Short-term in vivo exposure to the water contaminant triclosan: Evidence for disruption of thyroxine

Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) is a chlorinated phenolic antibacterial compound found as an active ingredient in many personal care and household products. The structural similarity of triclosan to thyroid hormones and recent studies demonstrating activation of the human pregnane X receptor (PXR) and inhibition of diiodothyronine (T(2)) sulfotransferases, have raised concerns about adverse effects on thyroid homeostasis. The current research tested the hypothesis that triclosan alters circulating concentrations of thyroxine. The hypothesis was tested using a 4-day oral triclosan exposure (0-1000mg/kg/day) in weanling female Long-Evans rats, followed by measurement of circulating levels of serum total thyroxine (T(4)). Dose-dependent decreases in total T(4) were observed. The benchmark dose (BMD) and lower bound on the BMD (BMDL) for the effects on T(4) were 69.7 and 35.6mg/kg/day, respectively. These data demonstrate that triclosan disrupts thyroid hormone homeostasis in rats.     

Altered maternal thyroid function: fetal and neonatal development of rat

Influence of maternal thyroid status on fetal and neonatal development of rats has been studied. Maternal hypothyroidism resulted impaired reproduction and intrauterine growth retardation of offsprings as revealed by their reduced body weight, heart weight, body length and tail length. Offsprings born to hypothyroid mothers showed very high rate of mortality and none of them survived beyond eight days. Maternal hyperthyroidism did not cause any abnormality on reproduction. Hyperthyroid mothers showed increased rate in body weight gain during pregnancy which was associated with increased weight of body and heart of fetuses born to hyperthyroid mothers. Plasma thyroxine was not measurable in fetus from hypothyroid mothers till 21st day of gestation. The results of the present study showed that maternal thyroid status plays an important role in fetal and neonatal growth and development.     

Developmental neurotoxicity of organophosphorous pesticides: fetal and neonatal exposure to chlorpyrifos alters sex-specific behaviors at adulthood in mice.

Developmental exposure to the organophosphorous insecticide chlorpyrifos (CPF) induces long-term effects on brain and behavior in laboratory rodents. We evaluated in adult mice the behavioral effects of either fetal and/or neonatal CPF exposure at doses not inhibiting fetal and neonatal brain cholinesterase. CPF (3 or 6 mg/kg) was given by oral treatment to pregnant females on gestational days 15-18 and offspring were treated sc (1 or 3 mg/kg) on postnatal days (PNDs) 11-14. Serum and brain acetylcholinesterase (AChE) activity was evaluated at birth and 24 h from termination of postnatal treatments. On PND 70, male mice were assessed for spontaneous motor activity in an open-field test and in a socioagonistic encounter with an unfamiliar conspecific. Virgin females underwent a maternal induction test following presentation of foster pups. Both sexes were subjected to a plus-maze test to evaluate exploration and anxiety levels. Gestational and postnatal CPF exposure (higher doses) affected motor activity in the open field and enhanced synergically agonistic behavior. Postnatal CPF exposure increased maternal responsiveness toward pups in females. Mice of both sexes exposed to postnatal CPF showed reduced anxiety response in the plus-maze, an effect greater in females. Altogether, developmental exposure to CPF at doses that do not cause brain AChE inhibition induces long-term alterations in sex-specific behavior patterns of the mouse species. Late neonatal exposure on PNDs 11-14 was the most effective in causing behavioral changes. These findings support the hypothesis that developmental CPF may represent a risk factor for increased vulnerability to neurodevelopmental disorders in humans.     

Developmental exposure to fenproporex: reproductive and morphological evaluation

This study was designed to evaluate the maternal toxicity and teratogenicity of fenproporex, one of the most widely-used anorectic drugs in many countries, including Brazil. Three periods of exposure were evaluated: (a) 30 days before mating; (b) from gestational day (GD) 0 to 14; and (c) 30 days before mating and during pregnancy, until GD 14. Female mice from experimental groups received, by gavage, 15 mg/kg of fenproporex. Treatment with fenproporex increased ambulation of dams in the open-field test and did not influence the mobility in the forced-swimming test. There was no significant difference in maternal weight gain between the controls and fenproporex-treated groups, although fenproporex treatment reduced the gravid uterus weight. No significant difference was observed in postimplantation loss, fetal viability and sex ratio. In addition, this compound did not impair intra-uterine growth. The reduction in the number of implantations in the groups receiving fenproporex indicates that this drug may have an adverse effect on implantation. Fenproporex treatment also increased the number of fetuses presenting small kidneys and cervical ribs. The present results indicate that fenproporex, in the dose and exposure periods tested, appears to exhibit a low maternal toxicity and teratogenic potential in mice.     

