环境内分泌干扰物引致儿童性早熟的机理及其中药治疗研究
|
摘要
目的：探讨环境内分泌干扰物(Environmental endocrine disruptors，EEDs)与性早熟发病的关系，制定针对EEDs拟雌激素作用的以中药为主的治疗方案，并深入研究中药治疗的作用机理。
方法：(1)运用反相高效液相色谱法检测73例性早熟患儿及年龄、性别匹配的38例正常儿童血清中数种有代表性的EEDs(包括：洗涤剂降解产物中的4-壬基酚(4-nonylphenol，4-NP)、有机氯农药DDT的代谢产物中的二氯二苯二氯乙烯(1，1-dichloro-2，2，bis(p-chlorophenyl)ethylene，p，p’-DDE)、塑料添加剂中的邻苯二甲酸-2-乙基己酯(di-2-ethylhexyl phthalate，DEHP)的含量；同时测定性早熟患儿的靶器官发育指标，包括子宫、卵巢体积，骨密度及血清雌二醇E_2水平。对两组儿童的EEDs血清含量进行分析，并将血清EEDs含量与靶器官发育指标进行相关性分析及多元线性回归分析。(2)以21d雌性SD大鼠为实验对象，选取4-NP、双酚A(bisphenol A，BPA)、DEHP为染毒物质，均设高中低剂量，并将4-NP和BPA以低剂量混合喂饲连续三天，于末次给药后24h处死。以子宫湿重、脏器系数、子宫内膜及平滑肌增生程度和细胞增殖核抗原(proliferating cell nuclear antigen，PCNA)的蛋白表达作为检测指标，采用单因素方差分析方法进行统计。(3)制定针对EEDs拟雌激素作用的中药治疗方案，治疗受EEDs暴露的性早熟患儿及染毒动物，以上述生殖器官及骨骼发育水平作为检测指标；并采用实时荧光定量聚合酶链式反应(real-time FQ-PCR)及免疫组织化学方法(immunohistochemistry，IHC)检测靶器官雌激素受体α(estrogen receptor alpha，ERα)、雌激素受体β(estrogen receptor beta，ERβ)、表皮细胞生长因子受体(epidermal growth factor receptor，EGFR)和胰岛素样生长因子-1受体(insulin-like factor-1 receptor，IGF-1R)的基因和蛋白的表达情况，采用单因素方差分析及t检验进行统计分析。
结果：(1)每一例正常儿童血清中均检测到一定含量的p，p’-DDE(14.93～40.39ng/ml)，部分正常儿童血清中检测到一定含量的4-NP及DEHP(ND～6.77ng/ml，ND～17.61ng/ml)。性早熟患儿血清中4-NP含量(ND～16.68ng/ml)、p，p’-DDE含量(40.03～91.68ng/ml)及DEHP含量(ND～64.71ng/ml)显著高于正常儿童(P＜0.01)。性早熟患儿血清中4-NP与子宫体积、卵巢体积、骨密度均呈显著正相关(r=0.394，0.286，0.237；P＜0.01)；p，p’-DDE与子宫体积呈显著正相关(r=0.306；P＜0.01)。4-NP对子宫体积的作用强度明显高于p，p’-DDE。(2)染毒动物实验结果显示，高中剂量的4-NP(200mg/kg，100mg/kg)和BPA(600mg/kg，400mg/kg)能够使染毒动物的子宫湿重及脏器系数明显增加(P＜0.01)，并且具有一定的剂量-效应关系；4-NP和BPA高中低三种剂量都能够使子宫内膜上皮增高，平滑肌增厚，PCNA蛋白表达增强(P＜0.05)。低剂量的4-NP(50mg/kg)和BPA(200mg/kg)混合喂饲后上述指标均较单独喂饲组显著增加(P＜0.01)。(3)第一部分筛查出的EEDs暴露水平增高的性早熟患儿经中药治疗三个月后，子宫体积、血清E_2含量、骨矿含量、骨密度、血清骨钙素含量较治疗前明显减小或降低(P＜0.01)。4-NP和BPA染毒的实验动物经中药治疗后，所有治疗组的子宫湿重、脏器系数、骨密度、子宫内膜上皮高度、子宫平滑肌厚度及PCNA蛋白表达均比实验组明显降低(P＜0.05)。中药治疗方案能够显著下调ERα及ERβmRNA在子宫、乳腺和骨骺端的表达水平(P＜0.05)，降低ERα及ERβ在子宫内膜上皮细胞、乳腺导管上皮细胞和骨骺端生长板软骨细胞的蛋白表达水平(P＜0.05)；能够显著下调EGFR mRNA在子宫、乳腺的表达水平(P＜0.05)，降低EGFR在子宫内膜上皮细胞、乳腺导管上皮细胞的蛋白表达水平(P＜0.05)；能够显著下调IGF-1R mRNA在干骺端的表达水平(P＜0.05)，降低IGF-1R在骨骺端生长板软骨细胞的蛋白表达水平(P＜0.05)。
结论：(1)当前正常儿童已经较普遍地暴露于环境内分泌干扰物，只不过暴露程度比性早熟患儿略轻而已；EEDs暴露与儿童性早熟的发病有密切关系，是其重要的致病因素之一；不同种类的EEDs对靶器官的致病作用强度有所不同。(2)动物染毒实验进一步证实了EEDs的拟雌激素作用及其剂量-效应关系；进一步验证了临床研究结果及其推论，证实EEDs的暴露程度与性早熟发病有密切关系；不同种类EEDs之间可以发挥联合增效作用，暴露人群更易受到不良影响；为子宫营养试验提供了更为敏感的检测指标。(3)制定了针对EEDs拟雌激素作用的中药治疗方案；研究结果表明所用中药能够有效拮抗EEDs的雌激素样活性，明显减轻EEDs对机体性发育及骨骼发育造成的不良影响；能够显著下调靶细胞雌激素受体的表达水平，降低机体对EEDs作用的敏感性；能够显著下调靶细胞生长因子受体的表达水平，干扰交叉对话机制，进一步加强其对EEDs拟雌激素活性的拮抗作用。
Objective: To explore the role of environmental endocrine disruptors(EEDs) in the onset of precocious puberty(PP) and the therapeutic effect of traditional Chinese medicine.
Methods: (1) The blood samples were collected from 73 cases of precocious puberty patients and 38 cases of normal children. The concentrations of 4-nonylphenol(4-NP) , 1,1-dichloro-2,2,bis(p-chlorophenyl)ethylene(p,p'-DDE) and di-2-ethylhexyl phthalate(DEHP) in the blood serum samples were measured by using reversed-phase high performance liquid chromatography(HPLC). The volume of uterus and ovary, bone density, and content of estradiol(E2) in the serum were determined at the same time. Contents of EEDs in the blood serums of precocious puberty cases and indices of the target organs were analyzed by correlation and regression methods. (2) The vehicle (peanut oil), ethinyl estradiol(EE, 0.3mg/kg positive control) , 4-NP(50mg/kg,100mg/kg,200mg/kg), bisphenol(BPA,200mg/kg,400mg/kg,600mg/kg),DEHP(100mg/kg,250mg/kg,500mg/ kg) and a mixture of 4-NP 50mg/kg and BPA 200mg/kg were given orally(by gavage ) q.d. to immature female Sprague-Dawley rats on the 21~(sd), 22~(nd),23~(rd) postnatal days. The rats were sacrificed 24 hours after the last administration. Uterine wet weight, uterine/body weight ratio, height of the luminal epithelium, thickness of the myometrium and protein level of proliferating cell nuclear antigen(PCNA) of rat uterine were analysed by one-way ANOVA. (3) The therapeutic project of traditional Chinese medicine was established to treat PP children and the experimental animals. Developing parameters of reproductive organs and bone were observed. Using methods of real— time fluorescence quantitative PCR and immunohistochemistry, we detected the expression level of four receptors on target organs(uterine, breast, bone), including estrogen receptor alpha(ERα) estrogen receptor beta(ERβ) epidermal growth factor receptor(EGFR) and insulin like factor-1 receptor( IGF-1R). The data were analysed by one-way ANOVA and T test.
Results: (1) In the normal control group, p,p'-DDE was detected in all the
blood samples(14.93 - 40.39ng/ml), but 4-NP and DEHP were only detected in some of the samples(ND - 6.77 ng/ml,ND - 17.61 ng/ml). Levels of 4-NP p,p'-DDE and DEHP in the serum of the precocious puberty group were notably higher than that of the control group (P < 0.01) .In the precocious puberty group, positive correlations were found between 4-NP and volume of uterus, volume of ovary and bone density ((r=0.394, 0.286,0.237; P < 0.01); p,p'-DDE and volume of uterus also had a positive correlation((r=0.306;P < 0.01). The influence intensity of 4-NP was higher than that of p,p'-DDE. (2) In animal experiments, uterine wet weight and uterine/body weight ratio were significantly higher in the 4-NP 200mg/kg and 100mg/kg, BPA 600mg/kg and 400mg/kg, and mixture group(4-NP 50mg/kg and BPA 200mg/kg) (P < 0.05) . Height of luminal epithelium, thickness of myometrium,as well as protein level of PCNA of rat uterine were significantly increased in the three groups of 4-NP, the three groups of BPA, and the mixture group (P < 0.05) , and a dose-response relationship was observed. Levels of aboved parameters in the mixture group were significantly higher than that in the single dose groups (P < 0.05) . (3) Volume of uterus, content of estradiol(E2) in the serum and bone density, bone mineral content, content of osteocalcin(OST) in the serum were decreased in patients after treating with traditional Chinese medicine (P < 0.05) . Uterine wet weight, uterine/body weight ratio, height of the luminal epithelium, thickness of the myometrium, protein level of PCNA of rat uterine and bone density of rats were notably decreased in animals treated with Chinese traditional medicine (P < 0.05) . After the therapy, mRNA and protein levels of ER α and ER β were significantly down regulated in uterine, breast and bone(P < 0.05). The mRNA and protein level of EGFR were significantly regulated down-ward in uterine and breast (P < 0.05) . The mRNA and protein level of IGF-1R were also significantly regulated down-ward in bones (P<0.05) .
Conclusions: (1) Normal children and children with precocious puberty are all contaminated by EEDs, and the later are exposured to higher EEDs. There is a close relationship between EEDs and the onset of precocious puberty, and EEDs are important factors inducing the disease. Different kinds of EEDs have different influence intensity on target organs. (2) The estrogenic effects of EEDs and their dose-response relationship were validated by uterotrophic assay in immature SD rats. Different kinds of EEDs below no effect levels, if combined, could also evoke additive effects, exerting estrogenic activitiy. (3) Traditional Chinese medicine could
regulate and decrease the expression of ERα ,ERβ,EGFR and IGF-1R on the target organs. Through this mechanism, treatment with traditional Chinese medicine, the medicine could inhibit the estrogenic effects of EEDs and slow down the accelerated development of reproductive organs and skeleton in PP patients.
