):164-168.
    [12]张晓峰,李姿,郑晶等.邻苯二甲酸二丁酯抑制大鼠睾酮合成的影响机制[J].环境与健康杂志,2008,25(2):117-119.
    [13]王玉邦,宋玲,朱正平,陈建锋等.邻苯二甲酸二丁酯对睾酮合成的影响[J].中国公共卫生,2005,21(10):1168-1170.
    [14]Barlow NJ, Phillips SL, Wallace DG, et al. Quantitative changes in gene expression in fetal rat testes following exposure to di(n-butyl) phthalate. Toxicol Sci 2003,73(2):431-41.
    [15]Wilson VS, Lambright C, Furr J, et al.Phthalate ester-induced gubernacular lesions are associated with reduced ins13 gene expression in the fetal rat testis[J]. Toxicol Lett,2004,146(3):207-215.
    [16]Borch J, Metzdorff SB, Vinggaard AM, et al.Mechanisms underlying the anti-androgenic effects of diethylhexyl phthalate in fetal rat testis[J]. Toxicology,2006, 223(1-2):144-155.
    [17]Lehmann KP, Phillips S, Sar M, et al. Dose-dependent alterations in gene expression and testosterone synthesis in the fetal testes of male rats exposed to di (n-butyl) phthalate[J]. Toxicol Sci,2004,81:60-68.
    [18]Thompson CJ, Ross SM, Gaido KW. Di (n-butyl) phthalate impairs cholesterol transport and steroidogenesis in the fetal rat testis through a rapid and reversible mechanism[J]. Endocrinology,2004,145:1227-1237.
    [19]Kawamura K, Kurnagai J, Sudo S, et al. Paracfine regulation of mamma li an oocyte maturation and male germ cell survival. Proc Natl Aead Sei UsA。2004 101: 7323-7328.
    [20]Wilson VS, Lambright C, Furr J, et al.Phthalate ester-induced gubernacular lesions are associated with reduced ins13 gene expression in the fetal rat testis[J].Toxicol Lett,2004,146(3):207-215.
    [21]宋晓峰,张德迎,魏光辉等.邻苯二甲酸二乙基己酯诱发小鼠隐睾与INSL3 mRNA表达的相关性研究生[J].生殖与避孕,2006,26(12):712-716.
    [22]宋晓峰,魏光辉,邓永继等.邻苯二甲酸二乙基己酯对胚胎及新生小鼠睾丸Leydig细胞INSL3mRNA表达的影响[J].第四军医大学学 报,2006,27(21):1973-1976.
    [23]Kembra L.Howdeshell,Johnathan Furr,Christy R.Lambright, et al.Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development:Altered fetal steroidHormones and genes[J].Toxicological Sciences,2007,99(1):190-202.
    [24]Shono T, Shima Y, Kondo T, et al. In utero exposure to mono-n-butyl phthalate impairs insulin-like factor 3 gene expression and the transabdominal phase of testicular descent in fetal rats[J].Pediatr Surg,2005,40:1861-1864.
    [25]WILSON V S, HOWDESHELL KL,LAMBRIGHT C S, et al. Differential expression of the phthalate syndrome in male Sprague-Dawley and Wistar rats after in utero DEHP exposure[J].Toxicol Lett,2007,170(3):177-184.
    [26]张蕴晖,刘志伟,陈秉衡等.邻苯二甲酸酯类对大鼠睾丸支持细胞毒性作用[J].中国药理学与毒理学杂志,2005,19(4):300-304.
    [27]敖红,林玲,阚海东等.邻苯二甲酸二丁酯雄性生殖毒性分子作用机制[J].中国公共卫生,2007,23(5):631-633.
    [28]王玉邦,宋玲,朱正平等.邻苯二甲酸二丁酯对大鼠睾丸支持细胞的影响[J].中华预防医学杂志,2005,39(3):179-181.
    [29]Kazuyasu K, Kaoru T, Masashi Y, et al. Gene expression analysis of the rat testis after treatment with di (2-ethylhexyl) phthalate using cDNA microarray and real-time RT-PCR [J].Toxicol Appl Pharmacol,2004,200 (2):103-110.
    [30]张蕴晖,曾郁,林玲等,Fas/FasL系统在邻苯二甲酸二丁酯睾丸毒性机制中的作用[J].复旦学报(医学版),2006,33(6):749-752.
    [31]Chandrasekaran Y, Richburg JH.The p53 Protein Influences the Sensitivity of Testicular Germ Cells to Mono-(2-Ethylhexyl) Phthalate-Induced Apoptosis by Increasing the Membrane Levels ofFas and DR5 and Decreasing the Intracellular Amount of c-FLIP1[J].Biol Reprod,2005,72(1):206-213.