Cocaine detection in maternal and neonatal hair: implications to fetal toxicology

Cocaine use during pregnancy is difficult to ascertain, and maternal reports are likely to be inaccurate. Presently, the dose-response characteristics between maternal cocaine use and fetal exposure and adverse effects are unknown. Clinically, some babies are harmed, whereas others are not adversely affected. Taking advantage of the fact that cocaine and its metabolite benzoylecgonine (BE) accumulate and can be detected months after exposure in maternal and neonatal hair, an analytical test for cocaine and BE was developed by the authors. The aim of this study was to describe the characteristics of maternal and neonatal hair cocaine as biomarkers of fetal exposure. Of nearly 10,000 cases, all mother-child pairs in whom at least one had cocaine and/or BE detected in hair were identified. The relationship between maternal and neonatal levels was studied. When available, these data were also compared with meconium levels of cocaine. Median cocaine concentration was 10-fold higher in hair of the mothers compared with the neonates (3.56 ng/mg vs 0.31 ng/mg of hair). Infants' cocaine in hair was positively correlated with maternal cocaine and BE in hair (r2 = 0.41 and r2 = 0.22, respectively, P < 0.001 for both correlations). Infants' BE was also correlated with maternal cocaine and BE concentrations in hair (r2 = 0.50 and r2 = 0.27, P < 0.001 for both correlations). Thirty-nine (40%) babies had negative cocaine and BE results despite their mothers being positive. Mothers whose infants were cocaine-positive had a median hair cocaine concentration of 7.34 ng/mg, significantly higher than those whose infants were negative (1.25 ng/mg). Maternal cocaine levels below 0.24 ng/mg may serve as a relative threshold for detectable fetal exposure during the third trimester of pregnancy. Fetal hair grows in the last trimester. Hence, a positive neonatal hair indicates maternal use after pregnancy became known, a strong indicator of maternal addiction. Transplacental exposure to cocaine of babies of addicted mothers is highly variable. The dose-response relationship of both cocaine and BE between maternal and neonatal hair suggests that the placenta protects some fetuses but not others. More research is needed to understand the mechanisms leading to placental defense against cocaine.     

Partition of metals in the maternal/fetal unit and lead-associated decreases of fetal iron and manganese: an observational biomonitoring approach

To systematically study the partition of environmental metals including lead, mercury, and cadmium and essential minerals such as iron, manganese, copper, and zinc in the maternal/fetal unit of healthy pregnant women, we analyzed blood and umbilical cord blood samples of 50 healthy mother/child pairs using a biomonitoring approach. The levels of essential minerals in healthy pregnant women were significantly different from those of the general population. The partition of essential minerals and environmental metals and their associations between maternal and umbilical cord blood were metal-specific. Lead entered the fetal environment nearly unaffected. The median fetal level was only 10?% lower than the corresponding maternal concentration (10.3 vs. 11.5?μg/l, P?=?0.0038). Mercury accumulated in the fetal unit resulting in more than a threefold increase in fetal compared to maternal exposure (1.48 vs. 0.44?μg/l, P?相似文献   

Course of pregnancy and fetal outcome following maternal exposure to carbamazepine and phenytoin: a prospective study.

This prospective study followed the pregnancy course of epileptic women at the Motherisk Program of The Hospital for Sick Children, Toronto. We compared fetal outcome of women treated with carbamazepine (CBZ), those treated with diphenylhydantoin (phenytoin, DPH), and a drug-free control group. Seizures were reported in 15 pregnancies; in a subgroup of 9 women without change in drug or schedule, an increase in seizure frequency was evident in 6, a decrease in 1, and no change in 2, regardless of the drug taken. Of 23 children exposed to CBZ in utero, one was born with a lumbar myelomeningocele and multiple congenital anomalies. Of 21 children exposed to DPH, there was one case of severe developmental delay and four with minor features of fetal hydantoin syndromes (FHS). The three groups did not differ in birth weights or gestational ages of the babies. Although much more experience is needed, as a result of this study and other similar reports, Motherisk now offers women treated with CBZ diagnostic tests to detect neural tube defects during the second trimester of pregnancy.     

