丙烯腈雄（男）性生殖毒性研究
摘要
丙烯腈(Acrylonitrile, ACN)是一种重要的化工生产原料，单体用作合成各种有机产品。到目前为止，有关于丙烯腈潜在的生殖危害，尤其是男性生殖危害，可提供的资料很少。而丙烯腈是对接触工人健康造成潜在危害的一种重要毒物，在我国，从事化工作业(包括丙烯腈)的工人多为男性，有必要对丙烯腈男(雄)性生殖系统毒性作用和可能机制作出较系统研究。
本课题结合人群流行病学调查、整体动物研究和体外实验，对丙烯腈接触男工配偶生殖结局以及男工生殖内分泌的情况进行了研究，对染毒动物生殖力、性腺形态改变、生化改变和基因表达、生殖细胞和性激素改变做出评价，并利用Sertoli细胞和蝾螈精原细胞探讨可能的毒性机制。
第一部分 职业流行病学研究
1)丙烯腈工人接触评价
结果显示该厂丙烯腈生产车间污染较严重，测定浓度最高达42.0mg／m~3，TWA最高达19.12mg／m~3，合格率仅仅为26.9％(现行作业场所有害物质卫生标准TWA1 mg／m~3)。其中不同车间浓度顺序依次为北纺车间≥南纺车间＞聚合车间＞＞溶剂车间。个人平均累计接触剂量为69.09g。
2)丙烯腈接触男工问卷调查
504份生殖问卷调查结果表明接触组工人妻子妊娠合并症发生率升高。空气中浓度最低的溶剂车间工人妻子不孕症和自然流产发生率显著的低于其他车间(P＜0.05)，夫妻双方都接触丙烯腈自然流产率明显高于仅男工一方接触组，接触丙烯腈男工性功能障碍显著高于对照组。
3)丙烯腈接触工人性激素水平研究
随年龄增加FSH略升高，40岁以上年龄段接触工人睾酮下降(P＜0.05)，随工龄增加工人血清FSH也略增高，而接触组睾酮随工龄增加逐渐下降，伴雌激素升高。空气中丙烯腈浓度相对较低的溶剂车间，男工血清睾酮水平高于浓度高的其他车间。接触工人血清FSH和T的水平随着接触剂量的增加呈下降趋势，累积接触剂量大于50g，睾酮下降有显著性，累及接触剂量大于100g，FSH和T下降均有显著性。
复旦大学博士研究生毕业论文丙烯睛雄(男)性生殖毒性研究摘要
第二部分动物实验
雄性Wistar大鼠分别以。，10，20，40mg瓜g灌胃染毒，连续13周，测定附
争精子参数，相关酶活力和分析交配实验结局;雄性SD大鼠分别以O，7.5，15，
30mg瓜g腹腔染毒，连续13周，恢复2周，观察辜丸病理损伤、抗氧化酶活力、
脂质过氧化水平、雄激素结合蛋白和抑制素基因表达;雄性ICR小鼠以O，6，
12，24m叭g灌胃染毒，连续5天，分析附肇尾精子畸形率和早期精细胞微核;
分析大、小鼠血清性激素，并通过大鼠子宫增重实验判断丙烯睛是否具有雌激素
活性。
结果表明:丙烯睛染毒各剂量组之间雌鼠受孕率，雄鼠生育率，交配指数无
差异，剂量为4omg/kg时，孕鼠平均每窝活胎数为5.88个，明显低于对照组(P
<0 .05)，胎吸收率为19.66%，明显高于对照组(P<0 .05)。各种酶活性与对照组
比较，无显著性差异。
大鼠辛丸受损程度随染毒剂量的增大而加重，光镜下可见部分曲细精管出现
退行性病变，管腔中生精细胞和精子数量减少，电镜下可看到正在凋亡变的，核
畸形的以及坏死初级精母细胞和崎形的精子.
染毒4周，大鼠辛丸中GSH含量和GPX活力明显升高(P<0 .01);8周后，
3omg/kg组oSH明显降低(P<0.01)，剂量大于15mg/kg组sOD活力明显升高
(p<0.01):13周后，剂量大于15mg/kg组时，GSH水平明显降低(p<0.01)，
GST活力下降，各染毒组GPX活力均明显低于对照组，而3Om留kg剂量组MDA
含量显著高于对照组。
染毒4周结束，各剂量组的雄激素结合蛋白表达呈增强趋势，高剂量组出现
显著升高，8周末各剂量组差异不明显，13周末，ABP表达显著下降。抑制素
随时间延长和剂量增加，表达明显下降.
染毒剂量》12.om叭g，早期精细胞微核明显增加;各染毒组附条尾精子畸形
率随染毒时间延长而增加。精子崎形种类主要以头部崎形为主，主要包括无钩、
不定型、香蕉型。
丙烯睛染毒8周后小鼠血清T水平随染毒剂量增加显著下降;大鼠血清中T
和EZ均表现为先升后降趋势，二者变化水平一致;丙烯睛染毒对未成年大鼠子
宫重量无明显改变。
复旦大学博士研究生毕业论文丙烯睛雄(男)性生殖毒性研究摘要
第三部分体外研究
支持细胞是辛丸毒物的主要靶部位之一。建立了支持细胞体外无血清原代单
室和双室培养。采用18天龄左右的大鼠作为细胞供体可获得纯度较高的培养细
胞。跨细胞上皮电阻和转铁蛋白反应体外支持细胞紧密单层构建成功，培养基中
加入辛酮和卵泡刺激激素可明显提高紧密连接形成效率。
50林g/m1浓度丙烯睛对体外培养的支持细胞具有明显的毒性，影响到支持细
胞的活力。丙烯睛对体外双室培养的支持细胞跨上皮电阻形成能力有明显的抑制
作用，存在剂量反应关系，同时对已经形成的跨上皮电阻，丙烯睛也能够有一定
的破坏。在各个染毒浓度组中，活化前后跨上皮电阻的变化表现出同步的改变，
活化前后没有明显的差异.