方法：(1)运用反相高效液相色谱法检测73例性早熟患儿及年龄、性别匹配的38例正常儿童血清中数种有代表性的EEDs(包括：洗涤剂降解产物中的4-壬基酚(4-nonylphenol，4-NP)、有机氯农药DDT的代谢产物中的二氯二苯二氯乙烯(1，1-dichloro-2，2，bis(p-chlorophenyl)ethylene，p，p’-DDE)、塑料添加剂中的邻苯二甲酸-2-乙基己酯(di-2-ethylhexyl phthalate，DEHP)的含量；同时测定性早熟患儿的靶器官发育指标，包括子宫、卵巢体积，骨密度及血清雌二醇E_2水平。对两组儿童的EEDs血清含量进行分析，并将血清EEDs含量与靶器官发育指标进行相关性分析及多元线性回归分析。(2)以21d雌性SD大鼠为实验对象，选取4-NP、双酚A(bisphenol A，BPA)、DEHP为染毒物质，均设高中低剂量，并将4-NP和BPA以低剂量混合喂饲连续三天，于末次给药后24h处死。以子宫湿重、脏器系数、子宫内膜及平滑肌增生程度和细胞增殖核抗原(proliferating cell nuclear antigen，PCNA)的蛋白表达作为检测指标，采用单因素方差分析方法进行统计。(3)制定针对EEDs拟雌激素作用的中药治疗方案，治疗受EEDs暴露的性早熟患儿及染毒动物，以上述生殖器官及骨骼发育水平作为检测指标；并采用实时荧光定量聚合酶链式反应(real-time FQ-PCR)及免疫组织化学方法(immunohistochemistry，IHC)检测靶器官雌激素受体α(estrogen receptor alpha，ERα)、雌激素受体β(estrogen receptor beta，ERβ)、表皮细胞生长因子受体(epidermal growth factor receptor，EGFR)和胰岛素样生长因子-1受体(insulin-like factor-1 receptor，IGF-1R)的基因和蛋白的表达情况，采用单因素方差分析及t检验进行统计分析。
结果：(1)每一例正常儿童血清中均检测到一定含量的p，p’-DDE(14.93～40.39ng/ml)，部分正常儿童血清中检测到一定含量的4-NP及DEHP(ND～6.77ng/ml，ND～17.61ng/ml)。性早熟患儿血清中4-NP含量(ND～16.68ng/ml)、p，p’-DDE含量(40.03～91.68ng/ml)及DEHP含量(ND～64.71ng/ml)显著高于正常儿童(P＜0.01)。性早熟患儿血清中4-NP与子宫体积、卵巢体积、骨密度均呈显著正相关(r=0.394，0.286，0.237；P＜0.01)；p，p’-DDE与子宫体积呈显著正相关(r=0.306；P＜0.01)。4-NP对子宫体积的作用强度明显高于p，p’-DDE。(2)染毒动物实验结果显示，高中剂量的4-NP(200mg/kg，100mg/kg)和BPA(600mg/kg，400mg/kg)能够使染毒动物的子宫湿重及脏器系数明显增加(P＜0.01)，并且具有一定的剂量-效应关系；4-NP和BPA高中低三种剂量都能够使子宫内膜上皮增高，平滑肌增厚，PCNA蛋白表达增强(P＜0.05)。低剂量的4-NP(50mg/kg)和BPA(200mg/kg)混合喂饲后上述指标均较单独喂饲组显著增加(P＜0.01)。(3)第一部分筛查出的EEDs暴露水平增高的性早熟患儿经中药治疗三个月后，子宫体积、血清E_2含量、骨矿含量、骨密度、血清骨钙素含量较治疗前明显减小或降低(P＜0.01)。4-NP和BPA染毒的实验动物经中药治疗后，所有治疗组的子宫湿重、脏器系数、骨密度、子宫内膜上皮高度、子宫平滑肌厚度及PCNA蛋白表达均比实验组明显降低(P＜0.05)。中药治疗方案能够显著下调ERα及ERβmRNA在子宫、乳腺和骨骺端的表达水平(P＜0.05)，降低ERα及ERβ在子宫内膜上皮细胞、乳腺导管上皮细胞和骨骺端生长板软骨细胞的蛋白表达水平(P＜0.05)；能够显著下调EGFR mRNA在子宫、乳腺的表达水平(P＜0.05)，降低EGFR在子宫内膜上皮细胞、乳腺导管上皮细胞的蛋白表达水平(P＜0.05)；能够显著下调IGF-1R mRNA在干骺端的表达水平(P＜0.05)，降低IGF-1R在骨骺端生长板软骨细胞的蛋白表达水平(P＜0.05)。
结论：(1)当前正常儿童已经较普遍地暴露于环境内分泌干扰物，只不过暴露程度比性早熟患儿略轻而已；EEDs暴露与儿童性早熟的发病有密切关系，是其重要的致病因素之一；不同种类的EEDs对靶器官的致病作用强度有所不同。(2)动物染毒实验进一步证实了EEDs的拟雌激素作用及其剂量-效应关系；进一步验证了临床研究结果及其推论，证实EEDs的暴露程度与性早熟发病有密切关系；不同种类EEDs之间可以发挥联合增效作用，暴露人群更易受到不良影响；为子宫营养试验提供了更为敏感的检测指标。(3)制定了针对EEDs拟雌激素作用的中药治疗方案；研究结果表明所用中药能够有效拮抗EEDs的雌激素样活性，明显减轻EEDs对机体性发育及骨骼发育造成的不良影响；能够显著下调靶细胞雌激素受体的表达水平，降低机体对EEDs作用的敏感性；能够显著下调靶细胞生长因子受体的表达水平，干扰交叉对话机制，进一步加强其对EEDs拟雌激素活性的拮抗作用。
Objective: To explore the role of environmental endocrine disruptors(EEDs) in the onset of precocious puberty(PP) and the therapeutic effect of traditional Chinese medicine.
Methods: (1) The blood samples were collected from 73 cases of precocious puberty patients and 38 cases of normal children. The concentrations of 4-nonylphenol(4-NP) , 1,1-dichloro-2,2,bis(p-chlorophenyl)ethylene(p,p'-DDE) and di-2-ethylhexyl phthalate(DEHP) in the blood serum samples were measured by using reversed-phase high performance liquid chromatography(HPLC). The volume of uterus and ovary, bone density, and content of estradiol(E2) in the serum were determined at the same time. Contents of EEDs in the blood serums of precocious puberty cases and indices of the target organs were analyzed by correlation and regression methods. (2) The vehicle (peanut oil), ethinyl estradiol(EE, 0.3mg/kg positive control) , 4-NP(50mg/kg,100mg/kg,200mg/kg), bisphenol(BPA,200mg/kg,400mg/kg,600mg/kg),DEHP(100mg/kg,250mg/kg,500mg/ kg) and a mixture of 4-NP 50mg/kg and BPA 200mg/kg were given orally(by gavage ) q.d. to immature female Sprague-Dawley rats on the 21~(sd), 22~(nd),23~(rd) postnatal days. The rats were sacrificed 24 hours after the last administration. Uterine wet weight, uterine/body weight ratio, height of the luminal epithelium, thickness of the myometrium and protein level of proliferating cell nuclear antigen(PCNA) of rat uterine were analysed by one-way ANOVA. (3) The therapeutic project of traditional Chinese medicine was established to treat PP children and the experimental animals. Developing parameters of reproductive organs and bone were observed. Using methods of real— time fluorescence quantitative PCR and immunohistochemistry, we detected the expression level of four receptors on target organs(uterine, breast, bone), including estrogen receptor alpha(ERα) estrogen receptor beta(ERβ) epidermal growth factor receptor(EGFR) and insulin like factor-1 receptor( IGF-1R). The data were analysed by one-way ANOVA and T test.
Results: (1) In the normal control group, p,p'-DDE was detected in all the
blood samples(14.93 - 40.39ng/ml), but 4-NP and DEHP were only detected in some of the samples(ND - 6.77 ng/ml,ND - 17.61 ng/ml). Levels of 4-NP p,p'-DDE and DEHP in the serum of the precocious puberty group were notably higher than that of the control group (P < 0.01) .In the precocious puberty group, positive correlations were found between 4-NP and volume of uterus, volume of ovary and bone density ((r=0.394, 0.286,0.237; P < 0.01); p,p'-DDE and volume of uterus also had a positive correlation((r=0.306;P < 0.01). The influence intensity of 4-NP was higher than that of p,p'-DDE. (2) In animal experiments, uterine wet weight and uterine/body weight ratio were significantly higher in the 4-NP 200mg/kg and 100mg/kg, BPA 600mg/kg and 400mg/kg, and mixture group(4-NP 50mg/kg and BPA 200mg/kg) (P < 0.05) . Height of luminal epithelium, thickness of myometrium,as well as protein level of PCNA of rat uterine were significantly increased in the three groups of 4-NP, the three groups of BPA, and the mixture group (P < 0.05) , and a dose-response relationship was observed. Levels of aboved parameters in the mixture group were significantly higher than that in the single dose groups (P < 0.05) . (3) Volume of uterus, content of estradiol(E2) in the serum and bone density, bone mineral content, content of osteocalcin(OST) in the serum were decreased in patients after treating with traditional Chinese medicine (P < 0.05) . Uterine wet weight, uterine/body weight ratio, height of the luminal epithelium, thickness of the myometrium, protein level of PCNA of rat uterine and bone density of rats were notably decreased in animals treated with Chinese traditional medicine (P < 0.05) . After the therapy, mRNA and protein levels of ER α and ER β were significantly down regulated in uterine, breast and bone(P < 0.05). The mRNA and protein level of EGFR were significantly regulated down-ward in uterine and breast (P < 0.05) . The mRNA and protein level of IGF-1R were also significantly regulated down-ward in bones (P<0.05) .
