邻苯二甲酸酯类化合物的雄性生殖毒性

邻苯二甲酸酯类化合物(PAEs)属于芳香族二羧酸酯,多为高沸点、低蒸气压液体,对塑料的稳定性起着重要作用,广泛用作多种塑料膜的增塑剂,特别用于纤维素与乙烯树脂,以增加其韧性和柔性。鉴于食品包装的需要,其中许多已做过急性毒性及慢性饲养试验,其毒性均较低 1978年美国国际商业局公布的PAEs产量约为200万吨。1987～1989年我国平均年产量约为18万     

砷的雄性生殖毒性研究进展

砷是一种天然类金属化学元素,广泛存在于自然界中[1].同时,砷也是一种雄性生殖毒物,可影响下丘脑—垂体—睾丸轴、损害支持细胞和生精细胞,引起精子质量下降[2].本文就长期砷暴露所引起的雄性生殖毒性及相关机制进行综述. 1砷的雄性生殖毒性 1.1砷对下丘脑—垂体—睾丸轴的影响下丘脑—垂体—睾丸轴是男性生殖的重要调节路径,...     

丙烯酰胺对雄性小鼠生殖毒性的研究

目的 评价丙烯酰胺(acrylamide,AA)对睾丸细胞DNA损伤及精子核成熟率的影响,为研究AA生殖系统损伤机制提供实验室数据.方法 以20、40和60 ms/kg AA经口灌胃染毒雄性小鼠,并设对照组,连续给药5 d,首次给药后14 d时,用彗星实验和吖啶橙荧光染色法检测睾丸细胞DNA损伤和小鼠精子核成熟率.结果...     

雄性生殖毒性评价体系及完善

人类工业文明在开拓大自然取得长足进步的过程中,所产生的各种副产品对人类的生殖健康也产生一系列的负面影响,精子数量下降,精液体积减少,生殖器官畸形、精子质量下降和生育力降低问题日益增多。如何有效评价外源物质对雄性生殖系统的潜在毒性,这是一个问题。系统评价一个外源     

三硝基甲苯对人和小鼠体内环核苷酸影响的初步探讨

三硝基甲苯(TNT)对肝、眼、血液等损害研究较多,而对机体内环磷酸腺苷(cAMP)和环磷酸乌苷(cGMP)影响的报道罕见。本研究就TNT对体内CAMP和cGMP影响的规律进行了探讨.     

羟基脲对雄性大鼠的生殖毒性

目的观察羟基脲(HU)对雄性大鼠的生殖毒性。方法雄性大鼠分别腹腔注射HU×100、200和400mg·kg-1,连续10d。末次给药后分别于d9、d23处死动物。结果停药d9时,200、400mg·kg-1组不活动精子增加明显(P<0.05或P<0.01);停药d23时,各给药组睾丸脏/体比都明显下降(P<0.05或P<0.01);400mg·kg-1组附睾脏/体比下降明显(P<0.05),并且仍然有大量不活动精子(P<0.01);200、400mg·kg-1组精子计数明显减少(P<0.01);随给药浓度增加,各组精子畸形数量增加(P<0.01)。结论雄性大鼠连续10d腹腔注射羟基脲100mg·kg-1以上,对生殖系统产生明显毒性。     

邻苯二甲酸二环己酯对雄性大鼠生殖内分泌的毒性

目的观察邻苯二甲酸二环己酯(DCHP)对雄性大鼠的生殖-内分泌毒性,探讨内分泌干扰物评价的效应终点。方法用雄性Wistar大鼠DCHP灌胃染毒,剂量分别为125、250和500 mg/(kg.d),对照组给与玉米油。观察临床症状,体重增长,血常规,血清生化,血Zn和激素以及解剖及组织病理学等指标。结果1252、50和500 mg/(kg.d)剂量组大鼠WBC数量减少,125和500 mg/(kg.d)剂量组大鼠CHO水平升高,125、250和500 mg/(kg.d)剂量组大鼠ALB水平升高,同时250和500 mg/(kg.d)剂量组A/G值增大,250和500 mg/(kg.d)剂量组血清睾酮水平降低,250和500 mg/(kg.d)剂量组血清雌激素水平升高,1252、50和500 mg/(kg.d)剂量组肝脏器系数均明显增高,250、500 mg/(kg.d)剂量组肾脏器系数增高,其他检测指标未见有明显毒理学意义的改变。结论在没有引起生殖毒性的剂量范围[(125~500 mg/(kg.d)]内,DCHP可以改变睾酮和雌激素水平,干扰生殖内分泌调节平衡。本研究结果为评价DCHP生殖内分泌毒性提供新的数据,同时为评价筛检可疑内分泌干扰物提供了效应终点。     