丙烯睛对支持细胞分泌转铁蛋白的影响不明显。在不影响到支持细胞活力
下，丙烯睛浓度‘25林留ml时，培养双室中内外室转铁蛋白浓度
Acrylonitrile ( ACN ) is an important intermediary for the synthesis of a variety of industrial organic products. Little attention was paid to the toxicity effects of ACN on the reproductive systems, especially on males. In China, males are the major part of workers in those operations. The reproductive toxicity of ACN has to be considered as an important hazardous effect on exposed workers, particularly on males.
In order to study male reproductive toxicity of ACN, epidemiological research and animal experiment in vivo and in vitro were conducted. In human study, the reproductive outcome of exposed male's wife and the alteration of male sexual hormone were investigated; In animals experiments, reproductive performance, morphology alteration, biochemical changes, expression of gene, and toxic effects on germ cells and on sex hormone were assayed; In vitro study, sertoli cell and spermatogonia of newt were applied to explore the potential toxic mechanism.
Parti. Epidemiological investigation
Exposure assessment was performed in male workers. The results showed that 73.1 percent of the air ACN concentration data in the workplaces exceeded the national hygienic standard. The maximum concentration was 42.00mg/m3 and the maximum PEC-TWA was 19.12mg/m3. The concentrations in the polymer and spinning workshop were much higher than in the solvent workshop. The average estimated cumulative uptake of exposed workers was 69.09 g.
The incidence of pregnancy complication in males' wives was higher than that in control group and the incidence of infertility and spontaneous abortion in the solvent workshop with the lowest concentration was significantly lower than those in other workshops (P<0.05). Spontaneous abortion incidence in couples both exposed to ACN was significantly higher than that in male only exposed to ACN.
FSH was increased with aging and T was declined in the ACN exposed workers
after 40 years old (P<0.05). Following working age increased, it also tended to increase in FSH while T declined and estrogens increased. T in the workers working in the solvent workshop with the lowest air ACN concentration was higher than those in other workshops. Both serum FSH and T in exposed workers were declined with the increase of cumulative dose. When ACN uptake was over 50g, T was significantly decreased, and when dose over lOOg, both FSH and T were decreased significantly.
Parti. Experimental Study in vivo
Male Wistar rats were daily administrated ACN by gavage 5 times a week for 13 weeks at the dose of 0, 10, 20 and 40mg/kg body weight, respectively. Mating experiment was conducted, and then the sperms parameters and the activities of enzymes were detected. Male Sprague-Dawley rats were daily administrated ACN by intraperitoneal 5 times a week for 13 weeks at the dose of 0, 7.5, 15 and 30 mg/kg body weight, respectively. The activities of antioxidant enzyme, the levels of glutathione and malonaldehyde, the mRNA expressions of androgen binding protein (ABP) and inhibin gene, and histopathology in testes were observed. ACN at dose of 6, 12 and 24mg/kg body weight were administrated by gavage to ICR mice for 5 consecutive days, the rate of abnormal sperms and micronucleus in early spermatogenic cells was analyzed. The effects on pituitary-gonad axis were investigated through the sex hormones detection from mice and rats and uterotrophic activity test.
The results showed that there was no significant difference in those detected enzymes of testis and epididymis. Mating experiment indicated that ACN has no effect on sexual function of rats, but a decrease in the number of live fetuses per litter (5.58) and an increase in the rate of embryonic absorption (19.66%) at dose of 40mg/kg b.w.
Testicular impairment in rats was observed with dose increasing. ACN caused degeneration of seminiferous tubule, decrease in the number of spermatogenic cells and spermatozoa in the tubule. Furthermore, apoptosis, necrosis and abnormal nucleus were observed on primary spermatocytes.
After 4 weeks of ACN treatment, the levels
本课题结合人群流行病学调查、整体动物研究和体外实验，对丙烯腈接触男工配偶生殖结局以及男工生殖内分泌的情况进行了研究，对染毒动物生殖力、性腺形态改变、生化改变和基因表达、生殖细胞和性激素改变做出评价，并利用Sertoli细胞和蝾螈精原细胞探讨可能的毒性机制。
第一部分 职业流行病学研究
1)丙烯腈工人接触评价
结果显示该厂丙烯腈生产车间污染较严重，测定浓度最高达42.0mg／m~3，TWA最高达19.12mg／m~3，合格率仅仅为26.9％(现行作业场所有害物质卫生标准TWA1 mg／m~3)。其中不同车间浓度顺序依次为北纺车间≥南纺车间＞聚合车间＞＞溶剂车间。个人平均累计接触剂量为69.09g。
2)丙烯腈接触男工问卷调查
504份生殖问卷调查结果表明接触组工人妻子妊娠合并症发生率升高。空气中浓度最低的溶剂车间工人妻子不孕症和自然流产发生率显著的低于其他车间(P＜0.05)，夫妻双方都接触丙烯腈自然流产率明显高于仅男工一方接触组，接触丙烯腈男工性功能障碍显著高于对照组。
3)丙烯腈接触工人性激素水平研究
随年龄增加FSH略升高，40岁以上年龄段接触工人睾酮下降(P＜0.05)，随工龄增加工人血清FSH也略增高，而接触组睾酮随工龄增加逐渐下降，伴雌激素升高。空气中丙烯腈浓度相对较低的溶剂车间，男工血清睾酮水平高于浓度高的其他车间。接触工人血清FSH和T的水平随着接触剂量的增加呈下降趋势，累积接触剂量大于50g，睾酮下降有显著性，累及接触剂量大于100g，FSH和T下降均有显著性。
复旦大学博士研究生毕业论文丙烯睛雄(男)性生殖毒性研究摘要
第二部分动物实验
雄性Wistar大鼠分别以。，10，20，40mg瓜g灌胃染毒，连续13周，测定附
争精子参数，相关酶活力和分析交配实验结局;雄性SD大鼠分别以O，7.5，15，
30mg瓜g腹腔染毒，连续13周，恢复2周，观察辜丸病理损伤、抗氧化酶活力、
脂质过氧化水平、雄激素结合蛋白和抑制素基因表达;雄性ICR小鼠以O，6，
12，24m叭g灌胃染毒，连续5天，分析附肇尾精子畸形率和早期精细胞微核;
分析大、小鼠血清性激素，并通过大鼠子宫增重实验判断丙烯睛是否具有雌激素
活性。
结果表明:丙烯睛染毒各剂量组之间雌鼠受孕率，雄鼠生育率，交配指数无
差异，剂量为4omg/kg时，孕鼠平均每窝活胎数为5.88个，明显低于对照组(P
<0 .05)，胎吸收率为19.66%，明显高于对照组(P<0 .05)。各种酶活性与对照组
比较，无显著性差异。
大鼠辛丸受损程度随染毒剂量的增大而加重，光镜下可见部分曲细精管出现
退行性病变，管腔中生精细胞和精子数量减少，电镜下可看到正在凋亡变的，核
畸形的以及坏死初级精母细胞和崎形的精子.