Conclusions: (1) Normal children and children with precocious puberty are all contaminated by EEDs, and the later are exposured to higher EEDs. There is a close relationship between EEDs and the onset of precocious puberty, and EEDs are important factors inducing the disease. Different kinds of EEDs have different influence intensity on target organs. (2) The estrogenic effects of EEDs and their dose-response relationship were validated by uterotrophic assay in immature SD rats. Different kinds of EEDs below no effect levels, if combined, could also evoke additive effects, exerting estrogenic activitiy. (3) Traditional Chinese medicine could
regulate and decrease the expression of ERα ,ERβ,EGFR and IGF-1R on the target organs. Through this mechanism, treatment with traditional Chinese medicine, the medicine could inhibit the estrogenic effects of EEDs and slow down the accelerated development of reproductive organs and skeleton in PP patients.
引文
1. Rice C, Birnbaum LS, Cogliano J, et al. Exposure assessment for endocrine disruptors: some considerations in the design of studies[J]. Environ Health Perspect, 2003,111 (13): 1683-1690.
2. Singleton DW, Khan SA. Xenoestrogen exposure and mechanisms of endocrine disruption s[J]. Front Biosci,2003,8:s110-118.
3. Colborn T, vom Saal FS, Soto AM. Developmental effects of endocrine-disrupting chemicals in wildlife and humans s[J]. Environ Health Perspect, 1993,101 (5):378-384.
4. Arnold SF, Collins BM, Robinson MK, et al. Differential interaction of natural and synthetic estrogens with extracellular binding proteins in a yeast estrogen screen[J]. Steroids, 1996,61 (11):642-646.
5. Gray LE Jr, Ostby J, Cooper RL, et al. The estrogenic and antiandrogenic pesticide methoxychlor alters the reproductive tract and behavior without affecting pituitary size or LH and prolactin secretion in male rats[J]. Toxicol Ind Health, 1999,15(1-2):37-47.
6. Jansen HT, Cooke PS, Porcelli J, et al. Estrogenic and antiestrogenic actions of PCBs in the female rat: in vitro and in vivo studies[J]. Reprod Toxicol, 1993,7(3):237-248.
7. Cohen Hubal EA, Sheldon LS, Burke JM, et al. Children's exposure assessment: a review of factors influencing children's exposure, and the data available to characterize and assess that exposure[J]. Environ Health Perspect, 2000, 108(6):475-486
8. Mukerjee D. Assessment of risk from multimedia exposures of children to environmental chemicals[J]. J Air Waste Manag Assoc, 1998,48(6):483-501.
9．宁寿葆．现代实用儿科学[M]．上海：复旦大学出版社，2004： 823.
10. Ehrhardt AA, Meyer-Bahlburg HF. Psychosocial aspects of precocious puberty[J]. Horm Res, 1994,41(Supp12):30-35
11. Lee PA. Central precocious puberty. An overview of diagnosis, treatment, and outcome[J]. Endocrinol Metab Clin North Am, 1999,28(4):901-918
12. Tato L, Savage MO, Antoniazzi F, et al. International Workshop on Management of Puberty for Optimum Auxological.Optimal therapy of pubertal disorders in precocious/early puberty[J]. J Pediatr Endocrinol Metab, 2001,14(Suppl 2):985-995.
13. Christine LM, Pierre BJ. Central and peripheral isosexual precocious puberty[J]. Current Opinion in Endocrinology & Diabetes, 200,18(1): 17-22.
14. Recchia AG, Vivacqua A, Gabriele S,et al. Xenoestrogens and the induction of proliferative effects in breast cancer cells via direct activation of oestrogen receptor alpha Central and peripheral isosexual precocious puberty[J]. Food Addit Contam, 2004,21(2):134-144.
15. Kim HS, Shin JH, Moon HJ,et al. Comparative estrogenic effects of p-nonylphenol by 3-day uterotrophic assay and female pubertal onset assay[J]. Reprod Toxicol, 2002,16(3):259-268.
16. Smith CL, Conneely OM, O'Malley BW. Modulation of the ligand-independent activation of the human estrogen receptor by hormone and antihormone[J]. Proc Natl Acad Sci U S A, 1993,90(13):6120-6124.
17. Levin ER. Bidirectional signaling between the estrogen receptor and the epidermal growth factor receptor[J]. Mol Endocrinol, 2003,17(3):309-317.
18. Dupont J, Karas M, LeRoith D. The potentiation of estrogen on insulin-like growth factor Ⅰ action in MCF-7 human breast cancer cells includes cell cycle components[J]. J Biol Chem, 2000,275(46):35893-35901.
19．蔡德培，季志英，时毓民．滋阴泻火中药及甲地孕酮治疗女性特发性性早熟的临床研究[J]．中国中两医结合杂志，2001，21(10)：732-735．
20. Shelby MD, Newbold RR, Tully DB, et al. Assessing environmental chemicals for estrogenicity using a combination of in vitro and in vivo assays[J]. Environ Health Perspect, 1996,104(12):1296-1300.
21. Recchia AG, Vivacqua A, Gabriele S, et al. Xenoestrogens and the induction of proliferative effects in breast cancer cells via direct activation of oestrogen receptor alpha[J]. Food Addit Contam, 2004,21 (2): 134-144.
22. Kim HS, Shin JH, Moon H J, et al. Comparative estrogenic effects of p-nonyiphenol by 3-day uterotrophic assay and female pubertal onset assay[J]. Reprod Toxicol, 2002,16(3):259-268.
23. Green T, Swain C, Van Miller JP, et al. Absorption, bioavailability, and metabolism of para-nonylphenol in the rat[J]. Regul Toxicol Pharmacol, 2003,38(1):43-51.
24. Vivacqua A, Recchia AG, Fasanella G, et al. The food contaminants bisphenol A and 4-nonylphenol act as agonists for estrogen receptor alpha in MCF7 breast cancer cells[J]. Endocrine, 2003,22(3):275-284.
25. Danzo BJ, Shappell HW, Banerjee A,et al .Effects of nonylphenol, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE), and pentachlorophenol on the adult female guinea pig reproductive tract[J]. Reprod Toxicol, 2002,16(1 ):29-43.
26. Matthews J, Celius T, Halgren R, et al. Differential estrogen receptor binding of estrogenic substances: a species comparison[J]. J Steroid Biochem Mol Bioi, 2000,74(4):223-234.
27. Andersen HR, Andersson AM, Arnold SF, et al. Comparison of short-term estrogenicity tests for identification of hormone-disrupting chemicals[J]. Environ Health Perspect, 1999,107 (Suppl 1 ):89-108.
28. Yuan SY, Liu C, Liao CS, et al. Occurrence and microbial degradation of phthalate esters in Taiwan river sediments[J]. Chemosphere, 2002,49(10):1295-1299.
29. Marttinen SK, Kettunen RH, Rintala JA. Occurrence and removal of organic pollutants in sewages and landfill leachates[J]. Sci Total Environ, 2003,301 (1-3):1-12.
30. TOXICOLOGICAL PROFILE FOR DI(2-ETHYLHEXYL)PHTHALATE[M]. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, Public Health Service Agency for Toxic Substances and Disease Registry. 2002.
31. Asai D, Tahara Y, Nakai M, et al. Structural essentials of xenoestrogen dialkyl phthalates to bind to the estrogen receptors[J]. Toxicol Lett, 2000,20;118(1-2):1-8.
32. Zacharewski TR, Meek MD, Clemons JH, et al. Examination of the in vitro and in vivo estrogenic activities of eight commercial phthalate esters[J]. Toxicol Sci, 1998,46(2):282-293.
33. Jobling S, Reynolds T, White R, et al. A variety of environmentally persistent chemicals, including some phthalate plasticizers, are weakly estrogenic[J]. Environ Health Perspect, 1995,103(6):582-587.
34. Blom A, Ekman E, Johannisson A, et al. Effects of xenoestrogenic environmental pollutants on the proliferation of a human breast cancer cell line (MCF-7) [J]. Arch Environ Contam Toxicol, 1998,34(3):306-310.
35．解玮，蒋颂辉，屈卫东，等．DEHP、DBP内分泌干扰活性的实验研究．中国环境科学，2004，24(1)：45-48．
36．曾畿生，王德芬．现代儿科内分泌学-基础与临床[M]．上海：上海科学技术文献出版社，2001：125-34．
37. Damgaard NI, Main KM, Toppari J, et al. Impact of exposure to endocrine disrupters in utero and in childhood on adult reproduction[J]. Best Pract Res Clin Endocrinol Metab, 2002,16(2):289-309.
38. Landrigan P, Garg A, Droller DB. Assessing the effects of endocrine disruptors in the National Children's Study[J]. Environ Health Perspect, 2003,111 (13): 1678-1682.
39. Tsutsui T, Barrett JC. Neoplastic transformation of cultured mammalian cells by estrogens and estrogen-like chemicals[J].Environ Health Perspect.1997,105(supple 3):621-623.
40. Final Report on the reproductive toxicity of nonylphenol[R]. National Toxicology Program( 1997),8989-9030.
41. Lascombe, I, Beffa D, Rüegg U, et al. Estrogenic activity assessment of environmental chemicals using in vitro assays: identification of two new estrogenic compounds[J]. Environ Health Perspect, 2000,108(7):621-629.
42. Krstevska-Konstantinova M, Charlier C, Craen M, et al. Sexual precocity after immigration from developing countries to Belgium: evidence of previous exposure to organochlorine pesticides[J].Hum Reprod, 2001,16(5): 1020-1026.
43. Balaguer P, Francois F, Comunale F, et al. Reporter cell lines to study the estrogenic effects of xenoestrogens[J]. Sci Total Environ, 1999,233(1-3):47-56.
44. Colon I, Caro 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(9): 895-900.
45. Hashimoto Y, Kawaguchi M, Miyazaki K, et al. Estrogenic activity of tissue conditioners in vitro. Dent Mater. 2003,19:341-6.
46. Paganetto G, Campi F, Varani K, et al. Endocrine-disrupting agents on healthy human tissues[J]. Pharmacol Toxicol. 2000, 86(1): 24-29.
47. Teilmann G, Juul A, Skakkebak NE, et al. Putative effects of endocrine disruptors on pubertal development in the human[J]. Best Prac Res Clin Endocrinol Metab,1997, 16:105-121.
48．李嫔，蔡德培，黄玉娟．性早熟女童骨骼发育异常的规律及滋阴泄火中药治疗的作用．中国中西医结合杂志．2004，24：979-82．
49. Kang KS, Kim HS, Ryu DY, et al. Immature uterotrophic assay is more sensitive than ovariectomized uterotrophic assay for the detection of estrogenicity of p-nonylphenol in Sprague-Dawley rats[J]. Toxicol Lett, 2000,118(1-2): 109-115.
