Prenatal exposure to lipopolysaccharide results in increases in blood pressure and body weight in rats

AIM: To investigate the effects of prenatal exposure to lipopolysaccharide (LPS) on blood pressure and body weight of offspring in rats. METHODS: Sixteen healthy, pregnant rats were randomly divided into 2 groups. The rats in the LPS group were injected intraperitoneally with LPS (0.79 mg/kg) on the d 8, d 10, and d 12 of gestation. Those in the control group were only treated with normal saline. After delivery, all offspring were weighed and blood pressure was measured by the tailcuff method once every 2 weeks from the 6th to the 24th week. In the 15th week, their food intake was weighed every day. At the end of the 24th week, the rats were killed by decapitation. Abdominal adipose tissues were weighed, and the serum level of leptin was detected by radioimmunoassay. RESULTS: The offspring with prenatal LPS exposure showed increased systemic arterial pressure, heavier body weight, elevated food intake, increased adipose tissue weight, and increased circulating leptin compared with the controls. CONCLUSION: Prenatal exposure to LPS leads to increases in blood pressure and body weight in rats.     

Influence of prenatal waterpipe tobacco smoke exposure on renal biomarkers in adult offspring rats

Background: Waterpipe tobacco smoke (WTS) is a popular form of tobacco consumption. Prenatal exposure to cigarette smoke altered kidney function and oxidative stress balance in offspring. However, the effect of prenatal WTS exposure on kidney function parameters, blood pressure and oxidative stress in adult offspring rats were unknown.

Methods: Pregnant Wister rats were exposed to either WTS for 2?hours per day utilizing a whole body exposure system or fresh air from day 0 of gestation to day 21. Systolic blood pressure, histological analysis of kidney, kidney function biomarkers [angiotensin converting enzyme (ACE), angiotensin I, angiotensin II, urea nitrogen, creatinine and albumin], and oxidative stress biomarkers (glutathione peroxidase (GPx), catalase and thiobarbituric acid reactive substances (TBARS)) were measured in male- and female- offspring rats on week 20.

Results: Prenatal exposure to WTS significantly decreased kidneys’ weight and glomeruli area (p?<?0.05) in offspring rats. Prenatal WTS exposure increased blood pressure in offspring rats (p?<?0.05). Further, prenatal WTS exposure increased the level of urine albumin (p?<?0.05) in offspring rats. Prenatal WTS exposure increased the level of ACE and angiotensin I (p?<?0.05) in female offspring rats. Prenatal WTS exposure increased the level of TBARS (p?<?0.05) in female offspring rats and there was a trend of decreased activity of GPx in male and female offspring rats, but was not significant (p?>?0.05).

Conclusions: Maternal WTS exposure during pregnancy resulted in detrimental effects on the renal system as indicated by altered kidney parameters and function, increased systolic blood pressure and oxidative stress in adult offspring rats.     

TLR2-deficiency promotes prenatal LPS exposure-induced offspring hyperlipidemia

Toll-like receptor 2(TLR2), which recognizes several lipopeptides and transduces inflammatory signaling, promotes the pathogenesis of diet-induced dyslipidemia and obesity. TLR2-deficient mice were shown to have improved insulin sensitivity and reduced diet-induced metabolic syndrome. Previous studies demonstrated that prenatal lipopolysaccharide(LPS) exposure causes dyslipidemia accompanied by increased body weight and insulin resistance in offspring. OBJECTIVE To determine whether TLRs are involved in this complex abnormal phenotype,we analyzed TLR2 and TLR4 expression levels in adipose tissues from offspring with prenatal LPS-exposure(offspringp LPS) and compared these levels to those of control offspring with prenatal saline-exposure(offspring-p Saline).METHODS and RESULTS TLR2 expression was specifically upregulated in the adipose tissue of offspring-p LPS mice. However, unexpectedly, TLR2-deficient offspringp LPS mice not only presented with an abnormal phenotype comparable to that of wild-type offspring-p LPS mice but also exhibited significantly more severe hyperlipidemia. Our further analyses revealed a dramatic upregulation of TLR4 expression and overactivation of the TLR4/Myd88 signaling pathway in TLR2-deficient offspringp LPS adipose tissue. CONCLUSION Our finding suggests a compensatory genetic interaction between TLR2 and TLR4 in the context of prenatal inflammatory stimulation,and this interaction likely contributes to the prenatal inflammation-induced hyperlipidemia and lipid overload-induced obesity, thus providing a potential mechanism for the fetal origin of adult metabolic diseases.     