甲胺磷对雄性小鼠的生殖毒性

本文采用一组试验方法对有机磷杀虫剂甲胺磷的雄性小鼠生殖毒性进行研究。以0.2,0.8和3.2mg/kg ig染毒小鼠,观察到精子活动率下降、畸形精子增多、精子线粒体酶活性下降以及睾丸组织细胞结构改变,并呈剂量-反应关系。甲胺磷对雄性小鼠生殖细胞具有潜在诱变能力,并可通过多种途径干扰生精细胞的分化和代谢。建议中毒的育龄男子定期检产精液直至结果恢复正常方可生育后代。     

美他多辛对雄性大鼠的生殖毒性

美他多辛 (Metadoxine ,MTDX)是意大利 80年代上市的一种代谢平衡药 ,它能减轻乙醇戒断综合征及早期标志物氨的排除 ,是目前临床用于治疗化学性和乙醇性肝病的药物[1 3 ] 。MTDX化学名称为吡哆素L 2 吡咯烷酮 5 羧酸酯 ,吡哆素是维生素B6由吡哆醇 (PN)、吡哆醛 (PL)和吡哆胺组成 ,L 2 吡咯烷酮 5 羧酸酯俗称L 焦谷氨酸 (L 2 Pyrrolidone 5 carboxylate ,L PCA) ,MTDX由二者 1∶1聚合而成 ,是 1对离子 ,在体内又分解成这 2种离子。目前 ,国内外对于MTDX的报道仅见于其药效机制方面 ,未见其对雄性生殖系统毒性作用及其机…     

Evaluation of the Reproductive and Developmental Toxicity of a Fluoroalkylethanol Mixture

The objective of these studies was to evaluate the reproductive and developmental toxicity of a commercial fluoroalkylethanol mixture, which is an intermediate in the production of fluorotelomers. The test substance was administered daily by gavage to Sprague–Dawley rats as a suspension in 0.5% aqueous methylcellulose. In a one-generation reproductive toxicity study, rats (20 per sex per group) were given dosages of 0, 25, 100, or 250 mg kg^{? 1} day^{? 1} for a period of 74 days prior to cohabitation, and during mating, gestation, and lactation. Body weights, feed consumption, clinical signs, gross pathology, sperm parameters, estrous cyclicity, and reproductive performance were evaluated for the P₁ generation. The F₁ offspring were evaluated during the lactation period for growth and survival and given a gross pathology examination at weaning. A subset of the offspring were retained; body weights, feed consumption, clinical signs, and age at onset of vaginal opening and preputial separation were evaluated, and gross pathology was performed on postnatal day 60. In the developmental toxicity study, groups of time-mated Sprague–Dawley female rats were given the test substance as a suspension in 0.5% aqueous methylcellulose at daily dosages of 0, 50, 200, or 500 mg kg^{? 1} day^{? 1} by gavage on gestation days 6–20. During the in-life portion of the study, growth parameters and clinical observations were made. On gestation day 21, dams were euthanized, and the thoracic and abdominal viscera were examined. The uterine contents were removed and examined, and fetuses were evaluated for any alterations. In the reproduction study, litter size at birth, number of live pups per litter on day 0 and 4 of lactation, and pup weights during lactation were reduced in groups administered ≥ 100 mg kg^{? 1} day^{? 1}. No other reproductive parameters were affected. There were no adverse reproductive effects observed at 25 mg kg^{? 1} day^{? 1}. In the developmental toxicity study, reduced maternal body weight parameters, increased perineal fur staining, and increased fetal skeletal alterations were observed at 500 mg kg^{? 1} day^{? 1}. There was no maternal or developmental toxicity at 50 or 200 mg kg^{? 1} day^{? 1}. Under the conditions of the studies, the no-observed adverse effect levels for this mixture were 25 mg kg^{? 1} day^{? 1} for subchronic toxicity and reproductive parameters and 200 mg kg^{? 1} day^{? 1} for developmental toxicity end points. No functional reproductive or developmental effects were observed at dose levels that did not adversely affect adult animals.     