50. Kwack SJ, Kwon O, Kim HS, et al. Comparative evaluation of alkylphenolic compounds on estrogenic activity in vitro and in vivo[J]. J Toxicol Environ Health A, 2002,65(5-6):419-431.
51. Frigo DE, Burow ME, Mitchell KA, et al. DDT and its metabolites alter gene expression in human uterine cell lines through estrogen receptor-independent mechanisms[J]. Environ Health Perspect, 2002,110(12): 1239-1245.
52. Cooper GS, Martin SA, Longnecker MP. et al. Associations between plasma DDE levels and immunologic measures in African-American farmers in North Carolina[J]. Environ Health Perspect,2004,112(10): 1080-1084.
53. Martin SA Jr, Harlow SD, Sowers MF, et al. DDT metabolite and androgens in African-American farmers[J]. Epidemiology, 2002,13(4):454-458.
54. Lee PC, Lee W. In vivo estrogenic action of nonylphenol in immature female rats[J]. Bull Environ Contam Toxicol, 1996,57(3):341-348.
55. Biedermann M, Grob K. Food contamination from epoxy resins and organosols used as can coatings: analysis by gradient NPLC[J]. Food Addit Contam, 1998,15(5):609-618.
56. Howe SR, Borodinsky L. Potential exposure to bisphenol A from food-contact use of polycarbonate resins[J]. Food Addit Contam. 1998,15(3):370-375.
57. Laws SC, Carey SA, Ferrell JM, et al. Estrogenic activity of octylphenol, nonylphenol, bisphenol A and methoxychlor in rats[J]. Toxicol Sci, 2000,54(1): 154-167.
58. Fang H, Tong W, Perkins R, et al. Quantitative comparisons of in vitro assays for estrogenic activities[J]. Environ Health Perspect, 2000,108(8):723-729.
59. Lascombe I, Beffa D, Ruegg U, et al. Estrogenic activity assessment of environmental chemicals using in vitro assays: identification of two new estrogenic compounds[J]. Environ Health Perspect, 2000,108(7):621-629.
60. Lemmen JG, Arends RJ, van der Saag PT, et al. In vivo imaging of activated estrogen receptors in utero by estrogens and bisphenol A[J]. Environ Health Perspect, 2004,112(15): 1544-1549.
61. Kim HS, Han SY, Yoo SD, et al. Potential estrogenic effects of bisphenol-A estimated by in vitro and in vivo combination assays[J]. J Toxicol Sci, 2001,26(3): 111-118.
62. Asai D, Tahara Y, Nakai M, et al. Structural essentials of xenoestrogen dialkyl phthalates to bind to the estrogen receptors[J]. Toxicol Lett, 2000,118(1-2):1-8.
63. Okubo T, Suzuki T, Yokoyama Y, et al. Estimation of estrogenic and anti-estrogenic activities of some phthalate diesters and monoesters by MCF-7 cell proliferation assay in vitro[J]. Biol Pharm Bull, 2003,26(8):1219-1224.
64. Diel P. Tissue-specific estrogenic response and molecular mechanisms[J]. Toxicol Lett, 2002,127(1-3):217-224.
65. 4-NONYLPHENOL(Branched) AND NONYLPHENOL. CAS No: 84852-15-3 and 25154-52-3.Summary Risk Assessment Report[R]. European Communities, 2002.
66. 4,4'-ISOPROPYLIDENEDIPHENOL(BISPHENOL-A). CAS No: 80-05-7. Summary Risk Assessment Report[R]. European Communities, 2003.
67. 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].Environ Health Perspect, 2001,109(8):785-794.
68. Zacharewski T. Identification and assessment of endocrine disruptors: limitations of in vivo and in vitro assays[J]. Environ Health Perspect, 1998,106(Suppl 2):577-582.
69. Bachmann S, Hellwig J, Jackh R, et al. Uterotrophic assay of two concentrations of migrates from each of 23 polystyrenes administered orally (by gavage) to immature female Wistar rats[J]. Drug Chem Toxicol, 1998,21(Suppl 1):1-30.
70. Jefferson WN, Padilla-Banks E, Clark G, et al.Assessing estrogenic activity of phytochemicals using transcriptional activation and immature mouse uterotrophic responses[J]. J Chromatogr B Analyt Technol Biomed Life Sci,2002,777(1-2): 179-189.
71. Kim KB, Seo KW, Kim YJ, et al. Estrogenic effects of phenolic compounds on glucose-6-phosphate dehydrogenase in MCF-7 cells and uterine glutathione peroxidase in rats[J]. Chemosphere, 2003,50(9):1167-1173.
72. Balajee AS, May A, Dianova I, et al. Efficient PCNA complex formation is dependent upon both transcription coupled repair and genome overall repair[J]. Mutat Res, 1998,409(3):135-146.
73. Shimazaki N, Yazaki T, Kubota T, et al. DNA polymerase lambda directly binds to proliferating cell nuclear antigen through its confined C-terminal region[J]. Genes Cells, 2005,10(7):705-715.
74. Tinwell H, Ashby J. Sensitivity of the immature rat uterotrophic assay to mixtures of estrogens[J]. Environ Health Perspect, 2004,112(5):575-582.
75. Simons SS Jr. Environmental estrogens: can two "alrights" make a wrong? [J].Science, 1996,272(5267):1451.
76. Diel P, Schulz T, Smolnikar K, et al. Ability of xeno- and phytoestrogens to modulate expression of estrogen-sensitive genes in rat uterus: estrogenicity profiles and uterotropic activity[J]. J Steroid Biochem Mol Biol, 2000,73(1-2):1-10.
77. Casanova M, You L, Gaido KW, et al. Developmental effects of dietary phytoestrogens in Sprague-Dawley rats and interactions of genistein and daidzein with rat estrogen receptors alpha and beta in vitro[J]. Toxicol Sci, 1999,51(2):236-244.
78. Ignar-Trowbridge DM, Pimentel M, Teng CT, et al. Cross talk between peptide growth factor and estrogen receptor signaling systems[J]. Environ Health Perspectn 1995,103(Suppl 7):35-38.
79. Townson SM, Kang K, Lee AV, et al. Structure-function analysis of the estrogen receptor alpha corepressor scaffold attachment factor-B1: identification of a potent transcriptional repression domain[J]. J Biol Chem, 2004,279(25):26074-26081.
80. Silva E, Rajapakse N, Kortenkamp A. Something from "nothing"--eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects[J]. Environ Sci Technol, 2002,36(8):1751-1756.
81．蔡德培，陈伯英，庄振杰．滋阴泻火中药对下丘脑 GnRH 的合成、分泌及其调节机制的影响[J]．中国中西医结合杂志，2001，21(8)：595-598．
82．蔡德培．性早熟治疗及药物作用机制的研究进展[J]．实用儿科临床杂志，2005，20(6)：502-505．
83. Knight PG, Glister C. Potential local regulatory functions of inhibins, activins and follistatin in the ovary[J]. Reproduction, 2001,121 (4):503-512.
84. Barrios-De-Tomasi J, Timossi C, Merchant H, et al. Assessment of the in vitro and in vivo biological activities of the human follicle-stimulating isohormones[J]. Mol Cell Endocrinol, 2002,186(2): 189-198.
85. Kang J S, Lee BJ, Ahn B, et al. Expression of estrogen receptor alpha and beta in the uterus and vagina of immature rats treated with 17 - ethinyl estradiol [J]. J Vet Med Sci, 2003,65 (12): 1293-1297.
86. Braidman I, Baris C, Wood L, et al. Preliminary evidence for impaired estrogen receptor-alpha protein expression in osteoblasts and osteocytes from men with idiopathic osteoporosis[J]. Bone, 2000,26(5):423-427.
87. Ambroszkiewicz J, Gajewska J, Laskowska-Klita T. Serum osteocalcin and bone alkaline phosphatase in healthy children in relation to age and gender[J]. Med Wieku Rozwoj, 2002,6(3):257-65.
88. Mora S, Pitukcheewanont P, Kaufman FR, et al. Biochemical markers of bone turnover and the volume and the density of bone in children at different stages of sexual development[J]. J Bone Miner Res,1999,14(10):1664-1671.
89．张镜如．生理学[M]．第4版．北京：人民卫生出版社，1999．414-417
90. Windahl SH, Norgard M, Kuiper GG, et al. Cellular distribution of estrogen receptor beta in neonatal rat bone[J]. Bone,2000,26(2): 117-121.
91．蔡德培，张炜．补肾中药对下丘脑 GnRH、垂体 FsH、LH及成骨细胞基因表达的调节作用[J]．中医杂志，2002；43(3)：221-223．
92. Lee HS, Sasagawa S, Kato S, et al. Yeast two-hybrid detection systems that are highly sensitive to a certain kind of endocrine disruptors[J]. Biosci Biotechnol Biochem, 2006,70(2):521-524.
93. Hom YK, Young P, Wiesen JF, et al. Uterine and vaginal organ growth requires epidermal growth factor receptor signaling from stroma[J]. Endocrinology, 1998,139(3):913-921.
94. Hawkins MB, Thornton JW, Crews D, et al. Identification of a third distinct estrogen receptor and reclassification of estrogen receptors in teleosts[J]. Proc Natl Acad Sci U S A,2000,97(20): 10751-10756.
95. Okada A, Sato T, Ohta Y, et al. Sex steroid hormone receptors in the developing female reproductive tract of laboratory rodents[J]. J Toxicol Sci, 2005,30(2):75-89.
96. Kousteni S, Bellido T, Plotkin LI, et al. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity[J].Cell, 2001,104(5):719-730.
97. Riese DJ 2nd, Stern DF. Specificity within the EGF family/ErbB receptor family signaling network[J]. Bioessays, 1998 ,20(l):41-48.
98. Ignar-Trowbridge DM, Nelson KG, Bidwell MC, et al. Coupling of dual signaling pathways: epidermal growth factor action involves the estrogen receptor[J]. Proc NatI Acad Sci U S A,1992,89(10):4658-4662.
99. Lai A, Sarcevic B, Prall OW, Sutherland RL. Insulin/insulin-like growth factor-1 and estrogen cooperate to stimulate cyclin E-Cdk2 activation and cell Cycle progression in MCF-7 breast cancer cells through differential regulation of cyclin E and p21(WAFl/Cipl) [J]. J Biol Chem, 2001,276(28):25823-25833.
100. Paech K, Webb P, Kuiper GG, et al. Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites[J]. Science, 1997,277(5331): 1508-1510.
101. Viau V, Meaney MJ. Alphal adrenoreceptors mediate the stimulatory effects of oestrogen on stress-related hypothalamic-pituitary-adrenal activity in the female rat[J]. J Neuroendocrinol, 2004,16(1):72-78.
