Differences in Production of Adrenal Steroid Hormones in Pubertal Rats Exposed to Low Doses of the Endocrine Disruptor DDT during Prenatal and Postnatal Development

Production of adrenal steroid hormones in pubertal male Wistar rats exposed to low doses of DDT during both prenatal and postnatal and only postnatal development has been investigated. Rats exposed to the disruptor prenatally and postnatally, and only postnatally were characterized by opposite changes in production of mineralocorticoids, glucocorticoids, male and female sex hormones. The study revealed that daily exposure to low doses of DDT enhanced conversion of progesterone to 17-OH-progesterone and did not exert selective antiandrogenic or proestrogenic action typical for the effect of toxic and subtoxic doses. In rats, exposed to DDT during their prenatal and postnatal development, impaired morphogenesis of the adrenal cortex and circulatory disorders in zona glomerulosa contributed to reduced aldosterone and sex steroid hormones production.     

Sex-Dependent Changes in Striatal Dopamine Transport in Preadolescent Rats Exposed Prenatally and/or Postnatally to Methamphetamine

Methamphetamine (MA) is the most commonly used psychostimulant drug, the chronic abuse of which leads to neurodegenerative changes in the brain. The global use of MA is increasing, including in pregnant women. Since MA can cross both placental and haematoencephalic barriers and is also present in maternal milk, children of chronically abused mothers are exposed prenatally as well as postnatally. Women seem to be more vulnerable to some aspects of MA abuse than men. MA is thought to exert its effects among others via direct interactions with dopamine transporters (DATs) in the brain tissue. Sexual dimorphism of the DAT system could be a base of sex-dependent actions of MA observed in behavioural and neurochemical studies. Possible sex differences in the DATs of preadolescent offspring exposed to MA prenatally and/or postnatally have not yet been evaluated. We examined the striatal synaptosomal DATs (the activity and density of surface expressed DATs and total DAT expression) in preadolescent male and female Wistar rats (31–35-day old animals) exposed prenatally and/or postnatally to MA (daily 5 mg/kg, s.c. to mothers during pregnancy and lactation). To distinguish between specific and nonspecific effects of MA on DATs, we also evaluated the in vitro effects of lipophilic MA on the fluidity of striatal membranes isolated from preadolescent and young adult rats of both sexes. We observed similar changes in the DATs of preadolescent rats exposed prenatally or postnatally (MA-mediated drop in the reserve pool but no alterations in surface-expressed DATs). However, prenatal exposure evoked significant changes in males and postnatal exposure in females. A significant decrease in the activity of surface-expressed DATs was found only in postnatally exposed females sensitized to MA via prenatal exposure. MA applied in vitro increased the fluidity of striatal membranes of preadolescent female but not male rats. In summary, DATs of preadolescent males are more sensitive to prenatal MA exposure via changes in the reserve pool and those of preadolescent females to postnatal MA exposure via the same mechanism. The combination of prenatal and postnatal MA exposure increases the risk of dopaminergic deficits via alterations in the activity of surface-expressed DATs especially in preadolescent females. MA-mediated changes in DATs of preadolescent females could be still enhanced via nonspecific disordering actions of MA on striatal membranes.     

Loss of Metabotropic Glutamate Receptor 5 Function on Peripheral Benzodiazepine Receptor in Mice Prenatally Exposed to LPS

Parental microglial induced neuroinflammation, triggered by bacterial- or viral infections, can induce neuropsychiatric disorders like schizophrenia and autism to offspring in animal models. Recent investigations suggest that microglia, the resident immune cells of the brain, provides a link between neurotransmission, immune cell activation, brain inflammation and neuronal dysfunction seen with the offspring. Relatively little is known about how reduction of brain inflammation and restoration of glial function are associated with diminution of brain degeneration and behavioral deficits in offspring. Increased mGluR5 expression and the long-lasting excitotoxic effects of the neurotoxin during brain development are associated with the glial dysfunctions. We investigated the relationship of mGluR5 and PBR and how they regulate glial function and inflammatory processes in mice prenatally exposed to LPS (120μg/kg, between gestational days 15 and 17), an inflammatory model of a psychiatric disorder. Using PET imaging, we showed that pharmacological activation of mGluR5 during 5 weeks reduced expression of classic inflammation marker PBR in many brain areas and that this molecular association was not present in LPS-exposed offspring. The post-mortem analysis revealed that the down regulation of PBR was mediated through activation of mGluR5 in astrocytes. In addition, we demonstrated that this interaction is defective in a mouse model of the psychiatric deficit offering a novel insight of mGluR5 involvement to brain related disorders and PBR related imaging studies. In conclusion, mGluR5 driven glutamatergic activity regulates astrocytic functions associated with PBR (cholesterol transport, neurosteroidogenesis, glial phenotype) during maturation and could be associated with neuropsychiatric disorders in offspring.     

