Effects of in utero and lactational exposure to bisphenol A on somatic growth and anogenital distance in F1 rat offspring

Bisphenol A (BPA), a xenoestrogen, has been reported to mimic the actions of estrogen or to affect the endocrine glands in vivo and in vitro. In this study, we examined whether in utero and lactational exposure to BPA altered the somatic growth and anogenital distance (AGD) of F1 offspring (1, 3, and 9 weeks of age) in vivo in rats. Dams were orally administered with various doses of BPA (0, 4, or 40 mg/kg body weight (BW)/day) from gestation day (GD) 6 through postnatal day (PND) 20. There were no significant changes in body weight, liver weight, kidneys weight, testes weight, AGD, the ratio of AGD to BW, or the ratio of AGD to the cube root of BW in BPA exposed pups compared to the vehicle-exposed control. This suggests that prenatal and postnatal exposure (indirect exposure) to BPA (4-40 mg/kg/day, GD 6-PND 20) does not affect on somatic growth or AGD of F1 generation of male and female rats.     

Effects of in utero and lactational exposure to di(2-ethylhexyl)phthalate on somatic and physical development in rat offspring

Di(2-ethylhexyl)phthalate (DEHP) has been reported to act as an antiandrogen and to affect the reproductive organs and accessory genital glands. Thus, to assess the reproductive toxicity of DEHP it is important to examine both its adverse effects on the development of offspring following maternal exposure and its effects on sexual function and fertility. In the present study, we examined whether in utero and lactational exposure to DEHP affects postnatal somatic growth of offspring in the rat. Pregnant females were orally administered various doses of DEHP (0, 25, 100 or 400 mg/kg body weight/day) from gestational day (GD) 6 through postnatal day (PND) 20. There were no significant changes in body weight, body length, tail length, or the weight of individual organs between the control and DEHP-treated groups. Somatic hormonal parameters were the same for all DEHP doses. These findings suggest that in utero and lactational exposure to various concentrations of DEHP has very little effect on postnatal development or endocrine and physical status of male and female rat offspring under the experimental conditions of the present study.     

Perinatally Administered Bisphenol A as a Potential Mammary Gland Carcinogen in Rats

Background: Environmental exposure to bisphenol A (BPA) affects mammary gland development in rodents and primates. Prenatal exposure to environmentally relevant doses of BPA increased the number of intraductal hyperplasias and ductal carcinomas in situ by 50 days of age in Wistar-Furth rats.Objective: We aimed to determine whether BPA exposure of dams during gestation only or throughout lactation affects the incidence of mammary gland neoplasia in female offspring.Methods: We treated pregnant Sprague-Dawley rats with BPA at 0, 0.25, 2.5, 25, or 250 μg BPA/kg BW/day from gestational day (GD) 9 to birth and from GD9 to postnatal day (PND) 21. Mammary glands from BPA-exposed offspring were examined at four time points for preneoplastic and neoplastic lesions. To assess circulating BPA levels, we exposed pregnant rats to vehicle or 250 μg BPA/kg BW/day during gestation only or during gestation/lactation and analyzed sera from dams, fetuses, and nursing pups for total and unconjugated BPA.Results: Total and unconjugated BPA were detected in sera from 100% of dams and fetuses and 33% of pups exposed to 250 μg BPA/kg BW/day. Unconjugated BPA levels in exposed dams and fetuses (gestational) and in exposed dams and pups (gestational/lactational) were within levels found in humans. Preneoplastic lesions developed in BPA-exposed female offspring across all doses as early as PND50. Unexpectedly, mammary gland adenocarcinomas developed in BPA-exposed offspring by PND90.Conclusions: Our findings suggest that developmental exposure to environmentally relevant levels of BPA during gestation and lactation induces mammary gland neoplasms in the absence of any additional carcinogenic treatment. Thus, BPA may act as a complete mammary gland carcinogen.Citation: Acevedo N, Davis B, Schaeberle CM, Sonnenschein C, Soto AM. 2013. Perinatally administered bisphenol A acts as a mammary gland carcinogen in rats. Environ Health Perspect 121:1040–1046; http://dx.doi.org/10.1289/ehp.1306734     