102. Razandi M, Pedram A, Greene GL, et al. Cell membrane and nuclear estrogen receptors(ERs) originate from a single transcript: studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells[J]. Mol Endocrinol,1999,13(2):307-319.
103. Song RX, McPherson RA, Adam L, et al. Linkage of rapid estrogen action to MAPK activation by ERalpha-Shc association and She pathway activation[J]. Mol Endocrinol, 2002,16(1):116-127.
104. Levin ER. Cell localization, physiology, and nongenomic actions of estrogen receptors[J]. J Appl Physiol,2001,91 (4): 1860-1867.
105. Bunone G, Briand PA, Miksicek RJ, et al. Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation[J]. EMBO J, 1996,15(9):2174-2183.
106. Lopez GN, Turck CW, Schaufele F, et al. Growth factors signal to steroid receptors through mitogen-activated protein kinase regulation of p160 coactivator activity[J]. J Biol Chem, 2001,276(25):22177-22182.
107. Ignar-Trowbridge DM, Pimentel M, Parker MG, et al. Peptide growth factor cross-talk with the estrogen receptor requires the A/B domain and occurs independently of protein kinase C or estradiol[J]. Endocrinology, 1996,137(5): 1735-1744.
108. Ignar-Trowbridge DM, Teng CT, Ross KA, et al. Peptide growth factors elicit estrogen receptor-dependent transcriptional activation of an estrogen-responsive element[J]. Mol Endocrinol, 1993,7(8):992-998.
109. Martin MB, Franke TF, Stoica GE, et al. A role for Akt in mediating the estrogenic functions of epidermal growth factor and insulin-like growth factor Ⅰ[J]. Endocrinology, 2000,141 (12):4503-4511.
110. Klotz DM, Hewitt SC, Ciana P, et al. Requirement of estrogen receptor-alpha in insulin-like growth factor-1 (IGF-1)-induced uterine responses and in vivo evidence for IGF-1/estrogen receptor cross-talk[J]. J Biol Chem, 2002,277(10):8531-8537.
111. Oesterreich S, Zhang P, Guler RL, et al. Re-expression of estrogen receptor alpha in estrogen receptor alpha-negative MCF-7 cells restores both estrogen and insulin-like growth factor-mediated signaling and growth[J]. Cancer Res, 2001,61 (15):5771-5777.
112. Adesanya OO, Zhou J, Samathanam C, et al. Insulin-like growth factor 1 is required for G2 progression in the estradiol-induced mitotic cycle[J]. Proc Natl Acad Sci U S A, 1999,96(6):3287-3291.
113. Klotz DM, Hewitt SC, Korach KS, et al. Activation of a uterine insulin-like growth factor I signaling pathway by clinical and environmental estrogens: requirement of estrogen receptor-alpha[J]. Endocrinology,2000,141 (9):3430-3439.
114. Le Roith D: The insulin-like growth factor system[J]. Exp Diabesity Res, 2003,4(4):205-212.
115. D'Ercole AJ. Insulin-like growth factors and their receptors in growth[J]. Endocrinol Metab Clin North Am, 1996,25(3):573-590.
116．陆炜，蔡德培．补肾中药对雌性青春期大鼠垂体GnRH受体mRNA及其受体蛋白表达的影响[J]．中国中西医结合杂志，2003，23(2)：120-122
117．李嫔，向正华，蔡德培．中药对大鼠下丘脑生长抑素及垂体生长激素基因表达与蛋白表达的调节作用[J]．中国中西医结合杂志，2003，23(3)：207-210．
118．蔡德培．滋阴泻火中药改善性早熟儿童骨骼发育的作用及机理探讨[J]．中医杂志，1997，38(10)：615．
1. Sonnenscein Carlos, Soto AM. An update review of environmental estrogen and androgen mimics and antagonists[J]. J Steroid Biocheim Mol Biok 1998,65(1): 143-150.
2. Norgil Damgaard I, Main KM, Toppari J, et al. Impact of exposure to endocrine disrupters in utero and in childhood on adult reproduction[J]. Best Pract Res Clin Endocrinol Metab. 2002,16(2):289-309.
3. Simons SS Jr. Environmental estrogens: can two "alrights" make a wrong? [J].Science,1996,272(5267):1451.
4. Levin ER. Cellular functions of plasma membrane estrogen receptors[J].Steroids, 2002,67(6):471-5.
5. Diel P.Tissue-specific estrogenic response and molecular mechanisms[J]. Toxicol Lett,2002,127(1-3):217-24.
6. Fortunati N. Sex hormone-binding globulin: not only a transport protein. What news is around the corner?[J].J Endocrinol Invest,1999,22(3):223-34.
7. Kirk CJ, Harris RM, Wood DM et al. Do dietary phytoestrogens influence susceptibility to hormone-dependent cancer by disrupting the metabolism of endogenous oestrogens? [J].Biochem Soc Trans,2001,29(Pt 2):209-16.
8. 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):231-5.
9. Rice C, Birnbaum LS, Cogliano J et al. Exposure assessment for endocrine disruptors: some considerations in the design of studies[J]. Environ Health Perspect, 2003,111(13):1683-90.
10.Cohen Hubal EA, Sheldon LS, Burke JM,et al. Children's exposure assessment: a review of factors influencing Children's exposure, and the data available to characterize and assess that exposure. Environ Health Perspect. 2000,108(6):475-86.
11 .Gurunathan S, Robson M, Freeman N, et al. Accumulation of chlorpyrifos on residential surfaces and toys accessible to children. Environ Health Perspect. 1998,106(1):9-16.
12.Vos JG, Dybing E, Greim HA et al. Health effects of endocrine-disrupting chemicals on wildlife, with special reference to the European situation[J]. Crit Rev Toxicol,2000,30(1):71-133.
13.Krstevska-Konstantinova M, Charlier C, Craen M et al. Sexual precocity after immigration from developing countries to Belgium: evidence of previous exposure to organochlorine pesticides[J]. Hum Reprod,2001,16(5): 1020-6.
14.Tiwary CM.Premature sexual development in children following the use of estrogen- or placenta-containing hair products[J].Clin Pediatr (Phila),1998,37(12):733-9.
15.Colon I, Caro 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(9):895-900.
16. Gladen BC, Ragan NB, Rogan WJ. Pubertal growth and development and prenatal and lactational exposure to polychlorinated biphenyls and dichlorodiphenyl dichloroethene. J Pediatr 2000;136(4):490-6.
17. Virdis R, Street ME, Zampolli M et al. Precocious puberty in girls adopted from developing countries. Arch Dis Childhood.l998;78(2);152-43.
1．宁寿葆，主编．现代实用儿科学．上海．复旦大学出版社．2004：823．
2. Cohen Hubal EA, Sheldon LS, Burke JM,et al. Children's exposure assessment: a review of factors influencing Children's exposure, and the data available to characterize and assess that exposure. Environ Health Perspect. 2000,108: 475-86.
3．曾畿生，王德芬．现代儿科内分泌学-基础与临床．上海．上海科学技术文献出版社．2001：125-34．
4．蔡德培，季志英，时毓民．滋阴泻火中药及甲地孕酮治疗女性特发性性早熟的临床研究．中国中西医结合杂志．2001，21：732-35．
5．李嫔，蔡德培，黄玉娟．性早熟女童骨骼发育异常的规律及滋阴泄火中药治疗的作用．中国中西医结合杂志．2004,24：979-82．
6. Damgaard NI, Main KM, Toppari J et al. Impact of exposure to endocrine disrupters in utero and in childhood on adult reproductio. Best Practice & Research Clinical Endocrinology and Metabolism.2002,16:289-309.
7. Landrigan P, Garg A, Droller DB. Assessing the effects of endocrine disruptors in the National Children's Study. Environ Health Perspect. 2003,111: 1678-82.
8. Tsutsui T, Barrett JC. Neoplastic transformation of cultured mammalian cells by estrogens and estrogen-like chemicals. Environ Health Perspect. 1997,105:621-23.
9. Rice C, Birnbaum LS, Cogliano J et al. Exposure assessment for endocrine disruptors: some considerations in the design of studies. Environ Health Perspect, 2003,111: 1683-90.
10. Final Report on the reproductive toxicity of nonylphenol. National Toxicology Program(1997),8989-30.
11. Lascombe, I, Beffa D, Rüegg U, et al. Estrogenic Activity Assessment of Environmental Chemicals Using in Vitro Assays: Identification of Two New Estrogenic Compounds. Environ Health Perspect,2000,108:621-29.
12. Krstevska-Konstantinova M,Charlier C, Craen M et al. Sexual precocity after immigration from developing countries to Belgium: evidence of previous exposure to organochlorine pesticides. Human Reproduction 2001,16:1020-1026.
13. Balaguer P, Francois F, Comunale F et al.Reporter cell lines to study the estrogenic effects of xenoestrogens[J]. Sci Total Environ. 1999,233:47-56
14. Colon I, Caro 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.
15. Hashimoto Y, Kawaguchi M, Miyazaki K, Nakamura M. Estrogenic activity of tissue conditioners in vitro. Dent Mater. 2003,19:34 1-6.
16. Paganetto G, Campi F, Varani K, Piffanelli A, Giovannini G, Borea PA. Endocrine-disrupting agents on healthy human tissues. Pharmacol Toxicol. 2000,86:24-9.
17. Teilmann G, Juul A,Skakkebak NE, et al. Putative effects of endocrine disruptors on pubertal development in the human. Best Practice & Research Clinical Endocrinology and Metabolism. 2002,16:105-21.
1. Partsch CJ, Sippell WG. Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens[J]. Hum Reprod Update. 2001,7(3):292-302.
2. Norgil Damgaard I, Main KM, Toppari J, et al. Impact of exposure to endocrine disrupters in utero and in childhood on adult reproduction[J]. Best Pract Res Clin Endocrinol Metab. 2002,16(2):289-309.
3. Sonnenscein C, Soto AM. An update review of environmental estrogen and androgen mimics and antagonists[J].J Steroid Biocheim Mol Biol, 1998,65(1): 143-150.
4. Gundersen JL. Separation of isomers of nonylphenol and select nonylphenol polyethoxylates by high-performance liquid chromatography on a graphitic carbon column. J Chromatogr A. 2001,914(1-2):161-166.
5．王正萍，周雯．环境有机污染物监洲分析．北京：化学工业出版社，2002，20．
6. Landrigan P, Garg A, Droller DB. Assessing the Effects of Endocrine Disruptors in the National Children's Study[J]. Environ Health Perspect. 2003,111 (13): 1678-1682.