三硝基甲苯对大鼠胆固醇和甘油三酯影响的研究

不同剂量的三硝基甲苯(TNT)染毒大鼠,从染毒后第四周开始,各剂量组血清甘油三酯的含量显著下降;从染毒后第六周开始,各剂量组肝脏甘油三酯和胆固醇的含量明显低于对照组,血清胆固醇含量明显高于对照组;至染毒后第八周各指标均未见恢复。表明 TNT 对大鼠的脂代谢有一定的影响。     

Reproductive and Developmental Toxicity Screening Study of 4-Aminophenol in Rats

Twelve male and female rats per group were given 4-aminophenol (PAP) by gavage at 0, 20, 100, or 500 mg/kg/day. Males were dosed for a total of 49 days, beginning 14 days before mating. Females were dosed for a total of 40–60 days, from 14 days before mating to Day 3 of lactation throughout the mating and gestation periods. Four males and 2 females died at 500 mg/kg/day, and all surviving males and females showed brown urine at 100 mg/kg/day and above. Body-weight gain was lower in males and females at 500 mg/kg/day, and food consumption was decreased in males at 500 mg/kg/day and in females at 100 and 500 mg/kg/day. Absolute and relative weights of the testes and epididymides were decreased at 500 mg/kg/day. Histopathological examinations revealed decreased spermatocyte and spermatid levels in the testis, debris of germ cell in the epididymis lumen, basophilic tubules in the kidney, and deposits of hemosiderin in the red pulp and extramedullary hematopoiesis in the spleen in males at 500 mg/kg/day. Longer gestation period, decreased delivery index, and lower body weight of pups on postnatal day (PND) 0 and increased number of stillborns at 500 mg/kg/day were also observed. At this dose, the viability of pups on PND 4 was decreased markedly. No adverse effects on reproduction or development were detected at 20 and 100 mg/kg/day. These findings indicate that PAP is general and reproductive/developmental toxic, but is unlikely to be teratogenic, in rats.     

环磷酰胺对雄性生殖系统毒性损伤的研究进展

环磷酰胺(cyclophosphamide,CP)是目前常用的一种烷化剂类抗肿瘤药物,临床常用于各种恶性肿瘤的化疗、类风湿关节炎及自身免疫性疾病的治疗。CP的常见不良反应包括肝肾功能损伤、出血性膀胱炎、恶心、呕吐、骨髓抑制等,然而目前备受关注的是CP对雄性生殖系统的毒性损伤。研究[1]发现,给大鼠一次性腹腔注射CP,剂量在75 mg/kg以上可造成明显生育能力损害。CP对雄性生殖系统的损伤和对后代的潜在致畸危险,已引起社     

Reproductive toxicity on female mice induced by microcystin-LR

There are increasing concerns about health risk of human exposure to microcystin-LR (MC-LR) over the past few decades. Nevertheless, its female mammalian reproductive toxicity has not been addressed yet. In the present study, we firstly reported MC-LR could impact female reproductive function of mammals. After 28 days MC-LR exposure, relative ovary weight significantly reduced in 20 μg/kg MC-LR group and this reduction may be relative with pathomorphological changes of ovary. The result of histological evaluation of follicles showed that primordial follicles decreased roughly in half at high dose level compared with control. Since serum hormone assay indicated that MC-LR induced decrease of progesterone but not FSH or LH, disturbance of estrus cycle was seemed to result from direct impact of ovary rather than indirectly from hypothalamus or pituitary. As expected, MC-LR was detected in the ovaries of MC-LR exposure mice by immunoblot analysis.     

Studies on the Male Reproductive Toxicity of Freon 22

Studies on the Male Reproductive Toxicity of Freon 22. Lee,I.P. and Suzuki, K. (1981). Fundam. Appl. Toxicol. 1:266–270Freons have been used extensively as refrigerants and as propellantsin household products, and yet their possible effects on malereproduction have received little attention. In the presentstudy, adult male Sprague-Dawley rats (nine weeks of age) wereexposed to 50 000 ppm Freon 22, five hrs per day for eight weeks.The control group received filtered air at an identical flowrate. At the end of the eight week exposure period, body andorgan weights, hematology, blood chemistry, plasma gonadotropins,and fertility parameters were not significantly different fromcontrols, with the exception of serum cholesterol levels, whichwere slightly higher, and glucose and triglyceride levels whichwere lower. The weight of coagulating glands was also lowerthan those of controls, but did not interfere with fertilityfunction.     