Developmental triclosan exposure decreases maternal and neonatal thyroxine in rats

Disruption of maternal thyroid hormones during fetal developmental may result in irreversible neurological consequences in offspring. The present study tested the hypothesis that perinatal triclosan exposure of dams decreases thyroxine in dams and offspring prior to weaning. Pregnant Long-Evans rats received triclosan by oral gavage (0-300 mg/kg/d) in corn oil from gestational day (GD)6 through postnatal day (PND)21. Serum was obtained from pups on PND4, 14, and 21, and from dams on PND22. Serum thyroxine (T4) was reduced 31% in dams on PND22. In pups, a unique pattern of hypothyroxinemia was observed; serum T4 decreased 27% in PND4 pups with no significant reduction observed on PND14 or PND21. Comparable reductions of approximately 30% in serum T4 at 300 mg/kg/d for dams and PND4 neonates and a lack of effect at PND14 and PND21 suggest that toxicokinetic or toxicodynamic factors may have contributed to a reduced exposure or a reduced toxicological response during the lactation period.     

In utero and lactational exposures to low doses of polybrominated diphenyl ether-47 alter the reproductive system and thyroid gland of female rat offspring

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are capable of disrupting thyroid hormone homeostasis. PBDE-47 (2,2',4,4'-tetrabromodiphenyl ether) is one of the most abundant congeners found in human breast adipose tissue and maternal milk samples. OBJECTIVES: We evaluated the effects of developmental exposure to low doses of PBDE-47 on the female reproductive system. METHODS: Pregnant Wistar rats were administered vehicle (peanut oil) or PBDE-47 [140 or 700 microg/kg body weight (bw)] on gestation day (GD) 6, or 5 mg 6-n-propyl-2-thiouracil (PTU)/L in the drinking water from GD7 through postnatal day (PND) 21. RESULTS: In female offspring sacrificed on PND38, there was a significant decrease in ovarian weight after exposure to PTU or 140 microg/kg PBDE-47. Alterations in folliculogenesis were apparent: we observed a decrease in tertiary follicles and serum estradiol concentrations in the offspring exposed to either PTU or 700 microg/kg PBDE-47. PTU exposure also resulted in a decrease in primordial follicles. On PND100, persistent effects on the thyroid glands included histologic and morphometric changes after exposure to either PTU or PBDE-47. No relevant changes in reproductive indices were observed after mating the exposed F1 females with nontreated males. CONCLUSIONS: Administration of PBDE-47 at doses relevant to human exposure led to changes in the rat female reproductive system and thyroid gland.     

In Utero Exposure to Bisphenol A Shifts the Window of Susceptibility for Mammary Carcinogenesis in the Rat

Background

Bisphenol A (BPA) is a ubiquitous environmental chemical with reported endocrine-disrupting properties.

Objective

Our goal in this study was to determine whether prenatal exposure to BPA predisposes the adult rat mammary gland to carcinogenesis.

Methods

Pregnant rats were treated orally with 0, 25, or 250 μg BPA/kg body weight (BW) from gestation day (GD) 10 to GD21. For tumorigenesis experiments, prenatally exposed female offspring received a single gavage of 7,12-dimethylbenz(a)anthracene (DMBA; 30 mg/kg BW) on postnatal day (PND) 50, or PND100.

Results

Prenatal exposure of the dam to 250 μg BPA/kg BW combined with a single exposure of female offspring to DMBA on PND100, but not on PND50, significantly increased tumor incidence while decreasing tumor latency compared with the control group. Prenatal exposure of the dam to 250 μg BPA/kg BW, in the absence of DMBA to the female offspring, increased cell proliferation and elicited differential effects at the protein level at PND100 compared with PND50. Differentially regulated proteins in the mammary gland included estrogen receptor-α, progesterone receptor-A, Bcl-2, steroid receptor coactivators, epidermal growth factor receptor, phospho-insulin-like growth factor 1 receptor, and phospho-Raf.