Exposure to Endocrine Disruptor Induces Transgenerational Epigenetic Deregulation of MicroRNAs in Primordial Germ Cells

In mammals, germ cell differentiation is initiated in the Primordial Germ Cells (PGCs) during fetal development. Prenatal exposure to environmental toxicants such as endocrine disruptors may alter PGC differentiation, development of the male germline and induce transgenerational epigenetic disorders. The anti-androgenic compound vinclozolin represents a paradigmatic example of molecule causing transgenerational effects on germ cells. We performed prenatal exposure to vinclozolin in mice and analyzed the phenotypic and molecular changes in three successive generations. A reduction in the number of embryonic PGCs and increased rate of apoptotic cells along with decrease of fertility rate in adult males were observed in F1 to F3 generations. Blimp1 is a crucial regulator of PGC differentiation. We show that prenatal exposure to vinclozolin deregulates specific microRNAs in PGCs, such as miR-23b and miR-21, inducing disequilibrium in the Lin28/let-7/Blimp1 pathway in three successive generations of males. As determined by global maps of cytosine methylation, we found no evidence for prominent changes in DNA methylation in PGCs or mature sperm. Our data suggest that embryonic exposure to environmental endocrine disruptors induces transgenerational epigenetic deregulation of expression of microRNAs affecting key regulatory pathways of germ cells differentiation.     

Bioaccumulation and Metabolic Effects of the Endocrine Disruptor Methoprene in the Lobster, Homarus americanus

Methoprene is a pesticide that acts as a juvenile hormone agonist.Although developed initially against insects, it has since beenshown to have toxic effects on larval and adult crustaceans.Methoprene was one of several pesticides applied to the WesternLong Island Sound (WLIS) watershed area during the summer of1999; the other pesticides were malathion, resmethrin, and sumethrin.These pesticides were applied as part of a county-by-countyeffort to control the mosquito vector of West Nile Virus. Subsequently,the seasonal lobster catches from the WLIS have decreased dramatically.The lethality of the pesticides to lobsters had been unknown.We studied the effects of methoprene while other investigatorsstudied effects of the other pesticides. We questioned whethermethoprene, through its effects on larvae, adults or both, couldhave contributed to this decline. We found that low levels ofmethoprene had adverse effects on lobster larvae. It was toxicto stage II larvae at 1 ppb. Stage IV larvae were more resistant,but did exhibit significant increases in molt frequency beginningat exposures of 5 ppb. Juvenile lobsters exhibited variationsin tissue susceptibility to methoprene: hepatopancreas appearedto be the most vulnerable, reflected by environmental concentrationsof methoprene inhibiting almost all protein synthesis in thisorgan. Our results indicated that methoprene concentrates in the hepatopancreas,nervous tissue and epidermal cells of the adult lobster. Methoprenealtered the synthesis and incorporation of chitoproteins (cuticleproteins) into adult postmolt lobster explant shells. SDS PAGEanalyses of adult post–molt shell extracts revealed changesin the synthesis of chitoproteins in the methoprene-treatedspecimens, suggesting that methoprene affects the normal pathwayof lobster cuticle synthesis and the quality of the post-moltshell. Although it is likely that a combination of factors ledto the reduced lobster population in WLIS, methoprene may havecontributed both by direct toxic effects and by disrupting homeostaticevents under endocrine control.     

Sexual Differentiation of Cognitive Abilities in Women Exposed to Diethylstilbestrol (DES) Prenatally

In nonhuman animals, prenatal exposure to androgens or estrogens enhances development of male-typical characteristics (masculinizes) and impairs development of female-typical characteristics (defeminizes). We investigated the hypothesis that prenatal exposure to the synthetic estrogen, diethylstilbestrol (DES), similarly masculinizes or defeminizes cognitive development in women. Forty-two DES-exposed women and 26 of their unexposed sisters were studied. No group differences were seen for abilities at which females excel on average (verbal fluency, perceptual speed and accuracy, and associative memory), for abilities at which males excel on average (visuospatial abilities), or for abilities that do not show sex differences (vocabulary, nonverbal intelligence). The time of prenatal exposure to DES correlated with visuospatial performance with later exposure associated with better performance. However, the subgroup of women exposed to DES late in gestation did not differ from unexposed women on these measures. Results support the conclusion that prenatal exposure to DES has little or no influence on cognitive development in women. However, they do not preclude other types of early hormonal influences on human cognition, such as prenatal influences of androgen or influences of androgens or estrogens during the early postnatal period.     