Age- and gender-dependent impairments of neurobehaviors in mice whose mothers were exposed to lipopolysaccharide during pregnancy

Lipopolysaccharide (LPS)-induced intrauterine infection has been associated with neurodevelopmental injury in rodents. The purpose of the present study was to analyze the dynamic changes of neurobehaviors in mice whose mothers were exposed to LPS during pregnancy. The pregnant mice were intraperitoneally (i.p.) injected with LPS (8 μg/kg) daily from gestational day (gd) 8 to gd 15. A battery of neurobehavioral tasks was performed in mice at postnatal day (PND) 70, 200, 400 and 600. Results showed that the spatial learning and memory ability, determined by radial six-arm water maze (RAWM), were obviously impaired in two hundred-day-old female mice and four hundred-day-old male mice whose mothers were exposed to LPS during pregnancy. Open field test showed that the number of squares crossed and peripheral time, a marker of anxiety and exploration activity, were markedly increased in two hundred-day-old female mice following prenatal LPS exposure. In addition, prenatal LPS exposure significantly shortened the latency to the first grid crossing in six hundred-day-old female offspring. Moreover, sensorimotor impairment in the beam walking was observed in two hundred-day-old female mice whose mothers were exposed to LPS during pregnancy. Species-typical behavior examination showed that prenatal LPS exposure markedly increased weight burrowed in seventy-day-old male offspring and six hundred-day-old female offspring. Correspondingly, prenatal LPS exposure significantly reduced weight hoarded in two hundred-day-old female offspring. Taken together, these results suggest that prenatal LPS exposure induces neurobehavioral impairments at adulthood in an age- and gender-dependent manner.     

Social behavior of juvenile rats after in utero exposure to morphine: dose-time-effect relationship.

In the present study, the effects of morphine exposure in utero on social behavior in juvenile male rats was investigated. Pinning, a measure for play behavior, and social grooming of the offspring were measured at postnatal day 21. The subjects were offspring of Wistar rat dams given sc. injections of 1 or 10 mg/kg body weight morphine HCl daily from gestational days 8 (GD8)-GD 21 and control dams injected daily with saline. Pinning and social grooming of the morphine-treated offspring were significantly elevated compared to saline controls. The doses of morphine used neither affected the gestation of pregnant mother rats nor sensorimotor development of the juvenile rats. Prenatal exposure to morphine of 10 mg/kg daily increased both pinning and social grooming, prenatal exposure to a lower dose of 1 mg/kg increased pinning behavior but not social grooming in the offspring. To study the importance of the gestational period, offspring of dams given 10 mg/kg body weight morphine HCl from GD8-GD15 and saline from GD16-parturition or morphine from GD16-parturition and saline from GD8-GD15 was tested. Pinning was only increased when morphine exposure occurred during the third week of gestation, social grooming was increased when morphine exposure had been in the second week of gestation. Subcutaneous administration of 1 mg/kg naltrexone 1 h before the test significantly decreased play behavior in control rats, but not in animals prenatally exposed to morphine. From these experiments we conclude that the long term effect of in utero exposure to morphine on play behavior is established by affecting the endogenous opioid system.     

Prenatal Fasudil exposure alleviates fetal growth but programs hyperphagia and overweight in the adult male rat

Numerous data indicate that Rho kinase inhibitors, such as Fasudil, may constitute a novel therapy for cardiovascular and metabolic diseases. We evaluated long-term effects of exposure to Fasudil during late gestation (10 mg/day) in male rat offspring from birth until 9 months. We also analyzed its effects in offspring from hypertensive mothers treated with a nitric oxide synthesis inhibitor (L-NAME; 50 mg/day). Prenatal exposure to Fasudil did not affect birth weight, but increased body weight from postnatal day 7 (P7) to 9 months. In intrauterine growth-restricted (IUGR) fetuses exposed to L-NAME, maternal Fasudil treatment increased birth weight. At P42 and P180, rats exposed to Fasudil and L-NAME showed alterations of their food intake as well as an increased basal glycemia associated with mild glucose intolerance at 6 months which was also observed in Fasudil-exposed rats. In 9 month-old rats, exposure to Fasudil increased the daily food intake as well as hypothalamic mRNA level of the orexigenic NPY peptide without modulation of the anorexigenic POMC gene expression. Altogether, our data suggest that prenatal Fasudil exposure alleviates fetal growth in IUGR rats, but programs long-term metabolic disturbances including transient perturbations of glucose metabolism, a persistent increase of body weight gain, hyperphagia and an augmented expression of hypothalamic NPY orexigenic gene. We postulate that Fasudil treatment during perinatal periods may predispose individuals to the development of metabolic disorders.     

