The effects of fetal exposure to danazol.

OBJECTIVE: To assess the consequences of exposure to danazol in utero. Additionally, by assessing the risk, to facilitate the counselling of pregnant women inadvertently exposed to danazol in early pregnancy. DESIGN: Retrospective review of reported case histories. SUBJECTS: 129 women exposed to danazol during pregnancy were identified from individual case reports, data from the Australian Drug Reactions Advisory Committee and the United States Food and Drug Administration and from the reports of danazol exposure made directly to the manufacturers. MAIN OUTCOME MEASURES: Teratogenic effects of fetal exposure to danazol in relation to dosage and duration of exposure. RESULTS: Of the 129 reported pregnancies, 12 miscarried and 23 were aborted. Of the 94 completed pregnancies, 37 resulted in the birth of normal males, 34 in non-virilized females and 23 in virilized females. Virilization occurred in a proportion of female fetuses with a pattern of cliteromegaly, fused labia and urogenital sinus formation. Surgery to the genital tract was usually, but not always, required in childhood. The abnormality has not been reported where danazol therapy had been discontinued before the 8th week of pregnancy. Although more common in the higher dosages, virilization was reported in one case with a 200 mg daily dosage. CONCLUSIONS: Danazol should remain contraindicated in pregnancy and clinicians should give careful contraceptive advice to patients commencing or continuing danazol therapy. Nonetheless it is possible to be cautiously optimistic about the outcome of danazol-exposed pregnancies, particularly if treatment is discontinued before 8 completed weeks gestation.     

Placental and fetal effects of antenatal exposure to antidepressants or untreated maternal depression

Objective: To assess systematically the effects of antidepressants and untreated maternal depression on human placenta and the developing fetus.

Methods: Pertinent medical literature information was identified using MEDLINE/PubMed, SCOPUS and EMBASE. Electronic searches, limited to human studies published in English, provided 21 studies reporting primary data on placental and fetal effects of antidepressant exposure or untreated gestational depression.

Results: The impact of antidepressants and non-medicated maternal depression on placental functioning and fetal biochemical architecture seems to be demonstrated, although its clinical significance remains unclear. More robust data seem to indicate that exposure to either antidepressants or untreated maternal depression may induce epigenetic changes and interfere with the physiological fetal behavior. Two cases of iatrogenic fetal tachyarrhythmia have also been reported.

Conclusions: Future research should clarify the clinical relevance of the impact of antidepressant and untreated maternal depression exposure on placental functioning. Moreover, ultrasound studies investigating fetal responses to antidepressants or maternal depressive symptoms are mandatory. This assessment should be performed during the whole duration of gestational period, when different fetal behavioral patterns become progressively detectable. Analyses of biochemical and epigenetic modifications associated with maternal mood symptoms and antidepressant treatment should also be implemented.     

Maternal dietary substrates and human fetal biophysical activity. I. The effects of tryptophan and glucose on fetal breathing movements

To study the effects of L-tryptophan and glucose on fetal breathing activity, we examined 40 women with normal term pregnancies, randomly assigned to four equal groups who either continued fasting (group C), received 1 gm of oral tryptophan (group T), received 100 gm of oral glucose (group G), or received both substrates (group T + G). Studies lasted 210 minutes, during which fetal breathing movements were observed with real-time ultrasonography and entered and analyzed for incidence, rate, and variability on a microcomputer. Plasma glucose and tryptophan levels were determined every 30 minutes. The incidence of fetal breathing movements declined in group C and rose significantly in the other groups. Breathing rates were unchanged in groups C and T but rose significantly in groups G and T + G during peak breathing intervals. Breath interval variability did not change significantly in any study group. Maternal administration of tryptophan is associated with an alteration in fetal breathing activity but to a lesser degree than that observed after maternal glucose loading.     

A safe strategy to decrease fetal lead exposure in a woman with chronic intoxication

Abstract

During pregnancy skeletal lead is mobilized by maternal bone turnover and can threaten fetal development. The exact strategy suggested to women of childbearing age, who were chronically exposed to lead, and, thus, have high bone lead burden, is not well established. We describe 4 years of follow-up of a 29-year-old woman with chronic lead intoxication. We (a) advised her to delay conception until ‘toxicological clearance’, (b) treated her with multiple courses of lead chelator, DMSA, and (c) prescribed oral calcium. Patient had low blood lead and protoporphyrin level during pregnancy until delivery. Delaying conception, lead chelation, and calcium supplementation can decrease fetal exposure.     

