Exposure to ethinyl estradiol prenatally and/or after sexual maturity induces endometriotic and precancerous lesions in uteri and ovaries of mice

Unrecognizable exposure to estrogenic substance may cause estrogen‐dependent diseases, endometriosis and cancer. Pregnant mice (ICR/Jcl, CLEA) were exposed to 0.01 mg ethinyl estradiol (EE₂)/kg per day or vehicle (olive oil) through oral intubation from day 11 to 17 of gestation. They delivered their offspring and raised them. When the experimental female F₁ mice were at 8 weeks of age, they were not exposed to EE₂ or to the same dose of EE₂ or to vehicle twice a week until 20 weeks of age. The control female F₁ mice were exposed to the same dose of EE₂ or vehicle alone, similarly. All mice were killed at 28 weeks of age. The resected uteri and ovaries were processed for microscopic examinations and for determination of the aromatase mRNA levels and aromatase protein through quantitative RT‐PCR and Western blotting, respectively. Adenomyosis and adenocarcinomatous changes were significantly discernible in the EE₂‐exposed uteri, and incidence of ectopic glands and serous cysts were significantly increased in the prenatally EE₂‐exposed ovaries as compared with respective controls. Significant upregulation of the aromatase mRNA was seen in the prenatally EE₂‐exposed uteri and in the EE₂‐exposed ovaries. The aromatase protein was identified in all ovaries examined, and in EE₂‐exposed uteri but not in controls and confirmed its localization in eutopic and ectopic glands, abnormally proliferated lesions and the lining of the cysts. Taken together, continuous EE₂ exposure may cause endometriotic and precancerous lesions due to excessive estrogen synthesis in both target organs.     

Distribution of the longevity gene product, SIRT1, in developing mouse organs

A longevity gene product, Sir2 (silent information regulator 2) is a NAD-dependent histone deacetylase involved in longevity in yeasts, worms and flies. The mammalian homolog of Sir2, SIRT1(sirtuin 1), has been shown to play important roles related to anti-aging effects (regulating apoptosis, stress tolerance, insulin resistance, and fat metabolism). Recently, SIRT1 expression has been demonstrated to occur at as early as embryonic day 10.5 in mice. SIRT1 during developing period may be involved in the mechanism of developmental origins of adult diseases, such as diabetes and cardiovascular disease. To investigate the contribution of SIRT1, it is important to reveal the distribution of this protein during development. In the present study, we demonstrated the distribution of immunoreactivity of SIRT1 in mouse organs during prenatal and neonatal development by staining a wide variety of serial sections. The SIRT1 immunoreactivity was strongly observed in the neuroepithelial layer, dorsal root ganglion, trigeminal ganglion, eyes, roots of whiskers, and internal organs, including the testis, liver, heart, kidney, and lung during the fetal period. Neurons which had finished migrating still showed relatively strong immunoreactivity. The immunoreactivity was completely absorbed by the blocking peptide in an absorption test. During the postnatal period, the immunoreactivities in most of these organs, except the heart and testis weakened, with the liver most dramatically affected. As SIRT1 expression was demonstrated in a wide variety of developing organs, further study to investigate prenatal factors which affect SIRT1 expression and its activity is important.     

The effects of prenatal exposure to structurally diverse chemicals on the ontogeny of rat dehydrogenases

Activity levels of sorbitol dehydrogenase (SDH), lactate dehydrogenase (LDH), and glucose-6-phosphate dehydrogenase (G6PDH) were measured in the livers and brains of rats treated prenatally with 3,4,3',4'-tetrachlorobiphenyl (4CB, 3 mg/kg/day), diethylstilbestrol (DES, 10 micrograms/kg/day), zeranol (ZN, 4mg/kg/day), and cadmium (Cd, 25 mg/kg/day) and compared with enzyme levels for control groups. Enzyme activities were measured at days 15, 17, 19, and 21 prenatally, and days 1, 5, 10, 21, 35, and 56 postnatally. SDH activity was not altered by treatment with 4CB, DES, or ZN, but Cd produced reduced levels in both liver and brain of sexually mature offspring. The patterns of LDH and G6PDH, including sexual differentiation of the latter in adult liver, were not affected by any of the treatments in either tissue. The developmental profiles of each of these enzymes in untreated animals is unique, suggesting that a similar catalytic mechanism is not a factor in determining the patterns of their developmental accumulation.     