Neu-P11抑制高糖高脂喂养大鼠体重的增长和脂肪的异位沉积

目的观察Neu-P11(一种新型的褪黑素受体激动剂),对高糖高脂喂养的SD大鼠体重及脂肪的影响。方法高糖高脂喂养SD大鼠5个月,建立肥胖动物模型。分组给予腹腔注射生理盐水、褪黑素(4mg/kg)、Neu-P11(10mg/kg),每周监测体重和食物摄入量。实验末处死动物,分离腹部脂肪组织并称重。结果与生理盐水组比较,Neu-P11或褪黑素处理组肥胖大鼠体重的增长明显受到抑制,腹部脂肪减少,各组相对摄食(每100g体重摄食量)无明显差异。结论Neu-P11能降低高糖高脂喂养大鼠的体重增长和脂肪沉积。     

Effect of chronic dietary treatment with L-tryptophan on the development of cold-induced hypertension in rats

This study was designed to assess the effect of chronic dietary administration (2.5 and 5.0% by weight) of the neutral amino acid, L-tryptophan, on the development of hypertension during chronic exposure to cold. In addition, a warm-adapted and cold-treated control group receiving unsupplemented food were used. Chronic administration of the lower dose of L-tryptophan (850 mg/day) prevented the elevation of blood pressure attenuated cardiac hypertrophy, and had no effect on body weight during exposure to cold. The higher dose of L-tryptophan (1,690 mg/day) attenuated the rate of blood pressure increase, did not affect cardiac hypertrophy, attenuated the gain in body weight, and increased the urinary output of epinephrine. Thus, this dose may be associated with some toxicity. Both doses of tryptophan failed to prevent certain other responses characteristically occurring during exposure to cold: i.e. increased weight of the kidneys, adrenal glands and brown adipose tissue; increased food and water consumption; increased dipsogenic responsiveness to angiotensin II, and increased plasma aldosterone concentration. The results indicate that chronic dietary administration of L-tryptophan (850 mg/day) can prevent the development of cold-induced hypertension, as it can in all other models of hypertension tested thus far in rats.     

Effects of fetal and neonatal exposure to nicotine on blood pressure and perivascular adipose tissue function in adult life

In Wistar rats, maternal exposure to nicotine was shown to impair the inhibitory function of perivascular adipose tissue on vascular contractility in the aorta of the offspring. It is not known whether an impairment of perivascular adipose tissue function occurs in smaller arteries, and whether the control of blood pressure is affected. Here we studied the blood pressure effects and the alteration of perivascular adipose tissue function in mesenteric arteries of the offspring born to Wistar-Kyoto rat (WKY) dams exposed to nicotine. Nulliparous female WKY rats were given either nicotine bitartrate (1 mg/kg/day) or saline (vehicle) by subcutaneous injection 2 weeks prior to mating, during pregnancy and until weaning. Blood pressure of the offspring and functional studies with mesenteric arteries were conducted. Tissue samples (thoracic aorta, mesenteric arteries, and kidneys) were collected for morphological and immunohistochemical examinations. Blood pressure increased from 14 weeks of age onwards in the offspring born to nicotine-exposed dams. Nicotine-exposed offspring showed a significant increase in the number of brown adipocytes in aortic perivascular adipose tissue relative to control offspring. In mesenteric arteries from control offspring, contractile responses induced by phenylephrine, serotonin, and 9,11-dideoxy-11alpha, 9alpha-epoxymethanoprostaglandin F(2)alpha (U44619) were significantly attenuated in the presence of perivascular adipose tissue, an effect not observed in the nicotine-exposed tissues. Endothelium-dependent relaxation responses to carbachol, kidney weight, the total number of nephrons and glomerulus' size were comparable in nicotine and saline groups. We conclude that fetal and neonatal exposure to nicotine caused blood pressure elevation. Alterations in perivascular adipose tissue composition and modulatory function are some of the mechanisms associated with this blood pressure increase.     