Effect of maternal glucose load on fetal activity.

The effect of a MGL upon fetal activity has been studied in 39 normal and 54 high-risk pregnant patients between 30 and 42 weeks' gestation. The perinatal morbidity and mortality rates were significantly lower in the group showing an increase in fetal activity following a MGL. It is suggested that this may be useful for identifying the fetus at risk.     

The effects of nicotine on the synthesis and secretion of surfactant in the rabbit fetal lung

The effects of nicotine administration on the synthesis and secretion of surfactant in the rabbit fetal lung were studied by measuring phosphatidylcholine (PC) and phosphatidylglycerol (PG) in the fetal lung tissue and amniotic fluid. The concentrations of both PC and PG in the lung tissue were decreased by administering nicotine to the mother. On the other hand, the concentrations of PC and PG in the amnniotic fluid were not altered by nicotine administration. Moreover, the PG/PC ratio in the amniotic fluid of the nicotine group was similar to that of the control group. The plasma catecholamine levels were elevated in the growth retarded fetuses from nicotine-treated mothers. These findings indicated that the administration of nicotine to the mother suppressed the synthesis of surfactant in the fetal lung but enhanced the secretion of surfactant to the alveolar cavity, probably via the stimulation of beta-receptor by catecholamine, and that the biochemical maturity of the surfactant was not altered by the administration of nicotine to the mother. The results of the present study might provide basic information to help to understand the clinical experiences reported by others i.e. that in the newborn from a smoking mother, respiratory distress occurred less frequently than in those from non-smokers.     

大气颗粒物暴露对小鼠妊娠和胚胎发育的影响

目的 探讨大气颗粒物(PM)亚急性暴露对小鼠妊娠和胚胎发育的影响.方法选择雌、雄小鼠各40只按1∶1合笼,将妊娠的雌鼠随机分为对照(A组)、小剂量PM暴露(B组)、中剂量PM暴露(C组)、大剂量PM暴露(D组)、超大剂量PM暴露(E组),每组8～11只.从妊娠0～19 d分别向A组小鼠咽后壁接种磷酸盐缓冲液,向B、C、D、E组小鼠咽后壁接种PM标准品SRM1649a混悬液(浓度分别为0.09、0.52、1.85、69.2μg/μl).于自动分娩发生时剖宫取胎,观察孕鼠体质量、妊娠天数、仔鼠宫内存活及生长情况和肝、肺组织的病理改变,计算仔鼠肺及肝脏体系数,检测仔鼠肺CYP1A1、肝CYP1A2蛋白及mRNA的表达.结果 (1)各组孕鼠均未出现自然死亡.各组孕鼠妊娠1、7 d时体质量比较,差异均无统计学意义(P＞0.05);妊娠至14、18 d时,E组孕鼠体质量[分别为(41.8±5.8)及(48.9±8.9)g]明显低于A组[分别为(45.9±1.8)及(56.2±4.9)g],差异均有统计学意义(P＜0.05).E组孕鼠妊娠天数[(19.3±1.3)d]也明显低于A组[(20.5±0.7)d],差异有统计学意义(P＜0.05);A、B、C、D组孕鼠间妊娠天数分别比较,差异均无统计学意义(P＞0.05).各组仔鼠肺体系数及肝体系数比较,E组孕鼠[(1.21±0.18)及(4.68±0.21)%]高于A、B、C及D组,且差异均有统计学意义(P＜0.05).(2)E组仔鼠的死亡率(23.0%)高于A(0.8%)、B(0.9%)、C(1.7%)及D组(3.7%),差异均有统计学意义(P＜0.05);A、B、C、D组仔鼠的死亡率依次升高,但差异无统计学意义(P＞0.05).(3)E组仔鼠肝、肺病理改变显著,肝脏特征性病理改变包括肝组织结构紊乱、肝细胞浊肿、胞质淡染;多数肝细胞胞质内出现脂肪变性,部分肝细胞固缩,胞质深染;肝组织内见炎细胞浸润和点灶状坏死.肺特征性病理改变包括肺细支气管管腔变窄、黏膜下层小血管充血;间质、肺泡水肿,肺泡间隔增厚,泡内、细支气管周中性粒细胞及淋巴细胞浸润.C、D组上述病变程度次之,A、B组正常或变化轻微.(4)E组仔鼠肺CYP1A1和肝CYP1A2蛋白表达水平(分别为1.20±0.40及2.55±0.89)高于A组(0.77±0.36及2.08±0.31),两组比较,差异有统计学意义(P＜0.05).肺CYP1A1 mRNA表达,C(0.36±0.12)、D(0.41±0.08)、E组(0.43±0.11)高于A组(0.21±0.10),D、E组高于B组(0.28±0.10),分别比较,差异均有统计学意义(P＜0.05).肝CYP1A2 mRNA表达,C(0.37±0.13)、D(0.36±0.14)、E组(0.43±0.16)高于A组(0.21±0.03),E组高于B组(0.24±0.11),分别比较,差异均有统计学意义(P＜0.05).结论 PM具有胚胎毒性作用.超大剂量PM亚急性暴露可导致小鼠的不良妊娠结局;中、高剂量PM暴露可导致癌相关基因CYP1 A1和CYP1 A2表达的上调,可能对个体的后期发育有潜在的不良效应.