Conclusions

Our study demonstrates that oral prenatal exposure to BPA increases mammary cancer susceptibility in offspring and shifts the window of susceptibility for DMBA-induced tumorigenesis in the rat mammary gland from PND50 to PND100. These changes are accompanied by differential effects of prenatal BPA exposure on the expression of key proteins involved in cell proliferation.     

Prenatal bisphenol A exposure induces preneoplastic lesions in the mammary gland in Wistar rats

BACKGROUND: Humans are routinely exposed to bisphenol A (BPA), an estrogenic compound that leaches from dental materials, food and beverage containers, and other consumer products. Prenatal exposure to BPA has produced long-lasting and profound effects on rodent hormone-dependent tissues that are manifested 1-6 months after the end of exposure. OBJECTIVE: The aim of the present work was to examine whether in utero exposure to BPA alters mammary gland development and increases its susceptibility to the carcinogen N-nitroso-N-methylurea (NMU). METHODS: Pregnant Wistar rats were exposed to BPA (25 pg/kg body weight per day) or to vehicle. Female offspring were sacrificed on postnatal day (PND) 30, 50, 110, or 180. On PND50 a group of rats received a single subcarcinogenic dose of NMU (25 mg/kg) and they were sacrificed on either PND110 or PND180. RESULTS: At puberty, animals exposed prenatally to BPA showed an increased proliferation/apoptosis ratio in both the epithelial and stromal compartments. During adulthood (PND110 and PND180), BPA-exposed animals showed an increased number of hyperplastic ducts and augmented stromal nuclear density. Moreover, the stroma associated with hyperplastic ducts showed signs of desmoplasia and contained an increased number of mast cells, suggesting a heightened risk of neoplastic transformation. Administration of a subcarcinogenic dose of NMU to animals exposed prenatally to BPA increased the percentage of hyperplastic ducts and induced the development of neoplastic lesions. CONCLUSIONS: Our results demonstrate that the prenatal exposure to low doses of BPA perturbs mammary gland histoarchitecture and increases the carcinogenic susceptibility to a chemical challenge administered 50 days after the end of BPA exposure.     

Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer Di(2-ethylhexyl) phthalate

Several members of the phthalate ester family have antiandrogenic properties, yet little is known about how exposure to these ubiquitous environmental contaminants early in development may affect sexual development. We conducted experiments to determine effects of in utero and lactational exposure to the most prevalent phthalate ester, di(2-ethylhexyl) phthalate (DEHP), on male reproductive system development and sexual behavior. Sprague-Dawley rats were dosed with corn oil or DEHP (0, 375, 750, or 1,500 mg/kg/day, per os) from gestation day 3 through postnatal day (PND) 21. Dose-related effects on male offspring included reduced anogenital distance, areola and nipple retention, undescended testes, and permanently incomplete preputial separation. Testis, epididymis, glans penis, ventral prostate, dorsolateral prostate, anterior prostate, and seminal vesicle weights were reduced at PND 21, 63, and/or 105-112. Additional dose-related effects included a high incidence of anterior prostate agenesis, a lower incidence of partial or complete ventral prostate agenesis, occasional dorsolateral prostate and seminal vesicle agenesis, reduced sperm counts, and testicular, epididymal, and penile malformations. Many DEHP-exposed males were sexually inactive in the presence of receptive control females, but sexual inactivity did not correlate with abnormal male reproductive organs. These results suggest that in utero and lactational DEHP exposure also inhibited sexually dimorphic central nervous system development. No major abnormalities were found in any of eight control litters, but DEHP caused severe male reproductive system toxicity in five of eight litters at 375 mg/kg/day, seven of eight litters at 750 mg/kg/day, and five of five litters at 1,500 mg/kg/day. These results demonstrate that the male reproductive system is far more sensitive to DEHP early in development than when animals are exposed as juveniles or adults. The effects of DEHP on male reproductive organs and sexual behaviors and the lack of significant effects on time to vaginal opening and first estrus in their littermates demonstrate that DEHP (and/or its metabolites) affects development of the male reproductive system primarily by acting as an antiandrogen. The pattern of effects of in utero and lactational DEHP exposure differed from patterns caused by other phthalate esters, and the preponderance of anterior prostate agenesis appears to be unique among all chemicals. These results suggest that DEHP acts partly by mechanisms distinct from those of other antiandrogens.     