染毒4周，大鼠辛丸中GSH含量和GPX活力明显升高(P<0 .01);8周后，
3omg/kg组oSH明显降低(P<0.01)，剂量大于15mg/kg组sOD活力明显升高
(p<0.01):13周后，剂量大于15mg/kg组时，GSH水平明显降低(p<0.01)，
GST活力下降，各染毒组GPX活力均明显低于对照组，而3Om留kg剂量组MDA
含量显著高于对照组。
染毒4周结束，各剂量组的雄激素结合蛋白表达呈增强趋势，高剂量组出现
显著升高，8周末各剂量组差异不明显，13周末，ABP表达显著下降。抑制素
随时间延长和剂量增加，表达明显下降.
染毒剂量》12.om叭g，早期精细胞微核明显增加;各染毒组附条尾精子畸形
率随染毒时间延长而增加。精子崎形种类主要以头部崎形为主，主要包括无钩、
不定型、香蕉型。
丙烯睛染毒8周后小鼠血清T水平随染毒剂量增加显著下降;大鼠血清中T
和EZ均表现为先升后降趋势，二者变化水平一致;丙烯睛染毒对未成年大鼠子
宫重量无明显改变。
复旦大学博士研究生毕业论文丙烯睛雄(男)性生殖毒性研究摘要
第三部分体外研究
支持细胞是辛丸毒物的主要靶部位之一。建立了支持细胞体外无血清原代单
室和双室培养。采用18天龄左右的大鼠作为细胞供体可获得纯度较高的培养细
胞。跨细胞上皮电阻和转铁蛋白反应体外支持细胞紧密单层构建成功，培养基中
加入辛酮和卵泡刺激激素可明显提高紧密连接形成效率。
50林g/m1浓度丙烯睛对体外培养的支持细胞具有明显的毒性，影响到支持细
胞的活力。丙烯睛对体外双室培养的支持细胞跨上皮电阻形成能力有明显的抑制
作用，存在剂量反应关系，同时对已经形成的跨上皮电阻，丙烯睛也能够有一定
的破坏。在各个染毒浓度组中，活化前后跨上皮电阻的变化表现出同步的改变，
活化前后没有明显的差异.
丙烯睛对支持细胞分泌转铁蛋白的影响不明显。在不影响到支持细胞活力
下，丙烯睛浓度‘25林留ml时，培养双室中内外室转铁蛋白浓度
Acrylonitrile ( ACN ) is an important intermediary for the synthesis of a variety of industrial organic products. Little attention was paid to the toxicity effects of ACN on the reproductive systems, especially on males. In China, males are the major part of workers in those operations. The reproductive toxicity of ACN has to be considered as an important hazardous effect on exposed workers, particularly on males.
In order to study male reproductive toxicity of ACN, epidemiological research and animal experiment in vivo and in vitro were conducted. In human study, the reproductive outcome of exposed male's wife and the alteration of male sexual hormone were investigated; In animals experiments, reproductive performance, morphology alteration, biochemical changes, expression of gene, and toxic effects on germ cells and on sex hormone were assayed; In vitro study, sertoli cell and spermatogonia of newt were applied to explore the potential toxic mechanism.
Parti. Epidemiological investigation
Exposure assessment was performed in male workers. The results showed that 73.1 percent of the air ACN concentration data in the workplaces exceeded the national hygienic standard. The maximum concentration was 42.00mg/m3 and the maximum PEC-TWA was 19.12mg/m3. The concentrations in the polymer and spinning workshop were much higher than in the solvent workshop. The average estimated cumulative uptake of exposed workers was 69.09 g.
The incidence of pregnancy complication in males' wives was higher than that in control group and the incidence of infertility and spontaneous abortion in the solvent workshop with the lowest concentration was significantly lower than those in other workshops (P<0.05). Spontaneous abortion incidence in couples both exposed to ACN was significantly higher than that in male only exposed to ACN.
FSH was increased with aging and T was declined in the ACN exposed workers
after 40 years old (P<0.05). Following working age increased, it also tended to increase in FSH while T declined and estrogens increased. T in the workers working in the solvent workshop with the lowest air ACN concentration was higher than those in other workshops. Both serum FSH and T in exposed workers were declined with the increase of cumulative dose. When ACN uptake was over 50g, T was significantly decreased, and when dose over lOOg, both FSH and T were decreased significantly.