产前感染对新生大鼠肺发育的影响

目的 动态观察产前炎症暴露后新生大鼠肺形态及炎症细胞表达变化,探讨产前感染对新生大鼠肺发育影响的病理机制.方法 Wistar孕鼠按照随机数字表分为实验组和对照组,分别于孕19d和20d腹腔注射脂多糖(lipopolysaccharide,LPS)2.5mg/kg和等量生理盐水,足月自然分娩后,于日龄1d、3d、7d、14d、21 d及28 d两组分别取8只新生鼠,麻醉处死后取肺组织,以髓过氧化物酶(myeloperoxidase,MPO)和CD68作为中性粒细胞及巨噬细胞标志物,计数炎症细胞数量、图像分析测定肺泡数量、肺泡面积占组织面积比例、肺泡间隔厚度.结果 随日龄增加,新生鼠肺泡数量、肺泡占组织面积比例逐渐增加,肺泡间隔变薄,实验组炎症细胞数量逐渐减少.日龄1d、3d、7d及14d,实验组平均肺泡数量(88、89、102、127,单位:个/mm2)明显少于同日龄对照组(105、109、123和156,单位:个/mm2),P分别为0.024、0.009、0.013和0.004;日龄1d、3d和7d,实验组肺泡占组织面积比例(0.552、0.603和0.533)明显大于同日龄对照组(0.478、0.485和0.404),P分别为0.003、0.001和0.000;日龄1d及3d,实验组肺泡间隔厚度(12.30和10.75,单位:μm)明显小于同日龄对照组(17.13和16.13,单位:μm),P分别为0.000和0.000.日龄1d、3d、7d及14d,实验组中性粒细胞数量(681、582、393和379,单位:个/mm2)明显多于同日龄对照组(164、211、145和179,单位:个/mm2),P分别为0.000、0.000、0.000及0.003;日龄1d、3d及7d,实验组巨噬细胞数量(613、578和337,单位:个/mm2)明显多于同日龄对照组(170、182和127,单位:个/mm2),P分别为0.000、0.000和0.000.结论 产前炎症暴露使新生大鼠肺泡增大,数量减少,炎症细胞增多.随着新生鼠日龄的增加,肺泡发育接近正常.     

妊娠压力与金属元素联合暴露对子代神经发育影响的研究进展

孕期环境对子代生长发育有重要影响.环境因素包括自然环境(空气、水、土壤等)和社会环境(睡眠剥夺、妊娠期压力、社会经济状况等).作为孕期不良社会环境的一种,妊娠压力对子代神经发育的影响日益引起研究者的重视.     

The relationship of prenatal maternal anxiety to infant behavior and mother-infant interaction during the first six months of life

The IPAT Anxiety Scale was administered to a large sample of primiparous women from an economically disadvantaged population in their third trimester of pregnancy. At birth and at three and six months postpartum, the infants and mothers were assessed using a variety of behavioral and standardized procedures. Results indicate that anxiety was not a factor in the incidence of pregnancy and delivery complications or infant anomalies. Neonatal behavior and mother-infant interaction did differ among the high anxious and the low anxious groups. These differences, however, were only significant for female infants, Results are discussed in terms of practical implications and future research.     