围生期双酚A暴露对雄鼠子一代生长和脑发育形态的影响

[目的]研究围生期双酚A暴露对雄性子一代(F1)出生后的生长及脑组织病理形态的影响。[方法]对母鼠从妊娠第11天直至产后断乳双酚A灌胃染毒,高、中、低剂量分别为2、20、100 mg/kg,同时设立对照组。每个剂量组分别在出生后第1、5、10、15、21、30、45天记录子代体重,各时相点取6只F1雄性子代大鼠,采用断头处死法,迅速取脑组织固定包埋进行组织病理学检测。[结果]中、低剂量组雄性子代在出生后(postnatal day,PND)第5、10、15、21、 30、45天体重均高于对照组,统计学上差异有非常显著性(P<0．01)。高剂量组雄性子代PND1、5、10体重均低于对照组, 差异有非常显著性(P<0．01)。组织病理学(HE染色)结果显示PND15、21、30各剂量组脑组织均有不同程度的异常改变, 主要表现为海马CA3区锥体细胞和大脑皮质神经元发生核固缩变性,其中高剂量组和中剂量组较为严重。在PND45各染毒组异常细胞减少,海马和皮质神经细胞总数减少。[结论]围生期暴露于双酚A可以影响F1雄性大鼠子代出生后的生长和引起脑组织的病理形态学改变。     

Immature rat uterotrophic assay of bisphenol A

We used the immature rat uterotrophic assay to determine the estrogenicity of bisphenol A (BPA). We administered BPA (in sesame oil) to rats subcutaneously (sc; 0, 8, 40, and 160 mg/kg/day) or orally (0, 40, 160, and 800 mg/kg/day) for 3 days beginning on postnatal day (PND) 18; rats were sacrificed 24 hr after the last administration. Uterine wet, blotted, and relative weights increased in all groups given BPA sc. After oral administration, uterine relative weight increased in 160 and 800 mg/kg BPA groups, and wet and blotted weights increased in the 800 mg/kg BPA group. Plasma concentrations of BPA at 1 hr after the last administration were detected in all groups given BPA sc and in groups given 160 and 800 mg/kg BPA orally, with a dose-response effect. The study was then reproduced under the same conditions. After sc injections, uterine wet and blotted weights increased in the 40 and 160 mg/kg BPA groups, and relative weight increased in all groups given BPA sc. By contrast, uterine wet, blotted, and relative weights increased only in the 160 and 800 mg/kg oral BPA groups. Also, to examine time-course changes in uterine weight, we administered BPA (in sesame oil) sc from PND 18 to PND 20 for 3 days at doses of 0, 8, 40, and 160 mg/kg/day; uterine weights were then measured at 6, 12, 18, and 24 hr after the last administration. Uterine wet, blotted, and relative weights increased in all BPA groups at 6 and 24 hr and in 40 and 160 mg/kg BPA groups at 12 hr. By contrast, at 18 hr, uterine wet, blotted, and relative blotted weights increased in all BPA groups and relative wet weight increased in 40 and 160 mg/kg BPA groups. The percentage increases in uterine wet and relative weights of 40 and 160 mg/kg BPA groups at 6 hr were higher than those at 24 hr relative to the controls, but the coefficient of variation in these weights in the group given 8 mg/kg BPA at 24 hr was smaller than that at 6 hr. These findings demonstrate BPA-induced uterotrophy in the immature uterotrophic assay in rats administered 8 mg/kg/day sc and in rats given 160 mg/kg/day orally, and suggest that the autopsy at 24 hr after the last administration is suitable.     