Parti. Experimental Study in vivo
Male Wistar rats were daily administrated ACN by gavage 5 times a week for 13 weeks at the dose of 0, 10, 20 and 40mg/kg body weight, respectively. Mating experiment was conducted, and then the sperms parameters and the activities of enzymes were detected. Male Sprague-Dawley rats were daily administrated ACN by intraperitoneal 5 times a week for 13 weeks at the dose of 0, 7.5, 15 and 30 mg/kg body weight, respectively. The activities of antioxidant enzyme, the levels of glutathione and malonaldehyde, the mRNA expressions of androgen binding protein (ABP) and inhibin gene, and histopathology in testes were observed. ACN at dose of 6, 12 and 24mg/kg body weight were administrated by gavage to ICR mice for 5 consecutive days, the rate of abnormal sperms and micronucleus in early spermatogenic cells was analyzed. The effects on pituitary-gonad axis were investigated through the sex hormones detection from mice and rats and uterotrophic activity test.
The results showed that there was no significant difference in those detected enzymes of testis and epididymis. Mating experiment indicated that ACN has no effect on sexual function of rats, but a decrease in the number of live fetuses per litter (5.58) and an increase in the rate of embryonic absorption (19.66%) at dose of 40mg/kg b.w.
Testicular impairment in rats was observed with dose increasing. ACN caused degeneration of seminiferous tubule, decrease in the number of spermatogenic cells and spermatozoa in the tubule. Furthermore, apoptosis, necrosis and abnormal nucleus were observed on primary spermatocytes.
After 4 weeks of ACN treatment, the levels
引文
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10. Sharief Y, Brown AM, Backer LC, et al. Sister chromatid exchange and chromosome aberration analyses in mice after in vivo exposure to acrylonitrile, styrene, or butadiene monoxide. Environ Mutagen. 1986,8(3):439-48.
11. Chang, C.-M., Hsia, M.T.S., Stoner, G.D., et al. acrylonitrile-induced sister-chromatid exchanges and DNA single-strand breaks in adult human bronchial epithelial cells. Mutat. Res.1990. 241,355-360.
12. Zhang H, Kamendulis LM, Jiang J, et al. Acryionitrile-induced morphological transformation in Syrian hamster embryo cells. Carcinogenesis. 2000 Apr;21(4):727-33.
13．吴维皑，苏江，黄美媛等．接触丙烯腈男工的生殖结局流行病学调查冲华劳动卫生职业病杂志，1994,12(5)：261-263
14．董定龙，王德启，艾晓清等．丙烯腈对作业工人生殖危害的调查．中国工业医学杂
志，1998，11(5)293y～295
15．肖卫，王振全，李芝兰等．丙烯腈的生殖毒性作用研究卫生研究2001，4：239～240
16. Ivanescu M, Berinde M, Simionescu L.Testosterone in sera of workers exposed to acrylonitrile. Endocrinologie. 1990 Jull-Dec;28(3-4): 187-92.
17. Tandon R, Saxena DK, Chandra SV, et al. Testicular effects of acrylonitrile in mice.Toxicol Lett.1988 Jul;42(1):55-63.
18．段志文，李海山，张玉敏等．丙烯腈对小鼠睾丸组织标志酶活性影响的研究．中国工业医学杂志．2001，1：17-19
19. Friedman MA, Beliles RP Three-generation reproduction study of rats receiving acrylonitrile in drinking water. Toxicol Lett. 2002 Jun 24; 132(3):249-61.
20. Ahmed AE, Abdel-Rahman SZ, Nour-al Deen AM. Acrylonitrile interaction with testicular DNA in rats. J Biochem Toxicol. 1992 Spring;7(1):5-11.
21. Abdel-Aziz AH, Abdel-Naim AB, Ahmed AE. In-vitro testicular bioactivation of acrylonitrile. Pharmacol Res.1997 Feb;35(2):129-34.
22. Darrall KG, Figgins JA, Brown RD, et al. Determination of benzene and associated volatile compounds in mainstream cigarette smoke. Analyst. 1998 May; 123(5):1095-101.
23. Byrd GD, Fowler KW, Hicks RD, et al. Isotope dilution gas chromatography-mass spectrometry in the determination of benzene, toluene, styrene and acrylonitrile in mainstream cigarette smoke. J Chromatogr. 1990 Mar 23;503(2):359-68.
24. Borba H, Monteiro M, Proenca MJ, et al. Evaluation of some biomonitoring markers in occupationally exposed populations to acrylonitrile.Teratog Carcinog Mutagen.1996;16(4):205-18.
25．蒋学之 李清壁 王簃兰．生殖医学．上海：上海翻译出版公司，1991
26．王簃兰 蒋学之 顾祖维．环境与生殖．上海医科大学出版社，1994
27．马玉敏 崔金山 段志文等 丙烯腈接触对男工性激素影响，中国工业医学杂志，2001，2：245-46
28．顾芝萍 桑国卫 陈俊康．生殖药理学．安徽教育出版社，1989，45
29. Telisman S, Cvitkovic P, Jurasovic J, et al. Semen quality and reproductive endocrine function relation to biomarkers of lead, cadmium, zinc, and copper in men. Environ Health Perspect,2000,108:45-53
30． Anderson RA. Hormonal contraception in the male. Br Med Bull. 2000;56(3) :717-28． Review.
31． Juul A, Skakkebaek NE. Androgens and the ageing male. Hum Reprod Update. 2002 Sep-Oct;8(5) :423-33． Review.
32． NTP, 2001． Toxicology and Carcinogenesis Studies of acrylonitrile (CAS Number 107-13-1) in B6C3F1 Mice (Gavage Studies). National Toxicology Program, Res Tri Park, NC.