已烯雌酚在人体各器官转移模型的变结构控制

本文通过线性系统极点配置,李雅普诺夫方法研究了已烯雌酚在人体各器官转移模型的变结构控制问题,得到了使系统尽快达到稳定平衡点的变结构控制器．该问题为生物模型综合控制问题的研究奠定了基础．     

Altered Function of Peripheral Organ Systems in Rats Exposed to Chronic Mild Stress Model of Depression

1. In depression, psychiatric symptoms are frequently associated with impaired cardiovascular function and perhaps also increased risk for cancer diseases. Pathophysiological basis of this comorbidity is not clearly understood. Molecular events involved, particularly factors modified by chronic stress exposure, may only be evaluated in animal models of depression.2. Present experiments were aimed to study parameters related to cardiovascular system (tyrosine hydroxylase (TH) gene expression in adrenal glands) and carcinogenesis (retinoic acid receptors in the liver) in the chronic mild stress model of depression.3. Chronic mild stress induced a rise in adrenal TH gene expression in both male and female rats. Gender dependent changes were found in retinoic acid receptor binding with stress-induced activation in females but not males. Ovariectomized animals exhibited higher retinoic acid receptor binding, slightly elevated TH mRNA levels and failed to respond to chronic mild stress exposure with further increase in TH mRNA levels. Similarly, chronic mild stress induced an anhedonic state manifested by decreased sucrose preference in control but not ovariectomized rats.4. Presented data document that central neurochemical and behavioral changes in animals exposed to chronic mild stress model of depression are associated with changes in adrenal TH gene expression and with gender dependent changes in retinoic acid receptor status in the liver. Such alterations may participate in the development of pathological changes and could participate on increased risk for cardiovascular and oncologic comorbidity in depressive patients.     

Imprinting of Cerebral and Hepatic Cytochrome P450s in Rat Offsprings Exposed Prenatally to Low Doses of Cypermethrin

Oral administration of low doses (1.25 or 2.5 or 5 mg/kg) corresponding to 1/200th or 1/100th or 1/50th of LD50 of cypermethrin, a synthetic type II pyrethroid, to pregnant Wistar rats from gestation day 5 to 21 produced a dose-dependent increase in the expression of xenobiotic metabolizing cytochrome P450 (CYP) 1A-, 2B- and 2E1 in the brain and liver of offsprings postnatally at 3 weeks that persisted up to 12 weeks. This persistent increase in CYPs was associated with alterations in circulating concentrations of testosterone, luteinizing hormone and follicle stimulating hormone, spontaneous locomotor activity and accumulation of cypermethrin in the brain of exposed offsprings. Rechallenge of exposed offsprings at adulthood (12 weeks old) with cypermethrin (p.o., 10 mg/kg × 6 days) led to a much higher increase in the expression of CYPs in the exposed offsprings when compared to the control offsprings treated with cypermethrin. Further, bioinformatic analysis demonstrating absence of specific short interspersed elements in CYPs suggests that persistence in the increase in CYPs in exposed offsprings could be attributed to the imprinting of the cerebral and hepatic CYPs following prenatal exposure to low doses of cypermethrin. This imprinting could be of toxicological relevance as it may modify the response of drugs or environmental exposures in exposed offsprings particularly for those chemicals which require CYP-mediated metabolism to produce their beneficial or toxic effects.     

Training in the Morris Water Maze of Female and Male Rats Exposed to Hypoxia at Various Periods of Prenatal Development

Capability for learning was studied in the offspring of rats exposed to hyporbaric hypoxia on the days 11–13, 14–16 or 18–20 of pregnancy. Training in the Morris water maze has been shown to lead to consequences of effect of prenatal hypoxia evident in males, but not in females. The most pronounced changes are found at training in the male rats whose mothers were exposed to hypoxia on the days 14–16 of pregnancy. The revealed differences in the character of learning depend on experimental conditions. Under “severe” stress conditions (at the water temperature of 16–17°C), prenatal hypoxia leads to an improvement of learning parameters as compared with control, while under more favorable conditions (at the water temperature of 23–24°C), to their deterioration.     

Regional Amino Acid Concentration in the Brains of Rats Exposed to High Pressures

Regional amino acid concentrations were measured in rat brain fixed by microwave irradiation at three levels of elevated atmospheric pressure corresponding to different phases of the high-pressure neurological syndrome [20 atmospheres absolute (ATA), no clinical signs; 60 ATA, tremor; 85 ATA, severe tremor and myoclonic jerks]. No changes in amino acid content occurred at 20 or 60 ATA. At 85 ATA glutamine content increased in hippocampus, striatum, cerebellum, and substantia nigra, and gamma-aminobutyric acid content increased in hippocampus. It is suggested that enhanced glutamate release in various subcortical structures contributes to the myoclonic activity observed at 85 ATA.     