Perinatal bisphenol A exposure increases estrogen sensitivity of the mammary gland in diverse mouse strains

BACKGROUND: Studies of low-dose effects of xenoestrogens have yielded conflicting results that may be attributed to differences in estrogen sensitivity between the rodent strains examined. Perinatal exposure of CD-1 mice to low doses of the xenoestrogen bisphenol A (BPA) alters peripubertal mammary gland development. Future studies to assess the role of estrogen receptors as mediators of BPA action require estrogen receptor knock-out mice that were generated on a C57Bl6 background. The sensitivity of the C57Bl6 strain to estradiol and BPA is unknown. OBJECTIVES: In the present study we examined whether the mammary glands of CD-1 and C57Bl6 mice exhibited similar responses to 17beta-estradiol (E(2)) and whether perinatal exposure to BPA equally enhanced sensitivity of the mammary glands to E(2) at puberty. METHODS: Immature mice were ovariectomized and treated for 10 days with one of eight doses of E(2). Morphological mammary gland parameters were examined to identify doses producing half-maximal effects. Mice were exposed perinatally to 0 or 250 ng BPA/kg body weight (bw)/day from gestational day 8 until postnatal day (PND) 2. On PND25, female offspring were ovariectomized and given an estrogen challenge of 0, 0.5, or 1 microg E(2)/kg bw/day for 10 days. Morphometric parameters of the mammary gland were compared between strains. RESULTS: Both strains exhibited similar responses to E(2). Perinatal BPA exposure altered responses to E(2) at puberty for several parameters in both strains, although the effect in CD-1 was slightly more pronounced. CONCLUSION: Both mouse strains provide adequate models for the study of perinatal exposure to xenoestrogens.     

围生期双酚A暴露对大鼠子代行为发育的影响

目的研究围生期暴露于双酚A对SD大鼠子代的行为发育的影响。方法 120只孕鼠随机分为6组,每组20只。从孕期d 6至仔鼠出生d 21断乳每天分别灌胃给予0、0.05、0.5、5、50、500mg/kg的双酚A。于仔鼠出生后d 3检测前、后肢定位反射;出生后4 d检测仔鼠的平面翻正、悬崖回避反射;出生后d 5检测负向地性;出生后d 11检测空中翻正反射。结果 0.05、0.5mg/kg剂量组的所有的神经反射均与对照组无明显差异,5mg/kg剂量组的平面翻正反射、负向地性反射、空中翻正反射达标天数与对照组相比显著延迟;50mg/kg剂量组,在前、后肢定位反射、空中翻正反射达标天数与对照组相比显著延迟;500mg/kg剂量组,在前、后肢定位反射、负向地性反射、空中翻正反射以及悬崖回避反射的达标天数与对照组相比显著延迟。结论大鼠围生期暴露于双酚A,可影响子代大鼠的神经行为发育。     

Behavioral alterations in response to fear-provoking stimuli and tranylcypromine induced by perinatal exposure to bisphenol A and nonylphenol in male rats

The purpose of this study was to examine whether perinatal exposure to two major environmental endocrine-disrupting chemicals, bisphenol A (BPA; 0.1 mg/kg/day orally) and nonylphenol [NP; 0.1 mg/kg/day (low dose) and 10 mg/kg/day (high dose) orally] daily from gestational day 3 to postnatal day 20 (transplacental and lactational exposures) would lead to behavioral alterations in the male offspring of F344 rats. Neither BPA nor NP exposure affected behavioral characteristics in an open-field test (8 weeks of age), in a measurement of spontaneous motor activity (12 weeks of age), or in an elevated plus-maze test (14 weeks of age). A passive avoidance test (13 weeks of age) showed that both BPA- and NP-treated offspring tended to delay entry into a dark compartment. An active avoidance test at 15 weeks of age revealed that BPA-treated offspring showed significantly fewer avoidance responses and low-dose NP-treated offspring exhibited slightly fewer avoidance responses. Furthermore, BPA-treated offspring significantly increased the number of failures to avoid electrical unconditioned stimuli within 5-sec electrical shock presentation compared with the control offspring. In a monoamine-disruption test using 5 mg/kg (intraperitoneal) tranylcypromine (Tcy), a monoamine oxidase inhibitor, both BPA-treated and low-dose NP-treated offspring at 22-24 weeks of age failed to show a significant increment in locomotion in response to Tcy, whereas control and high-dose NP-treated offspring significantly increased locomotion behavior after Tcy injection. In addition, when only saline was injected during a monoamine-disruption test, low-dose NP-treated offspring showed frequent rearing compared with the control offspring. The present results indicate that perinatal low-dose BPA or NP exposure irreversibly influenced the reception of fear-provoking stimuli (e.g., electrical shock), as well as monoaminergic neural pathways. Key words: behavior, bisphenol A, fear, learning, monoamine, nonylphenol.     