33． Hogy LL, Guengerich FP. In vivo interaction of acrylonitrile and 2-cyanoethylene oxide with DNA in rats. Cancer Res. 1986 Aug,46,(8) :3932-8．
34． Whysner J, Steward RE 3rd, Chen D, et al .Formation of 8-oxodeoxyguanosine in brain DNA of rats exposed to acrylonitrile. Arch Toxicol. 1998 Jun;72(7) :429-38．
35． Robert EC, Richard AS and Joseph K H. Reroductive endpoints in general toxicity studies: are the predictive? Reproductive tooxicology. 1998,4:489-94
36． Farooqui MY, Ybarra B, Piper J, Tamez A. Effect of dosing vehicle on the toxicity and metabolism of unsaturated aliphatic nitriles. J Appl Toxicol. 1995 Sep-Oct,15(5) :411-20
37． Rochelle WT, Marvin AF, Patricia EL Rat two-generation reproduction and dominant lethal study of acrylamide in drinking water .Reproductive Toxicology ,2000,14． 385-401
38． Bergmeyer HU. Methods of enzymatic analysis, Third Edition, 1979
39． Nancy L, et al. Sorbitor dehydrogenase from rat liver. In: colowick SP, methods in enzymology; Vol 89, New York; Academic Press, 1982:135
40． 吴鑫，钟先玖，金泰(?).丙烯腈生殖毒理学研究概况．劳动医学，2000,15(1) :50-51．
41． Farooqui MY, Ahmed AE. In vivo interactions of acrylonitrile with macromolecules in rats. Chem Biol Interact. 1983 Dec;47(3) :363-71．
42． Morrissey, RE, Lamb, JV, Schwetz,BA et al. Association of sperm,vaginal cytology,and reproductive organ weight data with results from continuous breeding reproduction studies in Swiss(CD) mice, Fundam Appl Toxicol. 1988,11:3 59-71
43． Youn YY, Choe JC, Kim MS. Discovery of long-lived excited electronic states of vinylchloride, vinylbromide, vinyliodide, and acrylonitrile cations. J Am Soc Mass Spectrom. 2003 Feb, 14(2) :110-6．
44． 阮素云，项翠琴，秦逸秋等．酒精对丙烯腈致神经细胞畸形及凋亡的影响．卫生毒理
学杂志，2000，14(2)：108-09
45. Kedderis GL, Batra R, Turner MJ Jr. Conjugation of acrylonitrile and 2-cyan9ethylene oxide with hepatic glutathione. Toxicol Appl Pharmacol. 1995 Nov; 135(1):9-17.
46. Saillenfait AM, Payan JP, Langonne I, et al. Modulation of acrylonitrile-induced embryotoxicity in vitro by glutathione depletion. Arch Toxicol. 1993;67(3):164-72.
47. Jiang J, Xu Y, Klaunig JE. Induction of oxidative stress in rat brain by acrylonitrile(ACN). Toxicol Sci. 1998 Dec,46(2):333-41.
48．张正东．丙烯腈的致癌机制研究．上海医科大学博士论文．2000．8-11
49. Nerland DE, Cai J, Pierce WM Jr, Benz FW. Covalent binding of acrylonitrile to specific rat liver glutathione S-transferases in vivo. Chem Res Toxicol. 2001 Ju1,14(7):799-806.
50. Gonzales GF. Function of seminal vesicles and their role on male fertility. Asian J Androl. 2001 Dec;3(4):251-8.
51. Dowling CR, Risbridger GP. The role of inhibins and activins in prostate cancer pathogenesis. Endocr Relat Cancer. 2000 Dec;7(4):243-56. Review.
52. Danzo BJ. The effects of environmental hormones on reproduction.Cell Mol Life Sci. 1998 Nov;54(11):1249-64. Review.
53. Wyrobek A.J, Bruce W.R. 1975. Chemical induction of sperm-head abnormalities in mice, Proc. Natl. Acad. Sci. U.S.A. 72, 4425-29.
54．黄幸纾，陈星若主编．环境化学物致突变、致畸形、致癌试验方法，第一版．浙江科学技术出版社，1985：264．
55. Sumner SC, Fennell TR, Moore TA, et al.. Role of cytochrome P450 2El in the metabolism of acrylamide and acrylonitrile in mice. Chem Res Toxicol.1999 Nov;12(11):1110-6.
56．徐德祥，Shen han-min，ONG Chun-nan．单细胞凝胶电泳试验检测接触丙烯腈男工DNA双链断裂．疾病控制杂志．1999，3(3)：175-7
57. Reel JR, Lamb JC and Neal BH. Survey and assessment of mammalian estrogen biological assays for hazard characterization. Fundamental and applied toxicology 34,288-305
58. Thier R, Lewalter J, Bolt HM. 2000,Species differences in acrylonitrile metabolism and toxicity between experimental animals and humans based on observations in human
accidental poisonings. Arch Toxicol. 74(4-5) , 184-9．
59． Kedderis GL, Batra R. Species differences in the hydrolysis of 2-cyanoethylene oxide, the epoxide metabolite of acrylonitrile. Carcinogenesis. 1993 Apr;14(4) :685-9．
60． Roberts AE, Kedderis GL, Turner MJ, et al.. Species comparison of acrylonitrile epoxidation by microsomes from mice, rats and humans: relationship to epoxide concentrations in mouse and rat blood. Carcinogenesis. 1991 Mar;12(3) :401-4．
61． Cote IL, Bowers A, Jaeger RJ. Effects of acrylonitrile on tissue glutathione concentrations in rat, mouse, and hamster. Res Commun Chem Pathol Pharmacol. 1984 Mar;43(3) :507-10．
62． Livera G, Rouiller-Fabre V, Durand P, et al. Multiple effects of retinoids on the development of sertoli , germ, and leydig cells of getal and neonatal rat testis in culture. Biology of reproduction 2000,62:1303-1314
63． Frederick L, Hisaw,J. Comparative effectiveness of estrogens of fluid imbibition and growth of trhe rats uterus. Hisaw 1985:62-289
64． Odum J, Lefevre P A. Tittensor S, et al. The rodent uterotrophic assayxritical protocol features,studies with nonyl phenols and comparison with a yeast estrogenicity assay Regulation toxicology and pharmacology:25． 176-188
65． Kedderis GL, Batra R, Held SD, Loos MA, Teo SK. Rodent tissue distribution of 2-cyanoethylene oxide, the epoxide metabolite of acrylonitrile. Toxicol Lett. 1993 Jul;69(1) :25-30．
66． Magre S, Jost A. Sertoli cells and testicular differentiation in the rat fetus. J Electron Microsc Tech 1991,19:172-188
67． Jinga VV, Bogdan I, Fruchter J.Experimental model for the quantitative estimation of transendothelial transport in vitro; a two-compartment system.Physiologie. 1986 Oct-Dec;23(4) :227-36．
68． Weber E, Hammerle H, Vatti R, Berti G, Betz E.Co-cultivation of endothelial and smooth muscle cells on opposite sides of a porous membrane. Appl Pathol. 1986;4(4) :246-52．
69． Byers SW, Hadleu, MA, Djakiew D,et al. Growth and characterization of polarized monolayers of epididymal epithelial cells and sertoli cells in dual environment culture chambers. J Androl. 1986 :7(1) :60-68
70． Janecki A, Steinberger A. Polarized Sertoli cell functions in a new two-compartment culture system. J Androl. 1986 Jan-Feb;7(1) :69-71．
71． Rutten AA, Bequet-Passelecq BG, Koeter HB.Two-compartment model for rabbit skin organ culture. In Vitro Cell Dev Biol. 1990 Apr;26(4) :353-60．
72． Denefle JP, Lechaire JP. Calcium-modulated desmosome formation and sodium-regulated keratinization in frog skin cultures. Calcium-modulated desmosome formation and sodium-regulated keratinization in frog skin cultures.