The Maternal Lifestyle Study (MLS): effects of prenatal cocaine and/or opiate exposure on auditory brain response at one month

OBJECTIVE: To study absolute and interpeak latencies of the auditory brain response in infants exposed to cocaine and/or opiates in utero.Study design The sample included 477 exposed and 554 comparison infants matched for race, sex, and gestational age. Mothers were recruited at 4 urban university-based centers; most were black, receiving public assistance, and had received adequate prenatal care. Exposure was determined by meconium assay and self-report with alcohol, marijuana, and tobacco present in both groups. At 1 month, infants were tested by masked examiners with the auditory brain response. RESULTS: Analyses were conducted for exposed and comparison groups and for level of prenatal cocaine exposure with adjustment for covariates (alcohol, marijuana, tobacco, gestational age at birth, social class, and site). Heavy prenatal cocaine exposure (>/=3 days per week, first trimester) led to an increase in the I-III, I-V, and III-V interpeak latencies and to a shorter latency to peak I. Infants with prenatal opiate exposure showed a longer latency to peak V and a longer III-V interpeak latency. CONCLUSIONS: Prenatal cocaine and/or opiate exposure affects neural transmission. Detection of these effects requires a large sample with control for gestational age, other drugs, and level of cocaine use.     

A neurobiological model for the effects of early brainstem functioning on the development of behavior and emotion regulation in infants: implications for prenatal and perinatal risk

Neurobiological models propose an evolutionary, vertical-integrative perspective on emotion and behavior regulation, which postulates that regulatory functions are processed along three core brain systems: the brainstem, limbic, and cortical systems. To date, few developmental studies applied these models to research on prenatal and perinatal risk. We propose a conceptual model that incorporates three integrated levels of observations for the study of early risk: (a) brainstem-related physiological regulation of cyclic processes and sensory integration, e.g., vagal regulation, circadian rhythms; (b) emotion and attention regulation capacities that draw on the integration of brainstem and limbic systems; and (c) higher-level outcomes that draw on the intactness of brainstem and limbic networks, including socio-emotional self-regulation, inhibitory control, and cognitive processing. We discuss implications of the model for the development of regulatory capacities during the prenatal and early postnatal stages in infants born with specific perinatal risk. We underscore the importance of assessing sub-cortical and brainstem systems and the longitudinal effects of transitory brainstem dysfunction on physiological homeostasis, motivation, arousal-modulated attention, stress reactivity, and mother-infant co-regulation. The assessment of brainstem dysfunction can be conducted during hospitalization and may help detect infants at risk for the development of self-regulatory deficits at the first weeks of life.     

Intra-uterine exposure to maternal opiate abuse and HIV: The impact on the developing nervous system

Background

Both intra-uterine exposure to maternal drugs and HIV are known to adversely affect the developing central nervous system.

Aims

(1) To describe the quality of GMs in infants who were intra-uterinely exposed to maternal opiate abuse and HIV; and (2) to analyze to what extent (a) perinatal events, (b) status of HIV-infection, and (c) the quality of GMs are associated with the neurodevelopmental outcome at 2 to 3 years of age.

Patients and method

Seventy-seven children intra-uterinely exposed to both maternal opiate abuse and HIV in utero (41 boys and 36 girls; 39 born preterm) were videoed twice: first during the first 2 months after term (writhing GMs) and again at 3–5 months (fidgety GMs). Neurodevelopmental outcome was assessed at 2–3 years of age.

Results

Thirty-eight infants showed abnormal writhing GMs; 25 infants had abnormal or absent fidgety movements; 22 children had an adverse neurodevelopmental outcome. The association between GM trajectories and outcome revealed a Cramer-V = 0.75 (p < 0.001). Those infants with active HIV-infection (n = 10) did not differ from the 67 infants who were HIV-exposed but uninfected with respect to their GM quality or outcome.

Conclusions

Serial assessment of GMs in infants who were intra-uterinely exposed to maternal opiates and to HIV can be utilized for early identification of infants at a higher risk for later deficits and needing early intervention.     