7. Cohen Hubal EA, Sheldon LS, Burke JM,et al. Children's exposure assessment: a review of factors influencing Children's exposure, and the data available to characterize and assess that exposure. Environ Health Perspect. 2000,108(6):475-486.
2. Singleton DW, Khan SA. Xenoestrogen exposure and mechanisms of endocrine disruption s[J]. Front Biosci,2003,8:s110-118.
3. Colborn T, vom Saal FS, Soto AM. Developmental effects of endocrine-disrupting chemicals in wildlife and humans s[J]. Environ Health Perspect, 1993,101 (5):378-384.
4. Arnold SF, Collins BM, Robinson MK, et al. Differential interaction of natural and synthetic estrogens with extracellular binding proteins in a yeast estrogen screen[J]. Steroids, 1996,61 (11):642-646.
5. Gray LE Jr, Ostby J, Cooper RL, et al. The estrogenic and antiandrogenic pesticide methoxychlor alters the reproductive tract and behavior without affecting pituitary size or LH and prolactin secretion in male rats[J]. Toxicol Ind Health, 1999,15(1-2):37-47.
6. Jansen HT, Cooke PS, Porcelli J, et al. Estrogenic and antiestrogenic actions of PCBs in the female rat: in vitro and in vivo studies[J]. Reprod Toxicol, 1993,7(3):237-248.
7. Cohen Hubal EA, Sheldon LS, Burke JM, et al. Children's exposure assessment: a review of factors influencing children's exposure, and the data available to characterize and assess that exposure[J]. Environ Health Perspect, 2000, 108(6):475-486
8. Mukerjee D. Assessment of risk from multimedia exposures of children to environmental chemicals[J]. J Air Waste Manag Assoc, 1998,48(6):483-501.
9．宁寿葆．现代实用儿科学[M]．上海：复旦大学出版社，2004： 823.
10. Ehrhardt AA, Meyer-Bahlburg HF. Psychosocial aspects of precocious puberty[J]. Horm Res, 1994,41(Supp12):30-35
11. Lee PA. Central precocious puberty. An overview of diagnosis, treatment, and outcome[J]. Endocrinol Metab Clin North Am, 1999,28(4):901-918
12. Tato L, Savage MO, Antoniazzi F, et al. International Workshop on Management of Puberty for Optimum Auxological.Optimal therapy of pubertal disorders in precocious/early puberty[J]. J Pediatr Endocrinol Metab, 2001,14(Suppl 2):985-995.
13. Christine LM, Pierre BJ. Central and peripheral isosexual precocious puberty[J]. Current Opinion in Endocrinology & Diabetes, 200,18(1): 17-22.
14. Recchia AG, Vivacqua A, Gabriele S,et al. Xenoestrogens and the induction of proliferative effects in breast cancer cells via direct activation of oestrogen receptor alpha Central and peripheral isosexual precocious puberty[J]. Food Addit Contam, 2004,21(2):134-144.
15. Kim HS, Shin JH, Moon HJ,et al. Comparative estrogenic effects of p-nonylphenol by 3-day uterotrophic assay and female pubertal onset assay[J]. Reprod Toxicol, 2002,16(3):259-268.
16. Smith CL, Conneely OM, O'Malley BW. Modulation of the ligand-independent activation of the human estrogen receptor by hormone and antihormone[J]. Proc Natl Acad Sci U S A, 1993,90(13):6120-6124.
17. Levin ER. Bidirectional signaling between the estrogen receptor and the epidermal growth factor receptor[J]. Mol Endocrinol, 2003,17(3):309-317.
18. Dupont J, Karas M, LeRoith D. The potentiation of estrogen on insulin-like growth factor Ⅰ action in MCF-7 human breast cancer cells includes cell cycle components[J]. J Biol Chem, 2000,275(46):35893-35901.
19．蔡德培，季志英，时毓民．滋阴泻火中药及甲地孕酮治疗女性特发性性早熟的临床研究[J]．中国中两医结合杂志，2001，21(10)：732-735．
20. Shelby MD, Newbold RR, Tully DB, et al. Assessing environmental chemicals for estrogenicity using a combination of in vitro and in vivo assays[J]. Environ Health Perspect, 1996,104(12):1296-1300.
21. Recchia AG, Vivacqua A, Gabriele S, et al. Xenoestrogens and the induction of proliferative effects in breast cancer cells via direct activation of oestrogen receptor alpha[J]. Food Addit Contam, 2004,21 (2): 134-144.
22. Kim HS, Shin JH, Moon H J, et al. Comparative estrogenic effects of p-nonyiphenol by 3-day uterotrophic assay and female pubertal onset assay[J]. Reprod Toxicol, 2002,16(3):259-268.
23. Green T, Swain C, Van Miller JP, et al. Absorption, bioavailability, and metabolism of para-nonylphenol in the rat[J]. Regul Toxicol Pharmacol, 2003,38(1):43-51.
24. Vivacqua A, Recchia AG, Fasanella G, et al. The food contaminants bisphenol A and 4-nonylphenol act as agonists for estrogen receptor alpha in MCF7 breast cancer cells[J]. Endocrine, 2003,22(3):275-284.
25. Danzo BJ, Shappell HW, Banerjee A,et al .Effects of nonylphenol, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE), and pentachlorophenol on the adult female guinea pig reproductive tract[J]. Reprod Toxicol, 2002,16(1 ):29-43.
26. Matthews J, Celius T, Halgren R, et al. Differential estrogen receptor binding of estrogenic substances: a species comparison[J]. J Steroid Biochem Mol Bioi, 2000,74(4):223-234.
27. Andersen HR, Andersson AM, Arnold SF, et al. Comparison of short-term estrogenicity tests for identification of hormone-disrupting chemicals[J]. Environ Health Perspect, 1999,107 (Suppl 1 ):89-108.
28. Yuan SY, Liu C, Liao CS, et al. Occurrence and microbial degradation of phthalate esters in Taiwan river sediments[J]. Chemosphere, 2002,49(10):1295-1299.
29. Marttinen SK, Kettunen RH, Rintala JA. Occurrence and removal of organic pollutants in sewages and landfill leachates[J]. Sci Total Environ, 2003,301 (1-3):1-12.
30. TOXICOLOGICAL PROFILE FOR DI(2-ETHYLHEXYL)PHTHALATE[M]. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, Public Health Service Agency for Toxic Substances and Disease Registry. 2002.
31. Asai D, Tahara Y, Nakai M, et al. Structural essentials of xenoestrogen dialkyl phthalates to bind to the estrogen receptors[J]. Toxicol Lett, 2000,20;118(1-2):1-8.
32. Zacharewski TR, Meek MD, Clemons JH, et al. Examination of the in vitro and in vivo estrogenic activities of eight commercial phthalate esters[J]. Toxicol Sci, 1998,46(2):282-293.
33. Jobling S, Reynolds T, White R, et al. A variety of environmentally persistent chemicals, including some phthalate plasticizers, are weakly estrogenic[J]. Environ Health Perspect, 1995,103(6):582-587.
34. Blom A, Ekman E, Johannisson A, et al. Effects of xenoestrogenic environmental pollutants on the proliferation of a human breast cancer cell line (MCF-7) [J]. Arch Environ Contam Toxicol, 1998,34(3):306-310.
35．解玮，蒋颂辉，屈卫东，等．DEHP、DBP内分泌干扰活性的实验研究．中国环境科学，2004，24(1)：45-48．
36．曾畿生，王德芬．现代儿科内分泌学-基础与临床[M]．上海：上海科学技术文献出版社，2001：125-34．
37. Damgaard NI, Main KM, Toppari J, et al. Impact of exposure to endocrine disrupters in utero and in childhood on adult reproduction[J]. Best Pract Res Clin Endocrinol Metab, 2002,16(2):289-309.
38. Landrigan P, Garg A, Droller DB. Assessing the effects of endocrine disruptors in the National Children's Study[J]. Environ Health Perspect, 2003,111 (13): 1678-1682.
39. Tsutsui T, Barrett JC. Neoplastic transformation of cultured mammalian cells by estrogens and estrogen-like chemicals[J].Environ Health Perspect.1997,105(supple 3):621-623.
40. Final Report on the reproductive toxicity of nonylphenol[R]. National Toxicology Program( 1997),8989-9030.
41. Lascombe, I, Beffa D, Rüegg U, et al. Estrogenic activity assessment of environmental chemicals using in vitro assays: identification of two new estrogenic compounds[J]. Environ Health Perspect, 2000,108(7):621-629.
42. Krstevska-Konstantinova M, Charlier C, Craen M, et al. Sexual precocity after immigration from developing countries to Belgium: evidence of previous exposure to organochlorine pesticides[J].Hum Reprod, 2001,16(5): 1020-1026.
43. Balaguer P, Francois F, Comunale F, et al. Reporter cell lines to study the estrogenic effects of xenoestrogens[J]. Sci Total Environ, 1999,233(1-3):47-56.
44. Colon I, Caro 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(9): 895-900.
45. Hashimoto Y, Kawaguchi M, Miyazaki K, et al. Estrogenic activity of tissue conditioners in vitro. Dent Mater. 2003,19:341-6.
46. Paganetto G, Campi F, Varani K, et al. Endocrine-disrupting agents on healthy human tissues[J]. Pharmacol Toxicol. 2000, 86(1): 24-29.
47. Teilmann G, Juul A, Skakkebak NE, et al. Putative effects of endocrine disruptors on pubertal development in the human[J]. Best Prac Res Clin Endocrinol Metab,1997, 16:105-121.
48．李嫔，蔡德培，黄玉娟．性早熟女童骨骼发育异常的规律及滋阴泄火中药治疗的作用．中国中西医结合杂志．2004，24：979-82．
49. Kang KS, Kim HS, Ryu DY, et al. Immature uterotrophic assay is more sensitive than ovariectomized uterotrophic assay for the detection of estrogenicity of p-nonylphenol in Sprague-Dawley rats[J]. Toxicol Lett, 2000,118(1-2): 109-115.
50. Kwack SJ, Kwon O, Kim HS, et al. Comparative evaluation of alkylphenolic compounds on estrogenic activity in vitro and in vivo[J]. J Toxicol Environ Health A, 2002,65(5-6):419-431.
51. Frigo DE, Burow ME, Mitchell KA, et al. DDT and its metabolites alter gene expression in human uterine cell lines through estrogen receptor-independent mechanisms[J]. Environ Health Perspect, 2002,110(12): 1239-1245.