73． Martins, Rita C.L.; Lima, Flavia R.S.; Werneck, Claudio C.; Moura Neto, Vivaldo; Silva, Luiz-Claudio F. Patterns of synthesis and secretion of sulfated glycosaminoglycans in primary cortical and cerebellar astrocytes in vitro Biology of the Cell Volume: 92, Issue: 6, September, 2000, pp.421-427
74． Versantvoort, C.H.M.; Leeman, W.R.; Duizer, E. et al. Comparison of drug transport in cell lines with transport in isolated intestinal segments Toxicology Letters Volume: 95, Supplement 1, July, 1998, pp. 200
75． Bourdon, Veronique; Abbe, Patricia; Cuzin, Francois; et. al. Immortalized cell lines: model for studies on cell-cell communication in the testis. Biology of the Cell Volume: 84, Issue: 1-2, 1995, pp. 108
76． Janecki A, Steinberger A.Experimental pitfalls in evaluating vectorial protein secretion in vitro; Sertoli cell secretion of androgen-binding protein and transferrin in two-compartment culture chambers. In Vitro Cell Dev Biol. 1988 Jun;24(6) :518-24
77． Janecki A, Jakubowiak A, Steinberger A. Effect of cadmium chloride on transepithelial electrical resistance of Sertoli cell monolayers in two-compartment cultures-a new model for toxicological investigations of the "blood-testis" barrier in vitro. Toxicol Appl Pharmacol. 1992 Jan;112(1) :51-7．
78． Pineau, C.; Dupaix, A.; Jegou, B. The Co-culture of Sertoli Cells and Germ Cells: Applications in Toxicology Toxicology in Vitro Volume: 13, Issue: 4-5, August 10, 1999, pp. 513-520
79． Janecki A, Jakubowiak A, Steinberger A.Effects of cyclic AMP and phorbol ester on transepithelial electrical resistance of Sertoli cell monolayers in two-compartment culture. Mol Cell Endocrinol. 1991 Nov;82(1) :61-9．
80． Janecki A, Steinberger A. Vectorial secretion of transferrin and androgen binding protein in Sertoli cell cultures: effect of extracellular matrix, peritubular myoid cells and medium composition. Mol Cell Endocrinol. 1987, 52(1-2) : 125-35
81． Isolation and culture of Sertoli cells from the testes of adult Siberian hamsters: analysis of proteins synthesized and secreted by sertoli cells cultured from hamsters raised in a long or short photoperiod. Biology of Reroduction 1995,52:658-666
82． Zhang H, Kamendulis LM, Klaunig JE. Mechanisms for the induction of oxidative stress in Syrian hamster embryo cells by acrylonitrile. Toxicol Sci. 2002 Jun;67(2) :247-55．
83． Saillenfait AM, Sabate JP.Comparative developmental toxicities of aliphatic nitriles: in vivo and in vitro observations.Toxicol Appl Pharmacol. 2000 Mar 1;163(2) :149-63．
84． Zabrodskii PF, Kirichuk VF, Germanchuk VG, Belikov VG.Mechanisms of immunotoxic effects of acrylonitrile. Bull Exp Biol Med. 2000 May;129(5) :463-5．
85． Steinberger A, Steinberger E.Replication pattern of sertoli cells in matering rat testis in vivo and organ culture.Biol Reprod 1971,4:84-87
86． Ramos P, De Miguel MP, Arenas MI, et al..Testicular cell cytoskeleton in the newt, Triturus marmoratus marmoratus, during the annual cycle. Microsc Res Tech. 1996 Apr 15;33(6) :501-9．
87． Ji ZS, Kubokawa K, Abe S. Promotion of differentiation of newt primary spermatocytes into spermatids by mammalian FSH via Sertoli cells. J Exp Zool. 1995 Aug 1;272(5) :374-83．
88． Paniagua R, Fraile B, Saez FJ. Effects of photoperiod and temperature on testicular function in amphibians. Histol Histopathol. 1990 Jul;5(3) :365-78． Review.