Chronic cadmium exposure during pregnancy in the mouse: influence of exposure levels on fetal and maternal uptake

The uptake and distribution of orally administered cadmium-109 was studied in pregnant mice. Female outbred QS mice were given cadmium (Cd) supplemented drinking water for 1 mo before pregnancy and for the duration of pregnancy. The water contained either 0.0015 ppm Cd, 0.24 ppm Cd, or 40 ppm Cd. For the duration of pregnancy, 1.48 micrograms Cd/l (0.0015 ppm) in each solution was in the form of 109Cd (1 mCi/l). Control mice were given distilled/deionized water. On the day before term the mice were killed and a variety of adult and fetal tissues were examined in a gamma counter to determine their 109Cd concentrations. For each group the 109Cd concentration was highest in the maternal gastrointestinal tract, liver, and kidneys and lowest in the central nervous system (CNS) and blood. In general, the 109Cd concentrations in each organ were similar for each group of mice and were therefore independent of the overall oral Cd dose. A notable exception was the lower level in the duodenum in the 40 ppm group. In the fetal unit the chorioallantoic placenta contained the highest concentration of 109Cd. Concentrations in the fetuses were very low, comparable to those in the adult CNS. The 109Cd levels in the fetuses from group A were about fivefold greater than those of the fetuses from group C. There was no statistically significant evidence of specific localization in the fetal brain, kidney, or liver.     

Maternal exposure to triclosan causes fetal development restriction,deregulation of the oestrous cycle,and alters uterine tissue in rat offspring

The aim of the present study was to evaluate the effects of maternal exposure to triclosan (TCS) during pregnancy and lactation on the uterine morphology of rat offspring. For this, 32 Wistar rat dams were distributed into four dose groups (eight mothers per group), and gavage daily, throughout pregnancy and lactation, as follows: Group I–control (GI): corn oil; Group II (GII): TCS diluted in corn oil at a dose of 75 mg/kg/d; Group III (GIII): TCS diluted in corn oil at a dose of 150 mg/kg/d; Group IV (GIV): TCS diluted in corn oil at a dose of 300 mg/kg/d. A female pup of each mother was selected, and at 90 days the pups were euthanized for weighing and collection of the uterus for histomorphometric analysis. The results showed that the mean litter weight was minor in all the groups treated with TCS, when compared with control. The levels thyroid hormones thyroxine (T4) and triiodothyronine (T3) in TCS mother rats were reduced; however the levels of thyroid stimulating hormone (TSH) were increases. The offspring of all groups exposed to TCS presented deregulation of the estrous cycle, compared with control. Analysis of the uterine histological structure demonstrated that all layers of the uterus were affected by the administration of TCS, and the morphometric analysis showed increased uterine layers thickness in the treated groups. We concluded that maternal exposure to TCS during pregnancy and lactation causes intrauterine development restriction, deregulation of the oestrous cycle, and alters uterine tissue in rat offspring.     

A polypeptide drug carrier for maternal delivery and prevention of fetal exposure

Abstract

Background: Pregnant females are largely overlooked in drug development due to concerns for fetal health. Additionally, pregnancy is often an exclusion criterion in clinical trials, so the safety of many drugs during pregnancy is unknown.

Purpose: The goal of this study was to evaluate Elastin-like Polypeptide (ELP), a synthetic protein derived from human elastin, for maternally sequestered drug delivery. ELP is a versatile drug carrier with a long plasma half-life, low immunogenicity, and the ability to be fused to nearly any small molecule or protein-based therapeutic.

Methods: We determined the pharmacokinetics, biodistribution, and fetal exposure to the ELP drug carrier using quantitative fluorescence techniques in a rat pregnancy model.

Results: After either bolus IV administration or continuous infusion over five days, ELPs accumulated strongly in the kidneys, liver, and placenta, but importantly, little to no ELPs were detectable in the fetus. Within the placenta, ELPs were localized to the chorionic plate and broadly distributed within the labyrinth, but were excluded from the fetal portion of the chorionic villi.

Conclusion: These data indicate that ELP does not cross the placenta, and they suggest that this adaptable drug delivery system is a promising platform for prevention of fetal drug exposure.     

