邻苯二甲酸二乙基己酯生殖发育毒性及其机制

邻苯二甲酸二乙基己酯(di-2-ethylhexyl phthalate,DEHP)是一种使用广泛的邻苯二甲酸酯类增塑剂,研究表明,其是一种具有生殖毒性和发育毒性的环境雌激素,可通过消化系统、呼吸系统及皮肤接触等途径进入人体,也可通过胎盘和乳汁到达下一代体内。生殖毒性机制主要有与睾丸Leydig细胞、Sertoli细胞、germ细胞等作用干扰雄激素合成,也可通过干扰芳香酶活性及与激素合成运输有关的基因及蛋白的表达影响激素的合成、分泌及运输。DEHP主要通过影响胎盘脂质及锌代谢影响胚胎发育。由于种属之间代谢差异,把动物实验结果外推到人类还有许多问题需要考虑,但流行病调查资料显示,DEHP对人类健康产生不利影响。     

邻苯二甲酸二烯丙酯对子代大鼠生殖发育的影响

目的研究邻苯二甲酸二烯丙酯(diallyl phthalate,DAP)对雌性大鼠发育、生殖功能的影响。方法将96只5周龄SPF级SD大鼠按体重随机分为4组,分别为对照(玉米油)组和250、500、1 000 mg/kg DAP染毒组,每组24只,雌雄各半。采用灌胃方式进行染毒,染毒容量为2 ml/kg,每天1次。于染毒第3周后,以雌∶雄各1只进行合笼。雄性大鼠共连续染毒13周,雌性妊娠大鼠继续染毒持续到仔鼠断乳(出生后第21天,PND21)。每窝保留4只仔鼠,雌雄各半,仔鼠与母鼠同笼饲养至断乳;仔鼠断乳后至出生后第49天按性别分笼饲养,喂饲方式和染毒剂量与其亲代母鼠相同。检测两代大鼠体重及相关脏器重量,并计算脏器系数;检测两代大鼠血清甲状腺素、雌二醇、睾酮及胆固醇浓度;检测亲代大鼠的生殖情况;记录仔鼠的发育情况及精子质量。结果与对照组比较,1 000 mg/kg DAP染毒组亲代大鼠及其仔鼠肝、脾的脏器系数均增加,血清甲状腺素的浓度及雄性血清睾酮的浓度均较低,而血清胆固醇浓度均较高,差异有统计学意义(P0.05);而各剂量DAP染毒组雌性血清雌二醇的浓度均无明显改变。与对照组比较,仅1 000 mg/kg DAP染毒组大鼠交配成功时间延长,差异有统计学意义(P0.05);而各剂量DAP染毒组亲代大鼠的交配率、仔鼠数、雌雄比均无明显改变。与对照组比较,仅1 000 mg/kg DAP染毒组雌性仔鼠阴道开口时间和雄性仔鼠包皮分离时间延长,差异均有统计学意义(P0.05);而各剂量DAP染毒组雌、雄仔鼠的睁眼时间均无明显改变。与对照组比较,仅1 000 mg/kg DAP染毒组仔鼠的精子计数及精子活力较低,而精子畸形率较高,差异均有统计学意义(P0.05);且随着DAP染毒剂量的升高,仔鼠的精子计数和精子活力均呈降低趋势,而精子畸形率呈升高趋势。精子畸形主要为头部畸形(包括双头、香蕉头、无沟)。结论 DAP暴露对子代大鼠生殖发育功能有影响,其作用机制可能与DAP作为内分泌干扰物改变血清激素的水平有关。     

砷的生殖发育毒性

砷的生殖发育毒性新疆医学院环境卫生学教研室（乌鲁木齐８３００５４）陈艳（综述）王国荃姚华（审校）我国新疆、内蒙、贵州等地相继发现了地方性砷中毒的病区，对居民健康产生了严重的危害。近年来对砷的毒性作用的研究工作也逐渐深入，认为砷对人体的损害是全身性的、...     