89． Abe SI, Ji ZS. Initiation and stimulation of spermatogenesis in vitro by mammalian follicle-stimulating hormone in the Japanese newt, Cynops pyrrhogaster. Int J Dev Biol. 1994 Jun;38(2) :201-8．
90． Uno S, Abe S. How is the flagellar length of mature sperm determined? I. Comparison of flagellar growth in spermatids between newt and Xenopus in vitro. Exp Cell Res. 1988 May; 176(1) : 194-7．
91． Shin ichi abe , Shuhsei uno. Nuclear Elongation of dissociated Newt spermatids in vitro and their nuclear shortening by antinmicrotubule agents. Experimental cell research 1984, 154:243-255
92． 范奇元．壬基酚对雄性生殖系统的潜在危害．复旦大学博士论文集．2002．
93． Bjorge C, Brunborg G, Wiger R, et al. A comparative study of chemically induced DNA damage in isolated human and rat testicular cells. Reprod Toxicol. 1996 Nov-Dec;10(6) :509-19
94． Youn YY, Choe JC, Kim MS. Discovery of long-lived excited electronic states of vinylchloride, vinylbromide, vinyliodide, and acrylonitrile cations. J Am Soc Mass Spectrom. 2003 Feb; 14(2) : 110-6．
95． Kamendulis LM, Jiang J, Xu Y, Klaunig JE. Induction of oxidative stress and oxidative damage in rat glial cells by acrylonitrile. Carcinogenesis. 1999 Aug;20(8) : 1555-60．
2．丁训诚，蒋学之，顾祖维，李灵宏．男性生殖毒理学．北京：中国人口出版社1997．1
3. Anonymous. Production soared in most chemical sectors. Chem Eng New, 1995,73:38-44
4．韩秀山，稽瑗，朱伟平．丙烯腈生产技术现状及发展趋势．化工生产与技术，2000，3(7)：15～17
5. IPCS. EHC acrylonitrile. Geneva: WHO,1984,28th.
6. IARC. Monographs on the evaluation of chemicals to humans Ed. Lyon; IARC,1999, Vol 17.
7. Collins JJ, Strother DE. CNS tumors and exposure to acrylonitrile: inconsistency between experimental and epidemiology studies. Neuro-oncol.1999 Jul;1(3):221-30.
8. Collins JJ, Acquavella JF. Review and meta-analysis of studies of acrylonitrile workers. Scand J Work Environ Health. 1998,24 Suppl 2:71-80.
9. Solomon JJ, Segal A. Direct alkylation of calf thymus DNA by acrylonitrile. Isolation of cyanoethyl adducts of guanine and thymine and carboxyethyl adducts of adenine and cytosine. Environ Health Perspect. 1985 Oct;62:227-30.
10. Sharief Y, Brown AM, Backer LC, et al. Sister chromatid exchange and chromosome aberration analyses in mice after in vivo exposure to acrylonitrile, styrene, or butadiene monoxide. Environ Mutagen. 1986,8(3):439-48.
11. Chang, C.-M., Hsia, M.T.S., Stoner, G.D., et al. acrylonitrile-induced sister-chromatid exchanges and DNA single-strand breaks in adult human bronchial epithelial cells. Mutat. Res.1990. 241,355-360.
12. Zhang H, Kamendulis LM, Jiang J, et al. Acryionitrile-induced morphological transformation in Syrian hamster embryo cells. Carcinogenesis. 2000 Apr;21(4):727-33.
13．吴维皑，苏江，黄美媛等．接触丙烯腈男工的生殖结局流行病学调查冲华劳动卫生职业病杂志，1994,12(5)：261-263
14．董定龙，王德启，艾晓清等．丙烯腈对作业工人生殖危害的调查．中国工业医学杂
志，1998，11(5)293y～295
15．肖卫，王振全，李芝兰等．丙烯腈的生殖毒性作用研究卫生研究2001，4：239～240
16. Ivanescu M, Berinde M, Simionescu L.Testosterone in sera of workers exposed to acrylonitrile. Endocrinologie. 1990 Jull-Dec;28(3-4): 187-92.
17. Tandon R, Saxena DK, Chandra SV, et al. Testicular effects of acrylonitrile in mice.Toxicol Lett.1988 Jul;42(1):55-63.
18．段志文，李海山，张玉敏等．丙烯腈对小鼠睾丸组织标志酶活性影响的研究．中国工业医学杂志．2001，1：17-19
19. Friedman MA, Beliles RP Three-generation reproduction study of rats receiving acrylonitrile in drinking water. Toxicol Lett. 2002 Jun 24; 132(3):249-61.
20. Ahmed AE, Abdel-Rahman SZ, Nour-al Deen AM. Acrylonitrile interaction with testicular DNA in rats. J Biochem Toxicol. 1992 Spring;7(1):5-11.
21. Abdel-Aziz AH, Abdel-Naim AB, Ahmed AE. In-vitro testicular bioactivation of acrylonitrile. Pharmacol Res.1997 Feb;35(2):129-34.
22. Darrall KG, Figgins JA, Brown RD, et al. Determination of benzene and associated volatile compounds in mainstream cigarette smoke. Analyst. 1998 May; 123(5):1095-101.
23. Byrd GD, Fowler KW, Hicks RD, et al. Isotope dilution gas chromatography-mass spectrometry in the determination of benzene, toluene, styrene and acrylonitrile in mainstream cigarette smoke. J Chromatogr. 1990 Mar 23;503(2):359-68.
24. Borba H, Monteiro M, Proenca MJ, et al. Evaluation of some biomonitoring markers in occupationally exposed populations to acrylonitrile.Teratog Carcinog Mutagen.1996;16(4):205-18.
25．蒋学之 李清壁 王簃兰．生殖医学．上海：上海翻译出版公司，1991
26．王簃兰 蒋学之 顾祖维．环境与生殖．上海医科大学出版社，1994
27．马玉敏 崔金山 段志文等 丙烯腈接触对男工性激素影响，中国工业医学杂志，2001，2：245-46
28．顾芝萍 桑国卫 陈俊康．生殖药理学．安徽教育出版社，1989，45
29. Telisman S, Cvitkovic P, Jurasovic J, et al. Semen quality and reproductive endocrine function relation to biomarkers of lead, cadmium, zinc, and copper in men. Environ Health Perspect,2000,108:45-53
30． Anderson RA. Hormonal contraception in the male. Br Med Bull. 2000;56(3) :717-28． Review.