Abstract：

Objective To investigate subacute exposure of airborne particulate matter (PM) on pregnancy and fetal development in female mice. Methods Forty female and forty male ICR adult mice group (A), small (B) , middle (C) , large (D) or overdose (E) PM challenge groups (n = 8 - 11), and were administered with 30 μl of phosphate buffered solution (A) or resuspended standard PM SRM 1649a at 0.09 (B), 0.52 (C), 1.85 (D) or 69.2 (E) μg/μl, once per trid from d 0 till d 19 of pregnancy via instillation onto the base of the tongue. Fetal mice were harvested by cesarean section at the time when spontaneous delivery occurred. Body weight of the pregnant mice, gestational days, intrauterine survival and growth, hepatic and pneumonic histopathological changes of the fetal mice were investigated. Lung/body and liver/body weight ratios were calculated. Expressions of mRNA and protein of CYP1A1 in the fetal lung and CYP1 A2 in the fetal liver were assayed. Results (1) All of the pregnant mice survived pregnancy throughout the entire experiment. Body weight of the pregnant mice was not significantly different among all the groups at gestational d 1 and 7 (P ＞ 0.05), but significantly lower in group E [(41.8 ± 5.8) and (48.9 ± 8.9) g] than in group A [(45.9 ± 1.8) and (56.2 ± 4.9) g] at gestational d 14 and 18 (P ＜0.05). The gestational days were significantly decreased in group E [(19.3 ± 1.3) d] when compared with group A [(20.5 ± 0.7) d; P ＜ 0.05] and were not significantly different among groups A, B, C and D (P ＞ 0.05). Lung/body and liver/body weight ratios of the fetal mice were significantly increased in group E [(1.21 ±0.18) and (4.68 ±0.21)%] as compared with groups A, B, C and D (P＜0.05). (2)Mortality rates of the fetuses were significantly higher in group E (23.0%) than in groups A (0.8%), B (0.9%), C (1.7%) and D (3.7%) (P ＜ 0.05), but were not significantly different among groups A,B, C and D (P ＞ 0.05) despite of an increasing tendency. (3) Pathological changes in the liver and lung of the fetuses were conspicuous in group E. The fetal liver injury was histopathologically evidenced by deranged tissue structure, degenerated parenchyma of hepatic cells, and mildly stained cytoplasm. Adipose degeneration was represented by clear-boundary intracytoplasmic vacuoles in most of the liver cells, and cell pyknosis with heavily stained cytoplasm was observed in some of the liver cells. Inflammatory cell infiltration and focal necrosis were occasionally found in the hepatic tissue. The fetal lung exhibited bronchiole with narrow lumina, vascular engorgement in the submucosal layer, interstitial and alveolar edema, thickened alveolar septum, granulocyte and lymphocyte infiltrations within the pulmonary alveoli and around the bronchioles. The above pathological changes were lesser in groups C and D, and were not or least found in groups A and B. (4) Protein expressions of CYP1A1 in the fetal lung and CYP1A2 in the fetal liver were significantly increased in group E (1.20 ± 0.40 and 2.55 ± 0.89) when compared with group A (0.77 ±0.36 and 2.08 ±0.31) (P ＜ 0.05). mRNA expressions of CYP1A1 in the fetal lung were significantly increased in groups C (0.36 ±0.12), D (0.41 ±0.08) and E (0.43 ±0.11) compared with group A (0.21 ±0.10), and significantly increased in groups D and E compared with group B (0.28 ±0.10,P＜0.05). mRNA expressions of CYP1 A2 in the fetal liver were significantly increased in groups C (0.37 ±0.13), D (0.36 ±0.14) and E (0.43 ±0.16) compared with group A (0.21 ±0.03), and significantly increased in group E compared with group B (0.24± 0.11, P ＜ 0.05). Conclusions PM elicited embryotoxigenicity and resulted in adverse pregnancy outcomes in mice by intrauterine exposure of overdose PM. The expressions of cancer-related genes CYP1A1 and CYP1A2 were up-regulated in organs after the middle- and large-dose subacute exposure of PM, which may have a potential role on the future development.     