邻苯二甲酸二丁酯宫内和哺乳期染毒对F_1代雄性大鼠的生殖发育毒性

目的　观察邻苯二甲酸二丁酯 (DBP)对F1代仔鼠的发育状况及性成熟期雄性仔鼠生殖系统损害情况 ,并期望得到现有文献中缺如的DBP对F1代仔鼠生殖发育毒性的最大无作用剂量 (NOAEL)。方法　选择在宫内暴露期和哺乳期 (受孕第 2天至仔鼠 2 1天断奶 ) ,通过灌胃方式给母鼠染毒 (DBP终浓度分别为 0、5 0、2 5 0和 5 0 0mg (kg·d) ,观察对仔鼠的影响。结果　DBP对母鼠无明显影响 ,中高剂量组 [2 5 0、5 0 0mg (kg·d) ]对F1代雄性仔鼠的出生体重、每窝活产数、体重增长及雄性仔鼠肛殖距有明显影响 ,对性成熟期雄性仔鼠生殖系统损害尤为严重 ,可观察到小睾丸、附睾发育不全甚至缺失、睾丸未降等现象 ,附睾尾精子参数和睾丸精子头计数及附睾、肝、肾、前列腺的脏器系数明显降低 ,而与激素合成相关的垂体系数却略有上升。低剂量组未观察到有害影响。结论　雄性生殖系统是DBP作用的主要靶器官 ,幼年敏感期所受的损害部分不可逆 ,并得到DBP经口染毒对F1代仔鼠生殖发育毒性的NOAEL为 5 0mg (kg·d)。据此 ,进一步提出DBP经口摄入的参考剂量 (RfD)为 5 0 0 μg (kg·d)。     

孕期二月桂酸二丁基锡暴露对大鼠妊娠结局及胎鼠性发育的影响

目的 研究二月桂酸二丁基锡(DBTD)暴露对Wistar大鼠妊娠结果的影响并评估其对胎鼠性发育的影响.方法 在妊娠第12～19天分别用玉米油和不同浓度的DBTD(10、20、30 mg/kg)灌胃染毒孕鼠,至妊娠第20天,检测母鼠妊娠结局.结果 妊娠20 d时,孕鼠体重随DBTD剂量升高呈下降趋势,但与对照组比较,差异无统计学意义,30 mg/kg组孕鼠子宫重量显著降低;所有DBTD染毒组雄性、雌性胎鼠体重均显著降低,20、30 mg/kg组胎鼠体长显著降低;所有DBTD染毒组雌性胎鼠肛门距生殖器的标化距离显著增长,而雄性胎鼠无显著变化.各DBTD暴露组均未导致胎鼠发生外部畸形,但导致胎鼠趾骨骨化延迟,且在20、30 mg/kg组出现死胎和吸收胎.结论 DBTD暴露影响胎鼠的发育,并可能对雌性胎鼠具有雌性雄性化影响.     