高氧对发育中人胎儿肺组织分化的影响及地塞米松作用的研究

目的：高氧可能通过改变未成熟肺组织正常结构发育而导致肺功能异常。该研究通过观察高氧时体外培养胎儿肺组织结构和细胞分化的变化特点及地塞米松对这些肺组织的作用,旨在了解高氧对胎儿肺组织发育的影响。方法：用培养人假腺体期胎儿肺组织模型分别于高氧(95%O2,5%CO2)及正常氧(21%O2,5%CO2)中培养72 h,两组又分为地塞米松组(10-6M)及无地塞米松组。收获的肺组织以细胞角蛋白(pancytokeratin)确定上皮细胞,K i-67作为增生性细胞标记物。形态学结果用计算机辅助图像分析系统处理,分别计算出平均气道厚度,气道占组织比例(%),平均气道面积及细胞增生指数。结果：正常氧培养72 h,肺结构无明显改变,而高氧组气道明显扩张。高氧组与正常氧组比较,气道面积6 662μm2vs 2 728μm2;气道厚度7.8μm vs 8.1μm;气道所占比例35.2%vs 23.4%,差异有显著性(均P<0.05)。高氧并用地塞米松组气道面积(3 174μm2)及气道所占比例(23.9%)与高氧组比较,均明显降低,P<0.05;气道厚度无明显变化。高氧组上皮增生指数(21.8%)明显高于正常氧组(5.1%)及并用地塞米松组(7.4%),P<0.05。结论：高氧促进假腺体期胎儿肺组织分化为类似囊状期样结构,这种变化与气道上皮细胞异常增生有关;地塞米松具有抑制高氧对胎儿肺组织的损伤作用。     

A longitudinal study on the effects of maternal smoking and secondhand smoke exposure during pregnancy on neonatal neurobehavior

Maternal smoking during pregnancy is one of the most modifiable causes of morbidity and mortality for both pregnant women and their fetuses. The long-term effects of prenatal exposure to smoke on child behavior and development have been the subject of more extensive research than have the short-term effects. Therefore, the aim of this work is to examine the effects of smoke exposure during pregnancy on neonatal behavior, including in our study a group of mothers exposed to secondhand smoke. The behavior of 282 healthy full-term newborns was assessed using the Neonatal Behavior Assessment Scale (NBAS) at 48-72 h of life. Sixty-two mothers smoked during pregnancy (no mother smoked more than 15 cig/day) and 17 were exposed to secondhand smoke. After adjusting for socio-demographic and obstetric factors, both newborns whose mothers smoked and those whose mothers were exposed to secondhand smoke showed significantly lower scores in the habituation cluster than non-smoking mothers. Exposure to secondhand smoke was also related to lower motor system cluster scores as well as some supplementary items and the newborns of smoking mothers showed significantly lower scores in the state regulation cluster and in some items of the state organization cluster than the newborns of non-smoking mothers. We conclude that active and passive smoking during pregnancy affects several aspects of neurobehavioral development, regardless of socio-demographic, obstetric and pediatric factors.     

Gender-related effects of prenatal administration of estrogen and progesterone receptor antagonists on VEGF and surfactant-proteins and on alveolarisation in the developing piglet lung

Background

Vascular endothelial growth factor (VEGF) is essential for embryonic lung development and has been shown to be regulated by estradiol (E2) and progesterone (P).

Aim

To investigate the effects of prenatal E2 and P withdrawal by specific receptor antagonists on the mRNA expression of VEGF, surfactant proteins (SP-B and SP-C) and on alveolarisation in lung tissue of male and female pig fetuses.

Methods

Fetuses from 10 sows were randomized to receive either both an intramuscular injection of the E2 receptor blocker ICI 182.780 and the P receptor blocker RTI 3021-022 (ICI + RTI, n = 5) or a placebo injection (n = 5) at 90 days of gestation (DOG, 115 = term). After delivery by cesarean section on 114 DOG, tissue of the left lingula of the piglet's lung (28 placebo, 26 ICI + RTI) was obtained to determine the mRNA expression of VEGF, SP-B and SP-C. Lungs from 15 placebo and 14 ICI + RTI group piglets were removed and alveolar counts performed.