The effects of hydrocortisone on the development of the amine systems in the fetal brain.

Human and animal studies suggest impaired central nervous system (CNS) development due to corticoid use in the perinatal period. In this study, hydrocortisone was given to pregnant rats and the development of the fetal dopamine (DA) and norepinephrine (NE) systems in the CNS was investigated. In the fetal rat brain DA and NE systems develop between days 12 and 17 of gestation. Hydrocortisone (HC), 57 mg/kg/day, or saline (SAL) was given intraperitoneally at day 12 or 15 of gestation. The offspring were studied at days 20 to 21 of gestation and days 12 to 13 in the neonatal period. Brain amine systems were visualized using a modified cryostat glyoxylic acid histofluorescence method, and DA and NE levels were determined in whole brains by means of a radioenzymatic assay. The visualized amine systems were evaluated semiquantitatively for distribution and fluorescence intensity without previous knowledge of the administered drug. The amine systems of the HC and SAL groups showed an equal maturation. In both groups cell bodies were demonstrable in areas A1 to A13 and axon terminals in all examined final regions. The distribution and the fluorescence intensity did not show consistent differences for the HC and SAL brains. The concentrations of DA and NE were similar in the offspring of the SAL- and HC-treated animals. The results indicate that HC given during pregnancy does not influence the proliferation of amine cell bodies or the arrival of axon terminals in the regions where the synapses form.     

The effects of embryonic and fetal exposure to x-ray, microwaves, and ultrasound

The term radiation evokes emotional responses both from lay persons 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 procedures. 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 less than 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, refer to Tables 4, 5, 6, 8, and 9. It is obvious that the risks of 1-rad or 5-rad acute exposure are far below the spontaneous risks of the developing embryo because 15 per cent of human embryos abort, 2.7 to 3.0 per cent of human embryos have major malformations, 4 per cent have intrauterine growth retardation, and 8 to 10 per cent have early- or late-onset genetic disease. The maximal risk attributed to a 1-rad exposure, approximately 0.003 per cent, is thousands of times smaller than the spontaneous risks of malformations, abortion, or genetic disease. Thus, the present maximal permissible occupational exposures of 0.5 rem for pregnant women (see Table 10) 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)     

环境因素对胚胎发育各阶段的影响

近年来 ,随着工业的发展和环境污染日趋严重 ,先天性畸形的发生率有逐渐上升的趋势。环境因素所导致的胎儿畸形越来越受到重视。1　胚胎对致畸因子的易感性在所有先天畸形个体中 ,单纯由遗传因素或环境因素引起的畸形是少数的 ,多数畸形是两者相互作用的结果。胚胎的基因型决定并影响胚胎对环境中致畸因子的易感程度 ;环境致畸因子也可通过引起染色体畸变或基因突变而引起胚胎畸形。这种易感性在种间或个体间有明显的差异[1 ] 。在进行流行病学的调查中发现 ,在同样条件下 ,同时怀孕的孕妇在同一次风疹的流行中都受到了感染 ,但其所生新生儿…     

Ovine fetal breathing and swallowing activity in response to plasma glucose changes.