Maternal exposure to 2,3,7,8-tetrachlorodibenzo-<Emphasis Type="Italic">p</Emphasis>-dioxin and the body burden in offspring of long-evans rats

Objectives   In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in a wide variety of developmental effects in pups at doses much lower than those causing overt toxicity in adult animals. We investigated the relationship between tissue concentrations of TCDD in dams and fetuses and developmental effects on pups. Materials and Methods  Pregnant Long-Evans rats were given TCDD at a single oral dose of 12.5, 50, 200, or 800 ng of TCDD or [³H]-TCDD/kg bw on gestation day (GD) 15. Dams were sacrificed on GD16 and GD21, and the tissue concentrations of TCDD were measured in dams and fetuses. Pups were sacrificed on postnatal day (PND) 49 and PND63 for males and PND70 for females, and the reproductive effects and tissue concentrations of TCDD were determined. Results  The sex ratio (male/female) on GD21 was significantly reduced at 50 ng TCDD/kg and at 12.5 and 50 ng TCDD/kg at birth, but not at other doses. Delayed puberty was observed in males at 200 ng TCDD/kg and in males and females at 800 ng TCDD/kg. Anogenital distance, testis weight, epididymal sperm count, sperm motility, and ejaculated sperm count were not affected. Estrous cyclicity was not different from that of the control in any treatment group. A dose-dependent decrease in weight of seminal vesicle and prostate on PND49 was observed. Prostate weight was significantly decreased at 800 ng TCDD/kg. At this dose, maternal body burden and TCDD concentration in fetuses were 290 pg TCDD/g and 52 pg TCDD/g on GD16, respectively. Reduced prostate weight is a sensitive and commonly observed endpoint so that the body burdens of dams and fetuses at the LOAEL of this endpoint could be served as the basis for establishing TDI for dioxins.     

孕期染毒双酚A对雄性子代生殖发育影响

目的 探讨母鼠孕期接触双酚A对子代雄鼠生殖发育的影响及作用机制.方法 将受孕SD雌鼠40只,随机分为双酚A0、10、50、250 mg/kg染毒组,以2 mL/kg容积自受孕第5d灌胃染毒至第20d;孕第21 d每组处理5只孕鼠,检测母鼠血中性激素水平,胎鼠数、死胎数、胎鼠重和胎盘重,高效液相色谱法检测母鼠血及胎盘中双酚A含量,另5只孕鼠自然分娩,待雄性子鼠性成熟后检测血中性激素水平,生殖器官脏器系数、病理、精子质量.结果 10、50 mg/kg剂量组母鼠血清中雌二醇(E2)含量分别为1 780.78、1 680.10 pmol/L,明显高于对照组的1361.74pmol/L(P＜0.01),低、中、高3个染毒组睾酮(T)含量分别为5.55、4.76、6.79 nmol/L,明显高于对照组的3.20 nmol/L(P＜0.01);50、250mg/kg剂量组雄性子鼠附睾及前列腺脏器系数分别为0.297、0.325和0.153、0.173,均高于对照组(P＜0.01),镜下可见附睾间质及前列腺上皮有增生改变;250 mg/kg剂量组精子活动率为52.9%,明显低于对照组的67.4% (P ＜0.05).结论 孕期染毒双酚A对胎鼠发育无明显影响,但影响子鼠生殖器官发育和精子生成质量.     