Effects of thiamine deficiency on food intake and body weight increment in adult female and growing rats

The present study compared the effects of thiamine (vitamin B1) deficiency (TD) on the patterns of food intake and body weight in adult female and neonatal Wistar rats. The adults weighed 250-270 g at the start and were fed for 60 days either with a synthetic TD diet (211 B1) or with the same synthetic diet+thiamine (210 B1). TD led to a marked reduction in food intake and the body weight set point, both recovering rapidly to their initial level in only 3 days after dietetic reversion. The effects of TD in developing rats were evaluated by subjecting pregnant rats to thiamine restriction during different time windows: prenatal (3 days before mating to parturition); perinatal (7 days after mating to the 10th postnatal day); and postnatal (from parturition to weaning). The effect of TD on the occurrence of low birth weight and ponderal growth retardation was examined from postnatal days 1 to 45. Only perinatal TD significantly decreased birth weight relative to untreated or pair-fed controls. Moreover, compared with the control treatments, ponderal growth retardation was not induced by prenatal TD, whereas induction of TD from perinatal into postnatal periods did cause ponderal growth retardation, with long-lasting effects persisting in adulthood. The results suggest a major physiological role of thiamine in the homeostasis of body weight programming, increment, and set point regulation in both offspring and adult female rats.     

Developmental effects of intermittent prenatal exposure to 1,1,1-trichloroethane in the rat

The effects of daily three 1-h exposures to 7000 ppm 1,1,1-trichloroethane (TCE) on physical and behavioral development were examined in Sprague–Dawley rats exposed during the last week of gestation. A sham group was exposed to filtered air. Offspring of both groups were fostered to untreated dams. No significant group differences were detected in total maternal weight gain or food and water consumption, but differences were observed in initial litter characteristics, including a longer gestation period in the TCE group, a smaller number of litters delivered in the TCE group, and fewer live pups per litter in the TCE group. At birth, the total litter weight was less in the TCE group, but there was no significant difference in average pup weight. Pups prenatally exposed to TCE did not differ from shams in day of eye opening, pinnae detachment, or incisor eruption. The TCE group weighed less the first 2 weeks of life, was impaired in its ability to perform the inverted screen, negative geotaxis, and vertical screen tests, and had less forelimb grip strength. Locomotor activity was reduced in the TCE group, and the ratio of brain to body weight was reduced in TCE-exposed offspring. These data provide evidence for neurobehavioral teratogenicity of intermittent prenatal exposure to high concentrations of TCE in rats.     

孕期脂多糖刺激对子代大鼠胰岛素抵抗的影响

目的 探讨孕期脂多糖（LPS）对子代成年大鼠胰岛素抵抗的影响。方法 SD 孕鼠 20 只随机分为 2 组,每组 10 只。LPS 组孕期第 8、 10、 12 天腹腔注射 LPS 0.40 mg/kg, 对照组腹腔注射无菌生理盐水 0.5 mL。子鼠 3 月龄时测血糖、 血胰岛素的浓度和瘦素（Leptin）水平, 计算稳态胰岛素抵抗指数（HOMA-IR）和胰岛素敏感指数（QUICKI）。结果 与对照组相比, 3 月龄 LPS 组子鼠血糖 （mmol/L：7.72±0.42 vs 7.02±0.42）、 血胰岛素 （mIU/L： 8.78± 4.10 vs 1.51±0.27）、 血 Leptin 水平 （μg/L： 3.88±1.40 vs 1.00±0.33）、 HOMA-IR 值 （3.01±1.41 vs 0.47±0.09） 明显高于对照组; LPS 组 QUICKI 值明显低于对照组 （0.57±0.07 vs 0.99±0.08）。结论 孕期 LPS 刺激会引起子代大鼠胰岛素抵抗。     

Weight loss and hypophagia after high-dose AT1-blockade is only observed after high dosing and depends on regular leptin signalling but not blood pressure