31． Juul A, Skakkebaek NE. Androgens and the ageing male. Hum Reprod Update. 2002 Sep-Oct;8(5) :423-33． Review.
32． NTP, 2001． Toxicology and Carcinogenesis Studies of acrylonitrile (CAS Number 107-13-1) in B6C3F1 Mice (Gavage Studies). National Toxicology Program, Res Tri Park, NC.
33． Hogy LL, Guengerich FP. In vivo interaction of acrylonitrile and 2-cyanoethylene oxide with DNA in rats. Cancer Res. 1986 Aug,46,(8) :3932-8．
34． Whysner J, Steward RE 3rd, Chen D, et al .Formation of 8-oxodeoxyguanosine in brain DNA of rats exposed to acrylonitrile. Arch Toxicol. 1998 Jun;72(7) :429-38．
35． Robert EC, Richard AS and Joseph K H. Reroductive endpoints in general toxicity studies: are the predictive? Reproductive tooxicology. 1998,4:489-94
36． Farooqui MY, Ybarra B, Piper J, Tamez A. Effect of dosing vehicle on the toxicity and metabolism of unsaturated aliphatic nitriles. J Appl Toxicol. 1995 Sep-Oct,15(5) :411-20
37． Rochelle WT, Marvin AF, Patricia EL Rat two-generation reproduction and dominant lethal study of acrylamide in drinking water .Reproductive Toxicology ,2000,14． 385-401
38． Bergmeyer HU. Methods of enzymatic analysis, Third Edition, 1979
39． Nancy L, et al. Sorbitor dehydrogenase from rat liver. In: colowick SP, methods in enzymology; Vol 89, New York; Academic Press, 1982:135
40． 吴鑫，钟先玖，金泰(?).丙烯腈生殖毒理学研究概况．劳动医学，2000,15(1) :50-51．
41． Farooqui MY, Ahmed AE. In vivo interactions of acrylonitrile with macromolecules in rats. Chem Biol Interact. 1983 Dec;47(3) :363-71．
42． Morrissey, RE, Lamb, JV, Schwetz,BA et al. Association of sperm,vaginal cytology,and reproductive organ weight data with results from continuous breeding reproduction studies in Swiss(CD) mice, Fundam Appl Toxicol. 1988,11:3 59-71
43． Youn YY, Choe JC, Kim MS. Discovery of long-lived excited electronic states of vinylchloride, vinylbromide, vinyliodide, and acrylonitrile cations. J Am Soc Mass Spectrom. 2003 Feb, 14(2) :110-6．
44． 阮素云，项翠琴，秦逸秋等．酒精对丙烯腈致神经细胞畸形及凋亡的影响．卫生毒理
学杂志，2000，14(2)：108-09
45. Kedderis GL, Batra R, Turner MJ Jr. Conjugation of acrylonitrile and 2-cyan9ethylene oxide with hepatic glutathione. Toxicol Appl Pharmacol. 1995 Nov; 135(1):9-17.
46. Saillenfait AM, Payan JP, Langonne I, et al. Modulation of acrylonitrile-induced embryotoxicity in vitro by glutathione depletion. Arch Toxicol. 1993;67(3):164-72.
47. Jiang J, Xu Y, Klaunig JE. Induction of oxidative stress in rat brain by acrylonitrile(ACN). Toxicol Sci. 1998 Dec,46(2):333-41.
48．张正东．丙烯腈的致癌机制研究．上海医科大学博士论文．2000．8-11
49. Nerland DE, Cai J, Pierce WM Jr, Benz FW. Covalent binding of acrylonitrile to specific rat liver glutathione S-transferases in vivo. Chem Res Toxicol. 2001 Ju1,14(7):799-806.
50. Gonzales GF. Function of seminal vesicles and their role on male fertility. Asian J Androl. 2001 Dec;3(4):251-8.
51. Dowling CR, Risbridger GP. The role of inhibins and activins in prostate cancer pathogenesis. Endocr Relat Cancer. 2000 Dec;7(4):243-56. Review.
52. Danzo BJ. The effects of environmental hormones on reproduction.Cell Mol Life Sci. 1998 Nov;54(11):1249-64. Review.
53. Wyrobek A.J, Bruce W.R. 1975. Chemical induction of sperm-head abnormalities in mice, Proc. Natl. Acad. Sci. U.S.A. 72, 4425-29.
54．黄幸纾，陈星若主编．环境化学物致突变、致畸形、致癌试验方法，第一版．浙江科学技术出版社，1985：264．
55. Sumner SC, Fennell TR, Moore TA, et al.. Role of cytochrome P450 2El in the metabolism of acrylamide and acrylonitrile in mice. Chem Res Toxicol.1999 Nov;12(11):1110-6.
56．徐德祥，Shen han-min，ONG Chun-nan．单细胞凝胶电泳试验检测接触丙烯腈男工DNA双链断裂．疾病控制杂志．1999，3(3)：175-7
57. Reel JR, Lamb JC and Neal BH. Survey and assessment of mammalian estrogen biological assays for hazard characterization. Fundamental and applied toxicology 34,288-305
58. Thier R, Lewalter J, Bolt HM. 2000,Species differences in acrylonitrile metabolism and toxicity between experimental animals and humans based on observations in human
accidental poisonings. Arch Toxicol. 74(4-5) , 184-9．
59． Kedderis GL, Batra R. Species differences in the hydrolysis of 2-cyanoethylene oxide, the epoxide metabolite of acrylonitrile. Carcinogenesis. 1993 Apr;14(4) :685-9．
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