哺乳期母鼠接触溴氰菊酯对其仔鼠神经行为发育的影响

目的探讨哺乳期母鼠接触溴氰菊酯(DM)对发育期仔鼠脑一氧化氮合酶(NOS)活力及神经行为发育的影响。方法妊娠大鼠随机分为对照组和2个染毒组,每组6只。染毒剂量分别为3．35和6．70 mg/kg,每只母鼠自产后1～19 d,隔日1次,经口染毒DM；对照组予等量玉米油。观察DM对出生后5、10和21 d仔鼠脑NOS活力及30d仔鼠学习、记忆能力的影响。结果2个染毒组仔鼠哺乳存活率(81．80%、78．60%)均明显降低于对照组(96．70%),差异有统计学意义(P＜0．01)；6．70 mg/kg染毒组10、21 d仔鼠体重[(16．62±2．28)、(31．34±6．94)g]明显低于对照组[(18．81±2．01)、(36．21±7．01)g],差异有统计学意义(P＜0．05)；6．70mg/kg染毒组仔鼠延迟时间为(3．05±1．20)s,被动逃避反应阳性率为21．5%；3．35 mg/kg染毒组被动逃避反应阳性率为22．5%,与对照组比较,差异均有统计学意义(P＜0．05)。旷场实验中,2个染毒组仔鼠行进格子数均明显降低,与对照组的差异均有统计学意义(P＜0．05)；产后5至21 d仔鼠脑NOS活力呈发育性增高趋势；6．70mg/kg染毒组出生后5 d仔鼠脑NOS活力[(0．60±0．07)U·mg pro~(-1)·h~(-1)]明显低于对照组,差异有统计学意义(P＜0．05)结论哺乳期母鼠接触DM可导致仔鼠神经行为发育迟缓,并伴有NOS活力下降。     

邻苯二甲酸(2-乙基己基)酯孕期暴露对雌性子代大鼠性发育的影响

目的 观察邻苯二甲酸(2-乙基己基)酯(DEHP)对雌性子鼠性发育的影响.方法 妊娠12 d(GD 12)Wistar孕鼠,称重编号,用随机数字表法分为玉米油对照组和1、250、750、1000 mg·kg~(-1)·d~(-1) DEHP染毒组,每组lO只,GD 12～17灌胃染毒.观察雌性子代大鼠出生后第14～17天(PND 14～17)眼睛完全睁开时间;PND 22处死计算脏器系数;PND 30～38观察阴道完全开口时间(若PND 30～38阴道未开口则持续观察至成年期),称量当日体重,并记录首次排卵时间.结果 对照组和1、250、750、1000 mg·kg~(-1)·d~(-1) DEHP染毒组子鼠眼睛完全睁开时间分别为(15.8±0.4)d、(16.3±0.6)d、(16.0±0.6)d、(15.9±0.6)d、(15.8±0.4)d,各组间比较差异无统计学意义(F=1.363,P=0.262).750及1000 mg·kg~(-1)·d~(-1)剂量组部分子鼠阴道永久未开口,未开口百分率分别为62.50%(15/24)、81.25%(26/32),与对照组比较,差异有统计学意义(χ~2值分别为84.92、132.79,P值均<0.01).对照组和1、250、750、1000 mg·kg~(-1)·d~(-1) DEHP染毒组雌性子鼠阴道开口时间分别为(32.7±1.3)d、(33.3±1.5)d、(32.2±1.5)d、(33.1±1.3)d、(33.3±1.2)d;阴道开口时体重分别为(91.56±6.65)g、(93.79±6.28)g、(92.98±8.48)g、(100.57±6.47)g、(103.83±8.24)g.协方差分析显示,修正体重后阴道开13时间各组间比较,差异有统计学意义(F=3.075,P<0.05),其中250 mg·kg~(-1)·d~(-1)组比对照组提前(t=-2.056,P<0.05);体重对阴道开口的影响有统计学意义(F=40.857,P<0.05).结论 GD 12～17 DEHP染毒可影响雌性子代大鼠阴道开口,引发阴道闭锁畸形,导致其性发育异常.     

围生期接触磺胺二甲嘧啶对子代大鼠甲状腺功能的影响

目的研究围生期母体接触磺胺二甲嘧啶对子代大鼠甲状腺功能的影响。方法受孕母鼠在受孕第7日起至哺乳期结束每天分别给予磺胺二甲嘧啶0、50、100和200mg/kg,HE染色观察20日龄子代大鼠甲状腺的组织病理学变化,并用免疫组织化学染色观察甲状腺内核增殖抗原的表达。结果各染毒剂量组子代大鼠甲状腺滤泡细胞出现不同程度的增生表现,核增殖抗原表达阳性细胞数显著高于对照组(P0.05)。结论磺胺二甲嘧啶可通过母体干扰子代大鼠甲状腺功能。