三硝基甲苯对大鼠睾丸某些酶活性与睾酮含量的影响

本研究观察了三硝基甲苯(TNT)对大鼠睾丸重量、睾丸和血清中睾丸酮(T)含量、睾丸内山梨醇脱氢酶(SDH)、乳酸脱氢酶(LDH)、葡萄糖-6-磷酸脱氢酶(G—6-PD)和酸性磷酸酶(ACP)活性的影响。结果发现,TNT染毒后6周起,各染毒组大鼠睾丸绝对重量均显著低于对照组;染毒后4周起,各染毒组睾丸及血清T含量持续下降直至染毒结束;各染毒组大鼠睾丸SDH在染毒后6与8周,G-6-PD与ACP活性在染毒后8周,出现显著变化。     

Reproductive toxicity of denosumab in cynomolgus monkeys

Denosumab is a monoclonal antibody that inhibits bone resorption by targeting RANKL, an essential mediator of osteoclast formation, function, and survival. Reproductive toxicity of denosumab was assessed in cynomolgus monkeys in an embryofetal development study (dosing GD20–50) and a pre-postnatal toxicity study (dosing GD20–parturition). In the embryofetal toxicity study, denosumab did not elicit maternal toxicity, fetal harm or teratogenicity. In the pre-postnatal toxicity study, there were increased stillbirths, and one maternal death due to dystocia. There was no effect on maternal mammary gland histomorphology, lactation, or fetal growth. In infants exposed in utero, there was increased postnatal mortality, decreased body weight gain, and decreased growth/development. Denosumab-related effects in infants were present in bones and lymph nodes. There was full recovery at 6 months of age from most bone-related changes observed earlier postpartum. The effects observed in mothers and infants were consistent with the pharmacological action of denosumab.     

Reproductive toxicity testing for pharmaceuticals under ICH

Reproductive toxicity testing of drugs is performed as a 2- or 3-segment package. The choice of species for routine studies with small molecule drugs is essentially limited to the rat, rabbit, mouse and minipig. The lack of alternative species is a threat to the successful screening of drugs for teratogenicity. A proposed revision of the ICH M3 guideline addresses contradictions concerning the timing of the various reproductive and juvenile studies. This M3 draft, however, raises questions concerning the confidence that can be attributed to preliminary embryotoxicity studies with as few as six females per group. The detection of reproductive hazards could be improved by implementing methods in routine use for the testing of chemicals, such as double staining of fetuses and primordial follicle counts. Modern imaging techniques hold promise for application in the morphological examination of fetuses. An assessment of developmental immunotoxicity should be included in any future revision of the reproductive toxicity guidelines.     

Reproductive and developmental toxicity of inhaled 2,3-dichloro-1,3-butadiene in rats

Inhalation developmental and reproductive toxicity studies were conducted with 2,3-dichloro-1,3-butadiene (DCBD), a monomer used in the production of synthetic rubber. In the reproductive toxicity study, Crl:CD^®(SD)IGS BR rats (24/sex/group) were exposed whole body by inhalation to 0, 1, 5, or 50 ppm DCBD (6 h/day) for approximately 10–11 weeks total, through premating (8 weeks; 5 days/week), cohabitation of mating pairs (up to 2 weeks, 7 days/week), post-cohabitation for males (7 days) and from conception to implantation (gestation days 0–7 [GD 0–7]), followed by a recovery period (GD 8–21) for presumed pregnant females. Estrous cyclicity was evaluated during premating (last 3 weeks) and cohabitation. Reproductive organs and potential target organs, sperm parameters, and GD 21 fetuses (viability, weight, external alterations) were evaluated. In the developmental study, pregnant Crl:CD^®(SD)IGS BR rats (22/group) were exposed whole body by inhalation to 0, 1, 10, or 50 ppm DCBD (6 h/day) on GD 6–20; dams were necropsied on GD 21 (gross post-mortem only) and fetuses were evaluated (viability, weight, and external, visceral and skeletal exams). During the in-life portion of the studies, body weight, food consumption, and clinical observation data were collected. At 50 ppm, gasping and labored breathing occurred in both studies during the first few exposures; body weight and food consumption parameters were affected in parental animals from both studies, but were more severely affected in the developmental study. Fetal weight was decreased in the developmental study at 50 ppm. Degeneration of the nasal olfactory epithelium was observed in the reproduction study at 50 ppm. There were no effects on reproductive function, embryo–fetal viability, or increases in fetal structural alterations in either study. The no-observed-adverse-effect level (NOAEL) for reproductive toxicity was 50 ppm. The NOAEL for systemic toxicity in the reproduction study was 5 ppm based on adverse effects on body weight and food consumption parameters and nasal olfactory epithelial toxicity at 50 ppm in parental rats. The NOAEL for maternal and developmental toxicity was 10 ppm based on reduced maternal weight gain and food consumption and reduced fetal weight at 50 ppm in the developmental toxicity study.