邻苯二甲酸二乙基已酯对未成年小鼠卵巢发育影响

目的观察邻苯二甲酸二乙基己酯(DEHP)对卵泡生长发育和性激素分泌影响,探讨DEHP对未成年雌性小鼠卵巢发育的毒性作用。方法将60只未成年(3周龄)清洁级ICR雌性小鼠随机分为4组,分别为对照(玉米油)组和低、中、高剂量 DEHP染毒组(100、400、1 600 mg/kg),每组15只,采用灌胃方式染毒,染毒容量为0.1 mL/kg,每天1次,每周5 d,连续6周;染毒结束后,检测小鼠血清促卵泡生成激素(FSH)、促黄体生成激素(LH)、雌激素、孕激素水平,取出小鼠卵巢组织连续切片观察卵巢各级卵泡数目构成比。结果 高剂量DEHP组血清中FSH水平为(0.72±0.04) mIU/mL 高于对照组的 (0.58±0.30) mIU/mL,差异有统计学意义(P<0.05);与对照组[(1.74±0.17) pg/mL]比较,低、中剂量DEHP组小鼠血清中雌激素水平[(1.62±0.18)、(1.69±0.16) pg/mL]均降低,高剂量组[(2.11±0.04) pg/mL]升高,差异均有统计学意义(P<0.05);各剂量染毒组LH和孕激素水平与对照组比较差异均无统计学意义。结论 DEHP暴露对未成年雌性小鼠的卵巢发育具有毒性作用。     

砷的生殖发育毒性研究

选用Ｗｉｓｔａｒ 大鼠,以三氧化二砷为受试物,采用两代一窝试验方法,观察砷的生殖发育毒性。结果显示,仔鼠出生后第１０ 、２０ 、３０ 天的体重高剂量组明显低于对照组和其它剂量组,且有显著性差异;两代大鼠的受孕率和幼仔哺育成活率高剂量组明显低于对照组和低剂量组,正常分娩率和幼仔出生存活率各组间无显著性差异;仔鼠体砷含量随染砷剂量的增加而增加,各组间比较均有显著性差异;高剂量染砷组脾和胸腺脏器系数明显低于对照组,Ｈｂ 、ＴＬＣ 显著降低,其它剂量组免疫学指标改变不明显。结果表明,砷可影响动物的生育能力,并可通过胎盘屏障影响子代的生长发育和生理功能     

草甘膦生殖发育毒性的研究进展

草甘膦是全球用量最大的除草剂.随着转基因抗草甘膦大豆和玉米作物的大量种植,使草甘膦的用量大增,这是否会对人类生殖发育构成潜在影响,已引起广泛关注.现就国内外学者在草甘膦的生殖发育毒性及其机制方面的相关研究作一综述报道,为进一步研究探讨草甘膦对人类生殖发育毒性的影响提供导向依据.     

汞的生殖和发育毒性研究

汞广泛用于工农业生产、医药、国防和科研。几个世纪以前,人们对汞毒性已有了解,古希腊名医被尊为“医学之父”的Hippocrates及Pliny,Dioscorides和Galen均有过报道。1557年Jean报道了第一例称作“Modern Galen“的工业性汞中毒。早在一个世纪以前,汞对神经的毒作用已有过报道。永对胚胎的毒性是在用汞治疗患梅毒的妇女后,发现频发的流产而提出的。1953年日本甲基汞中毒的暴发,甲基汞成为该领域内研究得最为深刻的金属之一,其致畸作用及胚胎毒性已较肯定,报道较多。故本文仪将收集到的有关金属汞和无机汞对生殖和发育的毒性作一文献综述。     

邻苯二甲酸二乙基已酯对环境和生物体的危害

环境内分泌干扰物邻苯二甲酸二乙基已酯（DEHP）作为增塑剂被广泛用于医疗用品和食品包装材料等领域，其对环境和生物体的潜在危害主要表现为对生物体生殖系统和子代的影响。本主要综述了DEHP在环境中的暴露情况，生殖毒性和致癌性作用及可能的作用机制。     

双酚A生殖与发育毒性研究现状

双酚A(bisphenol A,BPA)是一种常见的化工原料,主要用于合成环氧树脂和酚醛树脂,其制品被广泛应用.BPA是一种公认的动物内分泌干扰物,具有雌激素活性及抗雄激素活性,会干扰机体正常的内分泌功能,对生殖系统及子代生长发育造成影响.近年来的研究特别关注低剂量双酚A[＜50mg/(kg· d)]暴露是否会影响生殖系统的生长发育及其功能、大脑发育及行为.美国与欧盟制定的50μg/(kg·d)的参考剂量受到质疑.本文主要集中综述双酚A的整体动物研究及人群调查现状,进而认识双酚A暴露可能引起的不良结局.     