Fetal swallowing activity generally occurs simultaneously with fetal breathing movements (FBM) in sheep. The present study investigated the FBM and swallowing responses to altered fetal plasma glucose. Fetal lambs were chronically prepared with laryngeal, esophageal and diaphragm electromyogram (EMG) wires, an esophageal flow probe and vascular catheters. Beginning at 138 +/- 1 day, FBM and swallowing were monitored during control periods and in response to intravenous glucose infusions (14 mg/kg/min for 120 min) to fetuses of fed and fasted ewes. Glucose infusions to fetuses of fed ewes resulted in significant increases in fetal plasma glucose (21.2 +/- 0.7 to 40.5 +/- 1.9 mg/dl) and time breathing (46.2 +/- 6.3 to 60.0 +/- 9.5 min/2 h). In response to maternal fasting, fetal glucose levels (13.4 +/- 1.0 mg/dl) and time breathing (23.0 +/- 7.2 min/2 h) decreased significantly. Glucose infusion to fetuses of fasted ewes resulted in significant increases in time breathing (50.3 +/- 13.4 min/2 h) and diaphragmatic EMG activity (1,295 +/- 654 to 3,012 +/- 1,182 spikes/2 h). There was no change from basal levels of fetal EMG swallows (83.2 +/- 4.3 swallows/2 h) or esophageal flow (40.8 +/- 7.9 ml/2 h) in response to maternal fasting or fetal glucose infusions.     

Effect of fetal dexamethasone exposure on the development of adult insulin sensitivity in a rat model

Objective. A rat model was designed to determine if fetal dexamethasone exposure is associated with decreased insulin sensitivity in adulthood, manifested as decreased binding of p85 to phosphorylated insulin receptor substrate-1 (IRS-1) within the phosphatidylinositol 3-kinase (PI 3-kinase) pathway of insulin signaling. Additionally, the study investigated whether a differential effect exists in male and female rodent offspring, such that females demonstrate decreased binding of p85 to IRS-1 after exposure to dexamethasone in utero.

Methods. Timed-pregnant Sprague-Dawley rats received either tap water or dexamethasone in drinking water from day 13 of gestation until delivery. Fasting male and female offspring from each group were sacrificed on day 50 of life, and half of these rats were given insulin subcutaneously prior to sacrifice. Adipocyte, skeletal muscle, and liver cell lysates were analyzed by immunoprecipitation and Western blotting of IRS-1 and IRS-1-associated p85.

Results. In all tissues examined, a significant inverse relationship was found between dexamethasone treatment in utero and association of p85 with IRS-1 in adulthood. p85 association with IRS-1 was similar in tissues from fasting and insulin-stimulated states. Furthermore, tissues of male and female rats demonstrated similar binding of p85 to IRS-1.

Conclusions. In a rat model, fetal exposure to dexamethasone was associated with decreased insulin signaling at the level of p85 binding to IRS-1, a proximal step in insulin signaling within the PI 3-kinase pathway. This effect did not appear to be enhanced by administration of insulin prior to sacrifice, nor was a sex-dependent differential effect noted.     

The effects of isoproterenol on fetal oxygenation.

Infusion of isoproterenol (1 microgram/kg/min, i.v.) into the anesthetized pregnant rhesus monkey near term consistently reduced fetal oxygenation, despite diminishing myometrial activity. The decline in pO2 of fetal arterial blood (mean = 4.3 +/- 2.3 mmHg S.D.) was accompanied by an increase in pCO2 tension (mean = 4.6 +/- 2.7 mmHg) and a decline in pH (mean = 0.04 +/- 0.02 S.D.). There was an increase in heart rate and a widening of pulse pressure in the mother and also in the adequately oxygenated fetus providing evidence that the agent crosses the placenta. The poorly oxygenated fetuses developed bradycardia and hypotension. Administration of isoproterenol directly to the fetus elicited similar changes in the composition of blood, and in blood pressure and heart rate, to those observed after administration of the agent to the mother.