Chronic ethanol exposure and folic acid supplementation: fetal growth and folate status in the maternal and fetal guinea pig

Chronic ethanol exposure (CEE) can produce developmental abnormalities in the CNS of the embryo and developing fetus. Folic acid (FA) is an important nutrient during pregnancy and low folate status exacerbates ethanol-induced teratogenicity. This study tested the hypotheses that (1) CEE depletes folate stores in the mother and fetus; and (2) maternal FA supplementation maintains folate stores. CEE decreased fetal body, brain, hippocampus weights, and brain to body weight ratio but not hippocampus to body weight ratio. These effects of CEE were not mitigated by maternal FA administration. The FA regimen prevented the CEE-induced decrease of term fetal liver folate. However, it did not affect maternal liver folate or fetal RBC folate at term, and did not mitigate the nutritional deficit-induced decrease of term fetal hippocampus folate. This study suggests that maternal FA supplementation may have differential effects on folate status in the mother and the fetus.     

Preeclampsia: a couple's disease with maternal and fetal manifestations

Preeclampsia still ranks as one of obstetrics major problems. Clinicians typically encounter preeclampsia as maternal disease with variable degrees of fetal involvement. More and more the unique immunogenetic maternal-paternal relationship is appreciated, and as such also the specific 'genetic conflict' that is characteristic of haemochorial placentation. From that perspective preeclampsia can also been seen as a disease of an individual couple with primarily maternal and fetal manifestations. Factors that are unique to a specific couple would include the length and type of sexual relationship, the maternal (decidual natural killer cells) acceptation of the invading cytotrophoblast (paternal HLA-C), and seminal levels of transforming growth factor-beta and probably other cytokines. The magnitude of the maternal response would be determined by factors including a maternal set of genes determining her characteristic inflammatory responsiveness, age, quality of her endothelium, obesity/insulin resistance and probably a whole series of susceptibility genes amongst which the thrombophilias received a lot of attention in recent years.     

Does chronic prenatal methadone exposure affect beta-receptor subtypes in placental, fetal and maternal brain homogenates?

Computer competition analysis of 3H-DHA (3H-dihydroalprenolol, a nonselective beta-adrenergic radioligand) binding in the presence of unlabeled metoprolol (a beta 1-selective antagonist) indicates the existence of both beta 1- and beta 2-adrenergic receptor subtypes in the rat placenta and confirms previous reports that both beta-adrenoceptors are present in adult rat cortex. In the fetal brain (20th day of gestation), however, only beta 1-receptors were detected. Pregnant rats were chronically exposed to methadone from day 7 to day 20 of gestation via implanted osmotic minipumps (6.3-9.0 mg/kg/day). This treatment schedule did not induce a change in the affinity and density of either beta-receptor subtype in the placental, fetal and maternal brain homogenates. The results are discussed in terms of the reported monoaminergic and opiate receptor functional interactions.     

Chronic antiepileptic drug therapy: classification by medication regimen and incidence of decreases in serum thyroxine and free thyroxine index

Results are described on the association of decreased serum total thyroxine (T4) and free thyroxine index (FTI) with antiepileptic drug therapy in a group of randomly selected chronically medicated outpatients (n = 291). For monotherapy subgroups (n = 164), the highest incidence (T4, 23.9%; FTI, 25.4%) of below normal values occurred in patients medicated with carbamazepine (CBZ), followed by phenytoin [(PHT) T4, 13.2%; FTI, 7.9%], and phenobarbital [(PB) (T4, 3.4%; FTI, 0%]. No T4 and FTI values below normal were detected in any patients (n = 30) on chronic valproic acid (VPA) monotherapy. For CBZ monotherapy (n = 67), women (n = 37) had a higher frequency of below normal values of T4 (p less than 0.05) and FTI (p less than 0.001) than men (n = 30). Therefore, the order of decreasing T4 and FTI effect was as follows: CBZ (women) greater than CBZ (men) greater than PHT greater than PB greater than VPA. For polytherapy subgroups (n = 127), the highest incidence (T4, 51.9%; FTI, 48.1%) was found in patients medicated with PHT and CBZ, followed by PHT and VPA (T4, 37.0%; FTI, 23.9%), and PHT and PB (T4, 17.2%; FTI, 10.3%). For PHT and CBZ poly-therapy (n = 52), women (n = 21) had a higher frequency of below normal values of T4 (p less than 0.05) and FTI (p less than 0.001) than men (n = 31). The magnitude of the decreasing T4 and FTI effect was greater for polytherapy subgroups (versus monotherapy subgroups) and in order as follows: PHT + CBZ (women) greater than PHT + CB (men) greater than PHT + VPA greater than PHT + PB.(ABSTRACT TRUNCATED AT 250 WORDS)     