Perspectives on reproductive and developmental toxicity

Human reproduction and development is a cycle of interdependent events. Virtually all of its phases have been shown to be the primary target of one or more non-mutagenic exogenous agents. Such agents interfere with certain of the countless epigenetic or ontogenic events essential for normal completion of the cycle. Mutagens disrupt this cycle at some points, but the overwhelming majority of reproductive and developmental toxins are not mutagenic. As in all aspects of toxicology, the reproductive and developmental effects of chemicals are determined by the intrinsic nature of the chemical, the quantity of the chemical exposure, the duration of exposure and the stage of the cycle at which it occurs. Signs of reproductive toxicity range from reduced fertility to spontaneous abortion. Adverse effects on the conceptus are categorized as functional deficits, developmental retardation, structural abnormality and death. One or more of these is anticipated to occur as a result of excess exposure to most chemicals. Although the degree of hazard and risk potential can be calculated in each instance, chemicals differ markedly in their ability to interfere with reproduction (Amann, 1982) and/or development (Johnson, 1984). Standardized methods for reproductive and developmental toxicity safety evaluation are available for detecting adverse effects upon any aspect of reproduction and development. Data currently available establish that these state-of-the-art tests conducted in laboratory animals are often highly predictive of the type of adverse effect a particular chemical will have in humans, as well as the exposure level at which it will occur. By adding a modest safety factor to the no-observed-effect-level of well-executed animal studies, safe human exposure levels can be established. Responsibility for determining the intrinsic hazard potential and the risk estimate of exposure rests with manufacturers and major users of occupational and other environmental chemicals. As public awareness of reproductive and developmental hazards has increased in recent years, it has come to be understood that some chemicals have a predilection for causing reproductive impairment and/or disrupting development in the absence of other toxicity. Such substances must be identified to establish safe exposure levels and to determine the types of effects to be expected, should excessive human exposure occur. The setting of safe exposure levels is necessary both from the standpoints of ensuring public safety and avoiding product liability.     

The reproductive and developmental toxicity of High Flash Aromatic Naphtha

Catalytic reforming is a refining process that converts naphthenes to aromatics by dehydrogenation to make higher octane gasoline blending components. A portion of this wide boiling range hydrocarbon stream can be separated by distillation and used for other purposes. One such application is a mixture of predominantly 9-carbon aromatic molecules (C9 aromatics, primarily isomers of ethyltoluene and trimethylbenzene), which is removed and used as a solvent--High Flash Aromatic Naphtha. A program was initiated to assess the toxicological properties of High Flash Aromatic Naphtha since there may be human exposure through inhalation or external body contact. The current study was conducted to assess the potential for developmental toxicity in the mouse and for reproductive toxicity in the rat. In the developmental toxicity study in CD-1 mice, exposure of dams by inhalation to near lethal levels (1500 ppm) resulted in fetal mortality, reduced weight, delayed ossification, and an increased incidence of cleft palate. At 500 ppm, a level at which maternal weight gain was slightly reduced, fetal weight gain was also reduced, but there was no other evidence of developmental effects. The lowest exposure level (100 ppm) did not cause any maternal or developmental toxicity. There was no consistent evidence of reproductive toxicity in rats, even at exposure levels which resulted in significantly reduced parental weight gain. In addition, when parental exposure was stopped on GD (gestation day) 20, birth weights as well as postnatal survival were generally similar to control values, even in the 1500 ppm exposure group. Postnatal weight gain was also similar to controls early in weaning, but, if maternal exposure was reinitiated, weight gain was reduced in the high exposure group. However, when exposure was continued until delivery, pups in the high exposure group exhibited reduced litter size, birth weight and poor survival. Thus it was likely that the reduction in fetal weight, seen in the developmental toxicity study in mice, was transient and had no postnatal consequences if maternal exposure was terminated at any time prior to delivery.     