Proteomic Analysis of Kidney in Rats Chronically Exposed to Monosodium Glutamate

Background

Chronic monosodium glutamate (MSG) intake causes kidney dysfunction and renal oxidative stress in the animal model. To gain insight into the renal changes induced by MSG, proteomic analysis of the kidneys was performed.

Methods

Six week old male Wistar rats were given drinking water with or without MSG (2 mg/g body weight, n = 10 per group) for 9 months. Kidneys were removed, frozen, and stored at –75°C. After protein extraction, 2-D gel electrophoresis was performed and renal proteome profiles were examined with Colloidal Coomassie Brilliant Blue staining. Statistically significant protein spots (ANOVA, p<0.05) with 1.2-fold difference were excised and analyzed by LC-MS. Proteomic data were confirmed by immunohistochemistry and Western blot analyses.

Results

The differential image analysis showed 157 changed spots, of which 71 spots were higher and 86 spots were lower in the MSG-treated group compared with those in the control group. Eight statistically significant and differentially expressed proteins were identified: glutathione S-transferase class-pi, heat shock cognate 71 kDa, phosphoserine phosphatase, phosphoglycerate kinase, cytosolic glycerol-3-phosphate dehydrogenase, 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase, α-ketoglutarate dehydrogenase and succinyl-CoA ligase.

Conclusion

The identified proteins are mainly related to oxidative stress and metabolism. They provide a valuable clue to explore the mechanism of renal handling and toxicity on chronic MSG intake.     

Conditional Reflex Reaction of the Passive Avoidance in Female and Male Rats Exposed to Hypoxia at Different Terms of Prenatal Development

Elaboration of the conditional reflex reaction of passive avoidance was studied in the 42–46-day old offsprings of two groups of female rats: intact (control) and exposed to action of hypoxia at the 13th, 16th or 19th day of pregnancy. The parameter of learning was the time of stay of the rats in a dark camera, in which they obtained an electroshock. It is shown that the prenatal hypoxia has different effect on the ability to elaborate the conditional reflex reaction of passive avoidance in female and male rats. By this parameter, no differences were revealed in the male group between the control and the animals exposed to hypoxia at different terms of intrauterine development. In female exposed to hypoxia at the 19th day of gestation, it was not possible to elaborate the conditional reflex reaction of passive avoidance. In females exposed to hypoxia at the 13th day of gestation the parameters of learning were lower, whereas in the females exposed to hypoxia at the 16th gestation day they were higher than in control animals.     

人参皂甙对缺氧大鼠海马DG区神经细胞DNA损伤保护作用的研究

目的:用单细胞凝胶电泳技术(SCGE)研究急慢性缺氧大鼠海马DG区神经细胞细胞DNA损伤和人参皂甙对缺氧大鼠海马细胞DNA的保护作用.方法:健康成年SD大鼠随机分为急、慢性缺氧正常对照组、急性缺氧组和慢性缺氧组(分别在模拟海拔5000米高原环境连续缺氧暴露0d、3d和30d)、急性缺氧人参皂甙干预组、慢性缺氧人参皂甙干预组.应用SCGE检测海马DG区神经细胞DNA损伤.结果:随着缺氧时间的增加,海马DG区神经细胞DNA的损伤程度加重,尾长、尾部DNA百分含量和尾距显著增加(P＜0.05).人参皂甙能使缺氧损伤的海马DG区神经细胞的尾长、尾部DNA百分含量和尾距均较缺氧组减少(P＜0.05).结论:人参皂甙能有效地减轻缺氧引起的海马组织细胞DNA的断裂损伤.     

Structure and Function of the Adrenal Gland of Fishes

The structure and distribution of the adrenal gland in fishesis reviewed. Studies on the in vitro and in vivo biosynthesisof adrenocortical steroids and their occurrence in the bloodof fishes are evaluated in the light of modern techniques forthe identification and quantification of steroids. There followsan appraisal of some literature dealing with the adrenocorticalcontrol of intermediary metabolism and ion transport in fishes.     

脂肪细胞的内分泌和自分泌/旁分泌功能

脂肪细胞是高度特化的细胞,除了可通过内分泌、旁分泌和自分泌方式来调节脂肪组织本身的能量储存和释放外,还可以通过循环系统调控其他组织器官的代谢活动。