Results

The ICI + RTI group showed significantly lower SP-C mRNA expression and alveolar counts compared to the placebo group (p = 0.04 and 0.03, respectively). Diminished alveolarisation in the ICI + RTI group was mainly due to the reduction of alveolar counts in male piglets (p = 0.02). Within the placebo group VEGF and SP-B mRNA expression in male piglets were significantly lower compared to female piglets (p = 0.01 and 0.004, respectively). ICI + RTI treatment abolished this gender-related difference.

Conclusion

Estradiol and P antagonism affected gender-related differences of key proteins for pulmonary function and development and especially in males was associated with diminished alveolarisation.     

Language skills, peer rejection, and the development of externalizing behavior from kindergarten to fourth grade

Background: Children with poorer language skills are more likely to show externalizing behavior problems, as well as to become rejected by their peers. Peer rejection has also been found to affect the development of externalizing behavior. This study explored the role of peer rejection in the link between language skills and the development of externalizing behavior. Methods: Six hundred and fifteen (615) children were followed from kindergarten to grade 4. Receptive language skills were measured with the Peabody Picture Vocabulary Test in grade 2. Teachers reported externalizing behavior and peer reports of social rejection were measured annually. Results: Children with poorer receptive language skills showed increasing externalizing behavior, while children with better receptive language skills showed decreases in externalizing behavior. Children with poorer receptive language skills experienced peer rejection most frequently. The link between receptive language skills and the development of externalizing behavior was mediated by the development of peer rejection. Findings suggested that this mediational link applied mostly to boys. Conclusion: Children with poorer language skills are at increased risk of becoming rejected by mainstream peers, which adds to the development of externalizing behavior.     

The effects of ionizing radiation, microwaves, and ultrasound on the developing embryo: clinical interpretations and applications of the data

The term "radiation" evokes emotional responses both from lay individuals and from professionals. Many spokespersons are unfamiliar with radiation biology or the quantitative nature of the risks. Frequently, microwave, ultrasound, and ionizing radiation risks are confused. Although it is impossible to prove no risk for any environmental hazard, it appears that exposure to microwave radiation below the maximal permissible levels present no measurable risk to the embryo. Ultrasound exposure from diagnostic ultrasonographic imaging equipment also is quite innocuous. It is true that continued surveillance and research into potential risks of these low-level exposures should continue, but at present ultrasound not only improves obstetric care but also reduces the necessity of diagnostic x-ray procedure. In the field of ionizing radiation, we have as good a comprehension of the biologic effects and the quantitative maximum risks as of any other environmental hazard. Although the animal and human data support the conclusion that no increases in the incidence of gross congenital malformations, intrauterine growth retardation, or abortion will occur with exposures below 5 rad, that does not mean that there are definitely no risks to the embryo exposed to lower doses of radiation. Whether there exists a linear or exponential dose-response relationship or a threshold exposure for genetic, carcinogenic, cell-depleting, and life-shortening effects has not been determined. In establishing maximum permissible levels for the embryo at low exposures, we use the information in Tables 2, 3, 4, 7, 10, and 14. It is obvious that the risks of 1-rad or 5-rad acute exposure are far below the spontaneous risks of the developing embryo, since 15% of human embryos abort, 2.7%-3.0% of human embryos have major malformations, 4% have intrauterine growth retardation, and 8%-10% have early- or late-onset genetic disease. The maximum risk attributed to a 1-rad exposure, approximately 0.003%, is thousands of times smaller than the spontaneous risks of malformations, abortion, or genetic disease (see Table 10). Thus, the present maximum permissible occupational exposures of 0.5 rem for pregnant women and 5 rem for medical exposure are extremely conservative. Medically indicated diagnostic roentgenograms are appropriate for pregnant women, and there is no medical justification for terminating a pregnancy in women exposed to 5 rad or less because of a radiation exposure.(ABSTRACT TRUNCATED AT 400 WORDS)