AT₁-blockade has been shown to induce weight loss in animals or patients. The aim of this study was to investigate whether weight reduction after AT₁-blockade is dependent on dose, blood pressure reduction and leptin signalling. Spontaneously hypertensive rats (SHR) and lean and obese Zucker rats were treated for 4?weeks with candesartan (0, 2, 6 or 16?mg/kg/day). Body weight, food intake and hypothalamic mRNA levels of (an)orexigenic peptides were determined. Obese Zucker rats served as a model of primary leptin resistance. In SHR, body mass index and food intake were decreased selectively by 16?mg/kg/day candesartan but not after using normal (2?mg/kg/day) or supranormal (6?mg/kg/day) doses. Correlation analysis between blood pressure and body weight indicated no relationship of hypotensive potency on weight loss. The hypothalamic mRNA levels of the orexigenic peptide MCH (melanin-concentrating hormone) were diminished in parallel. Consistent to the results in SHRs, 16?mg/kg/day candesartan revealed a decrease of body weight, food intake and hypothalamic MCH mRNA levels in lean Zucker rats. In obese Zucker rats, none of these parameters were reduced by candesartan. Loss of body weight and hypophagia are not general features of AT₁-blockers, since neither was seen after normal or moderately supranormal doses, but they were, after the highest doses. These actions of AT₁-blockers occur independently of their ability to lower blood pressure. They do depend on an intact leptin signalling, since they were absent in obese Zucker rats that feature a genetic mutation of the leptin receptor.     

Dietary ethinyl estradiol exposure during development causes increased voluntary sodium intake and mild maternal and offspring toxicity in rats

Exogenous estrogen exposure during development often results in behavioral masculinization and/or defeminization of genetic females. Genetic males may be defeminized, hypermasculinized or even demasculinized after similar treatment. Here, pregnant Sprague-Dawley rats consumed phytoestrogen-free diets containing 0, 1, 5 or 200 ppb EE(2) beginning on gestational day (GD) 7. Offspring were weaned to the same maternal diet and maintained gonadally intact. There were mild effects on body weight and food consumption in dams of the 200 ppb group and their offspring weighed less at birth than those of the control group; however, gross assessments of nursing behavior were normal in all dietary groups. Postweaning, offspring of the 200 ppb group weighed less and consumed less food than controls. There were no EE(2)-related effects on open-field activity (tested at postnatal days (PND) 22-24, 43-45 and 64-66), play behavior (tested at PND 35), running wheel activity (PND 63-77) or intake of a 0.3% saccharin-flavored solution (PND 69-71). Intake of a 3.0% sodium chloride-flavored solution on PND 73-75 was increased in both male and female offspring of the 200 ppb group relative to same-sex controls, an effect that is reportedly estrogen mediated. Sodium chloride-flavored solution intake is a sexually dimorphic behavior for which female rats consume more than males. Here, while EE(2) exposure had few effects on the conventional tests of sexually dimorphic behaviors, exposure to 200 ppb in the diet appeared to feminize genetic males and hyperfeminize genetic females with regard to sodium intake.     

Prenatal exposure to dichlorvos: physical and behavioral effects on rat offspring

The effects of prenatal exposure to dichlorvos (DDVP), an organophosphate (OP) pesticide, on pups' physical and neurobehavioral developments were investigated. Forty pregnant rats were treated by gavage with 8.0 mg/kg DDVP or its vehicle (1 ml/kg) from the 6th to the 15th day of pregnancy. At birth, pups were weighed, the litters culled to eight animals (four male and four female), and then observed for physical (pinna detachment, incisor eruption, eye opening, testes descent, and vaginal opening) and neurobehavioral developments (palmar grasp, surface righting, negative geotaxis, and open-field behaviors). As adults, open-field, apomorphine-induced stereotypy, and passive avoidance behaviors were also assessed. Results showed no differences between the body weight of DDVP and control-treated groups. No differences were observed on the measures of physical and neurobehavioral development. Locomotor activity of male pups at 21 days of age was decreased by DDVP exposure. Adult experimental offspring showed a decreased locomotor frequency and an increased immobility duration on open-field behavior in relation to control animals; the apomorphine-induced stereotyped behavior was decreased by the pesticide exposure as well as performance on the passive avoidance task. These data suggest that prenatal DDVP exposure was able to decrease offspring motor function (adolescence and adults) and conditioned response learning, probably by interference with the cholinergic-dopaminergic balance of activity involved with the control of motor function as well as the cholinergic system that modulates learning process.     