52. Cooper GS, Martin SA, Longnecker MP. et al. Associations between plasma DDE levels and immunologic measures in African-American farmers in North Carolina[J]. Environ Health Perspect,2004,112(10): 1080-1084.
53. Martin SA Jr, Harlow SD, Sowers MF, et al. DDT metabolite and androgens in African-American farmers[J]. Epidemiology, 2002,13(4):454-458.
54. Lee PC, Lee W. In vivo estrogenic action of nonylphenol in immature female rats[J]. Bull Environ Contam Toxicol, 1996,57(3):341-348.
55. Biedermann M, Grob K. Food contamination from epoxy resins and organosols used as can coatings: analysis by gradient NPLC[J]. Food Addit Contam, 1998,15(5):609-618.
56. Howe SR, Borodinsky L. Potential exposure to bisphenol A from food-contact use of polycarbonate resins[J]. Food Addit Contam. 1998,15(3):370-375.
57. Laws SC, Carey SA, Ferrell JM, et al. Estrogenic activity of octylphenol, nonylphenol, bisphenol A and methoxychlor in rats[J]. Toxicol Sci, 2000,54(1): 154-167.
58. Fang H, Tong W, Perkins R, et al. Quantitative comparisons of in vitro assays for estrogenic activities[J]. Environ Health Perspect, 2000,108(8):723-729.
59. Lascombe I, Beffa D, Ruegg U, et al. Estrogenic activity assessment of environmental chemicals using in vitro assays: identification of two new estrogenic compounds[J]. Environ Health Perspect, 2000,108(7):621-629.
60. Lemmen JG, Arends RJ, van der Saag PT, et al. In vivo imaging of activated estrogen receptors in utero by estrogens and bisphenol A[J]. Environ Health Perspect, 2004,112(15): 1544-1549.
61. Kim HS, Han SY, Yoo SD, et al. Potential estrogenic effects of bisphenol-A estimated by in vitro and in vivo combination assays[J]. J Toxicol Sci, 2001,26(3): 111-118.
62. Asai D, Tahara Y, Nakai M, et al. Structural essentials of xenoestrogen dialkyl phthalates to bind to the estrogen receptors[J]. Toxicol Lett, 2000,118(1-2):1-8.
63. Okubo T, Suzuki T, Yokoyama Y, et al. Estimation of estrogenic and anti-estrogenic activities of some phthalate diesters and monoesters by MCF-7 cell proliferation assay in vitro[J]. Biol Pharm Bull, 2003,26(8):1219-1224.
64. Diel P. Tissue-specific estrogenic response and molecular mechanisms[J]. Toxicol Lett, 2002,127(1-3):217-224.
65. 4-NONYLPHENOL(Branched) AND NONYLPHENOL. CAS No: 84852-15-3 and 25154-52-3.Summary Risk Assessment Report[R]. European Communities, 2002.
66. 4,4'-ISOPROPYLIDENEDIPHENOL(BISPHENOL-A). CAS No: 80-05-7. Summary Risk Assessment Report[R]. European Communities, 2003.
67. 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].Environ Health Perspect, 2001,109(8):785-794.
68. Zacharewski T. Identification and assessment of endocrine disruptors: limitations of in vivo and in vitro assays[J]. Environ Health Perspect, 1998,106(Suppl 2):577-582.
69. Bachmann S, Hellwig J, Jackh R, et al. Uterotrophic assay of two concentrations of migrates from each of 23 polystyrenes administered orally (by gavage) to immature female Wistar rats[J]. Drug Chem Toxicol, 1998,21(Suppl 1):1-30.
70. Jefferson WN, Padilla-Banks E, Clark G, et al.Assessing estrogenic activity of phytochemicals using transcriptional activation and immature mouse uterotrophic responses[J]. J Chromatogr B Analyt Technol Biomed Life Sci,2002,777(1-2): 179-189.
71. Kim KB, Seo KW, Kim YJ, et al. Estrogenic effects of phenolic compounds on glucose-6-phosphate dehydrogenase in MCF-7 cells and uterine glutathione peroxidase in rats[J]. Chemosphere, 2003,50(9):1167-1173.
72. Balajee AS, May A, Dianova I, et al. Efficient PCNA complex formation is dependent upon both transcription coupled repair and genome overall repair[J]. Mutat Res, 1998,409(3):135-146.
73. Shimazaki N, Yazaki T, Kubota T, et al. DNA polymerase lambda directly binds to proliferating cell nuclear antigen through its confined C-terminal region[J]. Genes Cells, 2005,10(7):705-715.
74. Tinwell H, Ashby J. Sensitivity of the immature rat uterotrophic assay to mixtures of estrogens[J]. Environ Health Perspect, 2004,112(5):575-582.
75. Simons SS Jr. Environmental estrogens: can two "alrights" make a wrong? [J].Science, 1996,272(5267):1451.
76. Diel P, Schulz T, Smolnikar K, et al. Ability of xeno- and phytoestrogens to modulate expression of estrogen-sensitive genes in rat uterus: estrogenicity profiles and uterotropic activity[J]. J Steroid Biochem Mol Biol, 2000,73(1-2):1-10.
77. Casanova M, You L, Gaido KW, et al. Developmental effects of dietary phytoestrogens in Sprague-Dawley rats and interactions of genistein and daidzein with rat estrogen receptors alpha and beta in vitro[J]. Toxicol Sci, 1999,51(2):236-244.
78. Ignar-Trowbridge DM, Pimentel M, Teng CT, et al. Cross talk between peptide growth factor and estrogen receptor signaling systems[J]. Environ Health Perspectn 1995,103(Suppl 7):35-38.
79. Townson SM, Kang K, Lee AV, et al. Structure-function analysis of the estrogen receptor alpha corepressor scaffold attachment factor-B1: identification of a potent transcriptional repression domain[J]. J Biol Chem, 2004,279(25):26074-26081.
80. Silva E, Rajapakse N, Kortenkamp A. Something from "nothing"--eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects[J]. Environ Sci Technol, 2002,36(8):1751-1756.
81．蔡德培，陈伯英，庄振杰．滋阴泻火中药对下丘脑 GnRH 的合成、分泌及其调节机制的影响[J]．中国中西医结合杂志，2001，21(8)：595-598．
82．蔡德培．性早熟治疗及药物作用机制的研究进展[J]．实用儿科临床杂志，2005，20(6)：502-505．
83. Knight PG, Glister C. Potential local regulatory functions of inhibins, activins and follistatin in the ovary[J]. Reproduction, 2001,121 (4):503-512.
84. Barrios-De-Tomasi J, Timossi C, Merchant H, et al. Assessment of the in vitro and in vivo biological activities of the human follicle-stimulating isohormones[J]. Mol Cell Endocrinol, 2002,186(2): 189-198.
85. Kang J S, Lee BJ, Ahn B, et al. Expression of estrogen receptor alpha and beta in the uterus and vagina of immature rats treated with 17 - ethinyl estradiol [J]. J Vet Med Sci, 2003,65 (12): 1293-1297.
86. Braidman I, Baris C, Wood L, et al. Preliminary evidence for impaired estrogen receptor-alpha protein expression in osteoblasts and osteocytes from men with idiopathic osteoporosis[J]. Bone, 2000,26(5):423-427.
87. Ambroszkiewicz J, Gajewska J, Laskowska-Klita T. Serum osteocalcin and bone alkaline phosphatase in healthy children in relation to age and gender[J]. Med Wieku Rozwoj, 2002,6(3):257-65.
88. Mora S, Pitukcheewanont P, Kaufman FR, et al. Biochemical markers of bone turnover and the volume and the density of bone in children at different stages of sexual development[J]. J Bone Miner Res,1999,14(10):1664-1671.
89．张镜如．生理学[M]．第4版．北京：人民卫生出版社，1999．414-417
90. Windahl SH, Norgard M, Kuiper GG, et al. Cellular distribution of estrogen receptor beta in neonatal rat bone[J]. Bone,2000,26(2): 117-121.
91．蔡德培，张炜．补肾中药对下丘脑 GnRH、垂体 FsH、LH及成骨细胞基因表达的调节作用[J]．中医杂志，2002；43(3)：221-223．
92. Lee HS, Sasagawa S, Kato S, et al. Yeast two-hybrid detection systems that are highly sensitive to a certain kind of endocrine disruptors[J]. Biosci Biotechnol Biochem, 2006,70(2):521-524.
93. Hom YK, Young P, Wiesen JF, et al. Uterine and vaginal organ growth requires epidermal growth factor receptor signaling from stroma[J]. Endocrinology, 1998,139(3):913-921.
94. Hawkins MB, Thornton JW, Crews D, et al. Identification of a third distinct estrogen receptor and reclassification of estrogen receptors in teleosts[J]. Proc Natl Acad Sci U S A,2000,97(20): 10751-10756.
95. Okada A, Sato T, Ohta Y, et al. Sex steroid hormone receptors in the developing female reproductive tract of laboratory rodents[J]. J Toxicol Sci, 2005,30(2):75-89.
96. Kousteni S, Bellido T, Plotkin LI, et al. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity[J].Cell, 2001,104(5):719-730.
97. Riese DJ 2nd, Stern DF. Specificity within the EGF family/ErbB receptor family signaling network[J]. Bioessays, 1998 ,20(l):41-48.
98. Ignar-Trowbridge DM, Nelson KG, Bidwell MC, et al. Coupling of dual signaling pathways: epidermal growth factor action involves the estrogen receptor[J]. Proc NatI Acad Sci U S A,1992,89(10):4658-4662.
99. Lai A, Sarcevic B, Prall OW, Sutherland RL. Insulin/insulin-like growth factor-1 and estrogen cooperate to stimulate cyclin E-Cdk2 activation and cell Cycle progression in MCF-7 breast cancer cells through differential regulation of cyclin E and p21(WAFl/Cipl) [J]. J Biol Chem, 2001,276(28):25823-25833.
100. Paech K, Webb P, Kuiper GG, et al. Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites[J]. Science, 1997,277(5331): 1508-1510.
101. Viau V, Meaney MJ. Alphal adrenoreceptors mediate the stimulatory effects of oestrogen on stress-related hypothalamic-pituitary-adrenal activity in the female rat[J]. J Neuroendocrinol, 2004,16(1):72-78.
102. Razandi M, Pedram A, Greene GL, et al. Cell membrane and nuclear estrogen receptors(ERs) originate from a single transcript: studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells[J]. Mol Endocrinol,1999,13(2):307-319.