    [32]Yao PL, Lin YC, Sawhney P, et al.Transcriptional regulation of Fasl expression and participation of sTNF-alpha in response to sertoli cell injury[J].J Biol Chem, 2007,282(8):5420-5431.
    [33]李姿,张晓峰,张旸等.邻苯二甲酸二丁酯对大鼠生殖相关元素影响[J].中国公共卫生,2008,24(4):471-472.
    [34]王玉邦,宋玲,陈建锋等.邻苯二甲酸二丁酯对大鼠精子运动能力及氧化应激的影响[J].中华男科学,2004,10(4):253-256.
    [35]王玉邦,宋玲,朱正平等.邻苯二甲酸二丁酯对大鼠睾丸生化酶及脂质过氧化的影响[J].中华男科学杂志,2004,10(10):729-733.
    [36]Davis B J, Maronpot RR, Heindel JJ. Di-(2-ethylhexyl)phthalate suppresses estradiol and ovulation in cycling rats. Toxicol Appl Pharmaeol.1994,128:216-223.
    [37]靳秋梅,孙增荣.邻苯二甲酸二丁酯对小鼠卵功能的影响[J].环境与健康杂志,2007,24(5):310-2.
    [38]Lovekamp-Swan T,Davis BJ. Mechanisms of phthalate ester toxicity in the Female reproductive system.Environ Health Perspect,2003,111(2):139-145.
    [39]I Svechnikova, K Svechnikov, O Soder. The influence of di-(2-ethylhexyl) phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats[J]. Journal of Endocrinology 2007,194:603-609.
    [40]Gray LE, Jr., Laskey J, Ostby J. Chronic di-n-butyl phthalate exposure in rats reduces fertility and alters ovarian function during pregnancy in female Long Evans hooded rats[J]. Toxicol Sci 2006,93(1):189-95.
    [41]Treinen KA,Dod son W C. Heindel JJ Inhibition of FSH. Stimulated cAMP accumulation and progesterone production by mono(2-ethylbexyl)phthalate in rat granulosa cell cultures[J].Toxicol Appl Pharmaeol,1990,106:334-340.
    [42]Antonia MC, John WB, Manori JS, et al. Urinary and amniotic fluid levels of phthalate monoesters in rats after the oral administration of di(2-ethylhexyl) phthalate and di-n-butyl phthalate[J].Toxicology,2006,217:22-30.
    [43]Hermann F, Gabriele B, Holger MK,et al. Occurrence and daily variation of phthalate metabolites in the urine of an adult population[J].Int J Hyg Environ Health,2007,210:21-33.
    [44]Tina M, Gerda KM, Morten H,et al. Phthalate monoesters in perfusate froma dual placenta perfusion system, the placenta tissue and umbilical cord blood[J].Reproductive Toxicology,2007,23:83-91.
    [45]Barrettj R.The ugly side of beauty products [J].Environ Health Perspect, 2005,113(1):A24.
    [46]Swan SH, Main KM, Liu F, et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure[J]. Environ Health Perspect,2005,113:1056-1061.
    [47]Swan SH, Main KM, Liu F, et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure[J]. Environ Health Perspect,2005,113:1056-1061.
    [48]Lottrup G, Andersson AM, Leffers H, et al. Possible impact of phthalates on infant reproductive health[J]. Int J Androl,2006,29:172-180.
    [49]Bellis L,Latini G,De Feliee C,et al.High plasma concentrations of di-(2-ethylhexyl)-phthalate in women with endometriosis[J].Hum Reprod,2003,18(7):1512-1515.
    [50]ColonI, Cam D, Bourdony CJ, et al Identification of phthalate esters in the serum of young Puerto Rican girls with premature breast development. Environ Health Perspect,2000,108:895-900.
    [51]乔丽丽,郑力行,蔡德培.上海市女童血清中邻苯二甲酸二丁酯和邻苯二甲酸-2-乙基己酯水平与性早熟关系研究[J].卫生研究,2007,36(1):93-95.
    [52]宋晓峰,魏光辉,邓永继等.邻苯二甲酸二(2-乙基)己酯对原代培养小鼠胚胎睾丸Leydig细胞功能影响研究[J].第三军医大学学报,2006,28(12):1326-1329.

© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号

地址:北京市海淀区学院路29号 邮编:100083

电话:办公室:(+86 10)66554848;文献借阅、咨询服务、科技查新:66554700