新生儿黄疸动态监测及早期干预治疗疗效观察

目的 评价新生儿黄疸动态监测的意义及早期不同干预治疗的临床疗效。方法 对新生儿进行早期黄疸动态监测, 将动态监测中发现胆红素超标的患儿随机分成蓝光治疗组、蓝光辅助茵栀黄治疗组、蓝光辅助妈咪爱(枯草杆菌二联活菌)治疗组和对照组, 通过比较各组胆红素脑损伤的发生率及胆红素值的下降程度, 客观评定新生儿早期黄疸监测的临床意义及不同干预治疗的临床疗效。结果 治疗组黄疸峰值、高胆红素血症的发生率明显低于对照组, 差异有统计学意义(P<0.05)。与单一蓝光治疗相比, 蓝光治疗辅助茵栀黄或妈咪爱均能更有效降低胆红素值。结论 动态监测黄疸可尽早发现胆红素水平的异常, 为尽早干预治疗提供了保障。早期联合治疗能更有效降低胆红素, 有效预防新生儿胆红素脑损伤的发生。     

The perinatal effects of maternal caffeine intake on fetal and neonatal brain levels of testosterone,estradiol, and dihydrotestosterone in rats

Naunyn-Schmiedeberg's Archives of Pharmacology - Testosterone, estradiol, and dihydrotestosterone are the main sex steroid hormones responsible for the organization and sexual differentiation...     

Participation of maternal and fetal CRH in early phases of human implantation: the role of antalarmin

The hypothalamic neuropeptide corticotropin-releasing hormone (CRH) is produced by several tissues of the female reproductive system. It is also secreted at inflammatory sites and possesses potent pro-inflammatory properties influencing both innate and acquired immune processes. Uterine CRH participates in local immune early pregnancy phenomena, such as decidualization of endometrial strom a and protection of the fetus from maternal immune system. This is maintained through induction of the expression of apoptotic FasL on invasive extravillous trophoblast and maternal decidual cells at the fetal-maternal interface. Furthermore, CRH increases apoptosis of activated T lymphocytes through FasL induction participating in the process of implantation and early pregnancy. Female rats treated with the non-peptidic CRH receptor 1 (CRHR1) specific antagonist antalarmin, in the first 6 days of gestation, have undergone a decrease of endometrial implantation sites and live embryos and markedly diminished endometrial FasL expression.     

Chronic postnatal DE-71 exposure: Effects on learning,attention and thyroxine levels

Polybrominated diphenyl ethers (PBDEs) are ubiquitous, bioaccumulative flame retardants. Much remains to be learned about their developmental toxicological properties, particularly with regards to chronic exposure. In two experiments, male Long–Evans rats ingested the commercial pentaBDE mixture DE-71 from birth onward, first through the milk of lactating dams (who ingested 5 or 7.5 mg DE-71/day in a custom-mixed chow), then directly via chow consumption (at a dose of 3 or 4.5 mg/day). Control rats consumed the same brand of chow without DE-71. As adults, the rats were assessed for learning and attention using a series of five-choice serial reaction time tasks. A challenge with the muscarinic cholinergic antagonist scopolamine (0, 0.01, 0.03, or 0.05 mg/kg injected s.c.) was conducted on the final attention task. Serum total thyroxine (T4) levels were obtained at the end of testing. Total T4 was significantly lower in both DE-71 groups than in controls. Visual discrimination learning was unaffected by DE-71, but rats ingesting 4.5 mg/day DE-71 demonstrated significant impairments in sustained attention and inhibitory control, as evidenced by increased premature responding and decreased accuracy of responding in Attention Task 1. However, the DE-71-exposed rats did not respond differentially to the effects of scopolamine on attention compared to controls. These effects of chronic developmental DE-71 exposure differ from effects seen with brief postnatal exposure, suggesting that more research needs to be done on the more environmentally relevant chronic exposure model.