103. Song RX, McPherson RA, Adam L, et al. Linkage of rapid estrogen action to MAPK activation by ERalpha-Shc association and She pathway activation[J]. Mol Endocrinol, 2002,16(1):116-127.
104. Levin ER. Cell localization, physiology, and nongenomic actions of estrogen receptors[J]. J Appl Physiol,2001,91 (4): 1860-1867.
105. Bunone G, Briand PA, Miksicek RJ, et al. Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation[J]. EMBO J, 1996,15(9):2174-2183.
106. Lopez GN, Turck CW, Schaufele F, et al. Growth factors signal to steroid receptors through mitogen-activated protein kinase regulation of p160 coactivator activity[J]. J Biol Chem, 2001,276(25):22177-22182.
107. Ignar-Trowbridge DM, Pimentel M, Parker MG, et al. Peptide growth factor cross-talk with the estrogen receptor requires the A/B domain and occurs independently of protein kinase C or estradiol[J]. Endocrinology, 1996,137(5): 1735-1744.
108. Ignar-Trowbridge DM, Teng CT, Ross KA, et al. Peptide growth factors elicit estrogen receptor-dependent transcriptional activation of an estrogen-responsive element[J]. Mol Endocrinol, 1993,7(8):992-998.
109. Martin MB, Franke TF, Stoica GE, et al. A role for Akt in mediating the estrogenic functions of epidermal growth factor and insulin-like growth factor Ⅰ[J]. Endocrinology, 2000,141 (12):4503-4511.
110. Klotz DM, Hewitt SC, Ciana P, et al. Requirement of estrogen receptor-alpha in insulin-like growth factor-1 (IGF-1)-induced uterine responses and in vivo evidence for IGF-1/estrogen receptor cross-talk[J]. J Biol Chem, 2002,277(10):8531-8537.
111. Oesterreich S, Zhang P, Guler RL, et al. Re-expression of estrogen receptor alpha in estrogen receptor alpha-negative MCF-7 cells restores both estrogen and insulin-like growth factor-mediated signaling and growth[J]. Cancer Res, 2001,61 (15):5771-5777.
112. Adesanya OO, Zhou J, Samathanam C, et al. Insulin-like growth factor 1 is required for G2 progression in the estradiol-induced mitotic cycle[J]. Proc Natl Acad Sci U S A, 1999,96(6):3287-3291.
113. Klotz DM, Hewitt SC, Korach KS, et al. Activation of a uterine insulin-like growth factor I signaling pathway by clinical and environmental estrogens: requirement of estrogen receptor-alpha[J]. Endocrinology,2000,141 (9):3430-3439.
114. Le Roith D: The insulin-like growth factor system[J]. Exp Diabesity Res, 2003,4(4):205-212.
115. D'Ercole AJ. Insulin-like growth factors and their receptors in growth[J]. Endocrinol Metab Clin North Am, 1996,25(3):573-590.
116．陆炜，蔡德培．补肾中药对雌性青春期大鼠垂体GnRH受体mRNA及其受体蛋白表达的影响[J]．中国中西医结合杂志，2003，23(2)：120-122
117．李嫔，向正华，蔡德培．中药对大鼠下丘脑生长抑素及垂体生长激素基因表达与蛋白表达的调节作用[J]．中国中西医结合杂志，2003，23(3)：207-210．
118．蔡德培．滋阴泻火中药改善性早熟儿童骨骼发育的作用及机理探讨[J]．中医杂志，1997，38(10)：615．
1. Sonnenscein Carlos, Soto AM. An update review of environmental estrogen and androgen mimics and antagonists[J]. J Steroid Biocheim Mol Biok 1998,65(1): 143-150.
2. Norgil Damgaard I, Main KM, Toppari J, et al. Impact of exposure to endocrine disrupters in utero and in childhood on adult reproduction[J]. Best Pract Res Clin Endocrinol Metab. 2002,16(2):289-309.
3. Simons SS Jr. Environmental estrogens: can two "alrights" make a wrong? [J].Science,1996,272(5267):1451.
4. Levin ER. Cellular functions of plasma membrane estrogen receptors[J].Steroids, 2002,67(6):471-5.
5. Diel P.Tissue-specific estrogenic response and molecular mechanisms[J]. Toxicol Lett,2002,127(1-3):217-24.
6. Fortunati N. Sex hormone-binding globulin: not only a transport protein. What news is around the corner?[J].J Endocrinol Invest,1999,22(3):223-34.
7. Kirk CJ, Harris RM, Wood DM et al. Do dietary phytoestrogens influence susceptibility to hormone-dependent cancer by disrupting the metabolism of endogenous oestrogens? [J].Biochem Soc Trans,2001,29(Pt 2):209-16.
8. 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):231-5.
9. Rice C, Birnbaum LS, Cogliano J et al. Exposure assessment for endocrine disruptors: some considerations in the design of studies[J]. Environ Health Perspect, 2003,111(13):1683-90.
10.Cohen Hubal EA, Sheldon LS, Burke JM,et al. Children's exposure assessment: a review of factors influencing Children's exposure, and the data available to characterize and assess that exposure. Environ Health Perspect. 2000,108(6):475-86.
11 .Gurunathan S, Robson M, Freeman N, et al. Accumulation of chlorpyrifos on residential surfaces and toys accessible to children. Environ Health Perspect. 1998,106(1):9-16.
12.Vos JG, Dybing E, Greim HA et al. Health effects of endocrine-disrupting chemicals on wildlife, with special reference to the European situation[J]. Crit Rev Toxicol,2000,30(1):71-133.
13.Krstevska-Konstantinova M, Charlier C, Craen M et al. Sexual precocity after immigration from developing countries to Belgium: evidence of previous exposure to organochlorine pesticides[J]. Hum Reprod,2001,16(5): 1020-6.
14.Tiwary CM.Premature sexual development in children following the use of estrogen- or placenta-containing hair products[J].Clin Pediatr (Phila),1998,37(12):733-9.
15.Colon I, Caro 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(9):895-900.
16. Gladen BC, Ragan NB, Rogan WJ. Pubertal growth and development and prenatal and lactational exposure to polychlorinated biphenyls and dichlorodiphenyl dichloroethene. J Pediatr 2000;136(4):490-6.
17. Virdis R, Street ME, Zampolli M et al. Precocious puberty in girls adopted from developing countries. Arch Dis Childhood.l998;78(2);152-43.
1．宁寿葆，主编．现代实用儿科学．上海．复旦大学出版社．2004：823．
2. Cohen Hubal EA, Sheldon LS, Burke JM,et al. Children's exposure assessment: a review of factors influencing Children's exposure, and the data available to characterize and assess that exposure. Environ Health Perspect. 2000,108: 475-86.
3．曾畿生，王德芬．现代儿科内分泌学-基础与临床．上海．上海科学技术文献出版社．2001：125-34．
4．蔡德培，季志英，时毓民．滋阴泻火中药及甲地孕酮治疗女性特发性性早熟的临床研究．中国中西医结合杂志．2001，21：732-35．
5．李嫔，蔡德培，黄玉娟．性早熟女童骨骼发育异常的规律及滋阴泄火中药治疗的作用．中国中西医结合杂志．2004,24：979-82．
6. Damgaard NI, Main KM, Toppari J et al. Impact of exposure to endocrine disrupters in utero and in childhood on adult reproductio. Best Practice & Research Clinical Endocrinology and Metabolism.2002,16:289-309.
7. Landrigan P, Garg A, Droller DB. Assessing the effects of endocrine disruptors in the National Children's Study. Environ Health Perspect. 2003,111: 1678-82.
8. Tsutsui T, Barrett JC. Neoplastic transformation of cultured mammalian cells by estrogens and estrogen-like chemicals. Environ Health Perspect. 1997,105:621-23.
9. Rice C, Birnbaum LS, Cogliano J et al. Exposure assessment for endocrine disruptors: some considerations in the design of studies. Environ Health Perspect, 2003,111: 1683-90.
10. Final Report on the reproductive toxicity of nonylphenol. National Toxicology Program(1997),8989-30.
11. Lascombe, I, Beffa D, Rüegg U, et al. Estrogenic Activity Assessment of Environmental Chemicals Using in Vitro Assays: Identification of Two New Estrogenic Compounds. Environ Health Perspect,2000,108:621-29.
12. Krstevska-Konstantinova M,Charlier C, Craen M et al. Sexual precocity after immigration from developing countries to Belgium: evidence of previous exposure to organochlorine pesticides. Human Reproduction 2001,16:1020-1026.
13. Balaguer P, Francois F, Comunale F et al.Reporter cell lines to study the estrogenic effects of xenoestrogens[J]. Sci Total Environ. 1999,233:47-56
14. Colon I, Caro 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.
15. Hashimoto Y, Kawaguchi M, Miyazaki K, Nakamura M. Estrogenic activity of tissue conditioners in vitro. Dent Mater. 2003,19:34 1-6.
16. Paganetto G, Campi F, Varani K, Piffanelli A, Giovannini G, Borea PA. Endocrine-disrupting agents on healthy human tissues. Pharmacol Toxicol. 2000,86:24-9.
17. Teilmann G, Juul A,Skakkebak NE, et al. Putative effects of endocrine disruptors on pubertal development in the human. Best Practice & Research Clinical Endocrinology and Metabolism. 2002,16:105-21.
1. Partsch CJ, Sippell WG. Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens[J]. Hum Reprod Update. 2001,7(3):292-302.
2. Norgil Damgaard I, Main KM, Toppari J, et al. Impact of exposure to endocrine disrupters in utero and in childhood on adult reproduction[J]. Best Pract Res Clin Endocrinol Metab. 2002,16(2):289-309.
3. Sonnenscein C, Soto AM. An update review of environmental estrogen and androgen mimics and antagonists[J].J Steroid Biocheim Mol Biol, 1998,65(1): 143-150.
4. Gundersen JL. Separation of isomers of nonylphenol and select nonylphenol polyethoxylates by high-performance liquid chromatography on a graphitic carbon column. J Chromatogr A. 2001,914(1-2):161-166.
5．王正萍，周雯．环境有机污染物监洲分析．北京：化学工业出版社，2002，20．
6. Landrigan P, Garg A, Droller DB. Assessing the Effects of Endocrine Disruptors in the National Children's Study[J]. Environ Health Perspect. 2003,111 (13): 1678-1682.
7. Cohen Hubal EA, Sheldon LS, Burke JM,et al. Children's exposure assessment: a review of factors influencing Children's exposure, and the data available to characterize and assess that exposure. Environ Health Perspect. 2000,108(6):475-486.