电子烟生殖发育毒性的研究进展

在世界范围内,电子烟的使用人数急剧增加,其中,妊娠期妇女与处于发育阶段的青少年是电子烟的主要使用群体之一。已有研究表明电子烟暴露可对神经系统、心血管系统、呼吸系统的发育造成不良影响,并且,电子烟成分对生殖系统也会造成损害。因此,对于电子烟生殖和发育毒性的研究亟需完善。本文从人群流行病学调查、动物实验和体外实验研究出发,总结近年来有关电子烟对生殖和发育毒性的研究,阐述电子烟生殖发育毒性的研究现状及进展,为进一步探讨电子烟的毒性效应提供参考依据,并对电子烟市场的管理提出一定的参考意见。     

环境雌激素对生殖和发育毒性的分子机理

大量动物实验表明环境雌激素具有生殖和／或发育毒性，但其作用机制非常复杂，尤其在分子机理方面不甚明了，本文从信号通路，基因表达，诱变效应等几个方面介绍了近几年来国内外在分子机理研究方面所取得的进展。     

Concordance across species in the reproductive and developmental toxicity of tetrachloroethylene

Reproductive and developmental toxicities resulting from exposure to tetrachloroethylene include delayed or impaired conception, sperm quality, death during development, developmental neurotoxicity, and growth retardation. In most cases there was concordance between rodents and humans. The risk assessments indicated that neurotoxicity was the most sensitive endpoint for inhalation, whereas growth retardation was the most sensitive endpoint when exposure was by the oral route. The reference concentration (RfC) of 0.01 ppm was based on neurotoxicity among human subjects. The reference dose (RfD) of 0.0006 mg/kg per day was based on small for gestation age infants. In both cases, studies in rodents supported the credibility of these assessments. For the RfD, similar findings for other trihalomethanes have been reported. The latter part of pregnancy and early life may constitute a susceptible period for alterations leading to behavioral deficits. During this period, the capacity to metabolize tetrachloroethylene is reduced and may further contribute to the sensitivity during this phase of development. Studies suggest that an effect on dopamine metabolism is a plausible mode of action for some types of neurotoxicity. In addition, it has been suggested that this alteration may affect reproductive integrity by influencing prolactin levels.     

Lead acetate induced reproductive and paternal mediated developmental toxicity in rats

Lead was administered orally to adult male rats at exposure level of 273 or 819 mg/L (0.05% or 0.15% lead acetate, respectively) for 45 days via drinking water. At the end of the exposure period, control and experimental males were mated with untreated females. Of the females mated with treated males, 73.3% in the 0.05% group and 53.33% in the 0.15% group showed copulatory plugs. Significant decrease in number of implantations and pre- and post-implantation loss was also observed in females mated with treated males. Significant decrease in the weight of the reproductive organs, reduction in epididymal sperm count, motile sperm and viable sperm were observed in lead-exposed rats indicating decreased sperm production and deteriorated sperm quality. Significant decrease in serum testosterone levels were also observed in treated rats indicating decreased steroidogenesis. The decreased serum testosterone levels and deteriorated sperm quality might be responsible for the suppressed reproduction in rats after exposure to lead.     

Recent TDI derivation of dioxin based on the reproductive and developmental toxicity

In 1998, WHO-IPCS re-assessed the TDI of dioxin, which was derived from the body burdens of TCDD exposed to the experimental animals. Then, the international assessment agencies and governmental assessment agencies have conducted the dioxin fs health assessment using the similar method to the WHO-IPCS approach. The key endpoints were reproductive and developmental toxicity caused by in utero and lactational exposure. Each assessment agencies used the similar data set of the toxicity studies, however, there are some differences about the TDI derivation method and the selection of adverse endpoints. This report reviewed the recent reproductive and developmental toxicity studies of the dioxins and summarized the health assessment in the international or governmental agencies, and discussed the appropriate TDI derivation.     

饮用水中卤乙酸的生殖和发育毒性研究进展

卤乙酸是饮用水中主要的氯化消毒副产物,由于难以挥发和降解,其健康危害特别是生殖与发育毒性研究越来越受到重视。许多研究表明一些卤乙酸影响实验动物生殖细胞功能和胚胎发育,导致生育力降低胎仔畸形和生长迟缓。本文就饮用水中卤乙酸生殖与发育毒性的研究工作进行具体论述。     

邻苯二甲酸二丁酯宫内暴露对大鼠子代的生殖发育毒性研究

[目的]研究邻苯二甲酸二丁酯(DBP)宫内暴露对亲代孕鼠及F1代子鼠生殖毒性的影响。[方法]染毒组通过灌胃方式给母鼠染毒,染毒剂量分别为20 mg/(kg·d)、100 mg/(kg·d)和500 mg/(kg·d)。用酶联免疫法检测血清中雌二醇(E2)、黄体生成素(LH)、促卵泡刺激素(FSH)及睾酮(T)的水平。[结果]本实验剂量的DBP对母鼠各脏器无明显毒作用,但对血清中性激素水平影响显著,与溶剂对照组相比,中、高剂量组(100、500 mg/(kg·d))母鼠的T水平均明显下降(P<0.05),而高剂量组的母鼠血清中FSH含量增加(P<0.001);随着DBP染毒剂量增加,母鼠妊娠期体重增长明显下降(P<0.05);雌性子鼠血清中性激素水平测定结果显示:分娩后第7天(PND7),雌性子鼠的LH、T水平随DBP染毒剂量增加而下降,各处理组间均存在差异(P<0.05);至第26天(PND26),雌性子鼠的E2水平随染毒剂量的增加下降明显,各组间差异显著(P<0.05),中、高剂量组的雌性子鼠FSH水平低于对照组(P<0.05),高剂量组的T水平明显升高(P<0.05)。[结论]母鼠妊娠后期DBP暴露对子代有明显的毒性效应,较低剂量的DBP也可改变子代血清中性激素水平。     

低剂量亚慢性砷染毒对雄性大鼠生殖功能及子代的影响

目的探讨低剂量砷染毒对雄性大鼠生殖毒性及胚胎发育毒性的影响。方法健康普通级雄性sD大鼠48只,按体质量随机分为4组,分别饮用含亚砷酸钠0（蒸馏水组）、0．01（低剂量组）、0．05（中剂量组）和0．25mg／L（高剂量组）的水。染毒12周后,与正常成年雌性大鼠按1：2合笼,确定雌鼠怀孕后,处死雄鼠取其附睾丸,观察雄性大鼠精子畸形并用原子荧光谱法测定其血砷和精液砷浓度。于妊娠第20天处死雌鼠,观察雌雄交配受孕情况、受精卵着床数、活胎数、死胎数、吸收胎数及胚胎的生长发育情况。结果染毒12周后,低、中、高剂量组与蒸馏水组大鼠的体重分别为（347．6±18．7）、（308．3±19．2）、（301．4±17．4）和（316．7±17．7）g,低剂量组体重较蒸馏水组增加,高剂量组体重较蒸馏水组降低,差异均有统计学意义;精子数量分别为（9．7±0．8）、（5．5±0．5）、（4．3±0．4）和（9．3±0．9）×10^6／ml,活精率分别为（65．4±7．2）％、（41．3±6．9）％、（37．9±4．6）％和（63．8±8．2）％,中高剂量组较蒸馏水组降低,差异有统计学意义;精子畸形率和死胎／吸收胎发生比例分别为（9．1±4．4）％、（14．0±3．9）％、（21．4±5．9）％、（9．3±2．5）％和1．7％、4．2％、7．3％、0．8％,中和高剂量组较蒸馏水组增加,差异有统计学意义。结论0．01mg／L亚砷酸钠染毒对大鼠生殖功能未见明显的毒性作用;0．05mg／L及以上浓度亚砷酸钠亚慢性染毒12周可对雄性大鼠产生生殖毒性,并对胚胎有一定的致畸作用。