Effect of chronic administration of an oral contraceptive on the blood pressure of rats

Dietary administration of the oral contraceptive, Enovid, to female rats at 7.5 mg/kg of food (420 mg/kg body weight/day) for 20 weeks was accompanied by an elevation of systolic blood pressure and an increase in the ratios of both heart weight to body weight and renal weight to body weight. A second study, in which Enovid was administered at the same dose for 24 weeks revealed significant increases in systolic, diastolic and mean blood pressures of treated female rats measured by direct cannulation of the carotid artery. A third study tested the effect of the same dose of Enovid on systolic blood pressure of female rats receiving 0.15 m NaCl solution as their sole drinking fluid. The first significant elevation of blood pressure in these rats occurred during week 6 of drug treatment and continued for the remainder of the 12-week experiment. The ratio of heart weight to body weight was also increased significantly in the treated group. Thus, chronic administration of Enovid at the dosage used was accompanied by hypertension in rats.     

Changes of ghrelin and leptin levels in plasma by cigarette smoke in rats

Cigarettes smoke (CS) limits food intake and body weight increase. Ghrelin and leptin are hormones regulating appetite and energy balance. While ghrelin increases food intake and causes a positive energy balance, leptin decreases food intake and enhances a negative energy balance. To investigate the possible role of ghrelin and leptin regarding the negative energy balance caused by CS, 10-week old male Wistar rats (n = 10) were exposed to CS from 30 cigarettes twice a day for 5 days a week for four weeks. In the smoking group, food intake and body weight gain were less than those in the non-smoking group (n = 10) during the entire CS exposure. In the smoking group, the plasma levels of acyl ghrelin were significantly higher (75.9 ± 5.1 fmol/ml versus 46.5 ± 3.3 fmol/ml, p < 0.01), while those of leptin were significantly lower than those in the non-smoking group (434.9 ± 41.1 ng/ml versus 744.0 ± 45.4 ng/ml, p < 0.01) after the final CS exposure. However, the plasma des-acyl ghrelin levels were not affected by CS exposure. These results suggested that acyl ghrelin and leptin levels in plasma may change to compensate for the negative energy balance by CS.     

Effects of prenatal hydrocortisone acetate exposure on fertility and sexual behavior in male rats

The aim of the present study was to investigate the effects of hydrocortisone during the prenatal period and its later repercussions on the fertility and sexual behavior of male rats. Pregnant rats were treated (s.c.) with hydrocortisone acetate, at 1.5 mg/day on the 17th, 18th, and 19th days of gestation. Decreased body weight and no alteration in anogenital distance were observed in male offspring. Adulthood, presented reductions of body weight, plasma testosterone levels, and seminal-vesicle wet weight without secretion as well as no alteration in the wet weights of the testes, epididymis, and seminal vesicle with secretion in the treated group. Males exposed to hydrocortisone during the prenatal period were able to mate with normal females, which became pregnant but exhibited an increased number of post-implantation losses. In spite of this, these treated males exhibited decreased male sexual behavior and the appearance of female sexual behavior after these male rats were castrated and pretreated with exogenous estrogen. These results indicate that exposure to hydrocortisone in the later stages of pregnancy may have a long-term effect on the fertility and sexual behavior of male rats, suggesting an incomplete masculinization and defeminization of the central nervous system.     

Prenatal inflammation exposure-programmed hypertension exhibits multi-generational inheritance via disrupting DNA methylome

The multi-generation heredity trait of hypertension in human has been reported, but the molecular mechanisms underlying multi-generational inheritance of hypertension remain obscure. Recent evidence shows that prenatal inflammatory exposure (PIE) results in increased incidence of cardiovascular diseases, including hypertension. In this study we investigated whether and how PIE contributed to multi-generational inheritance of hypertension in rats. PIE was induced in pregnant rats by intraperitoneal injection of LPS or Poly (I:C) either once on gestational day 10.5 (transient stimulation, T) or three times on gestational day 8.5, 10.5, and 12.5 (persistent stimulation, P). Male offspring was chosen to study the paternal inheritance. We showed that PIE, irrespectively induced by LPS or Poly (I:C) stimulation during pregnancy, resulted in multi-generational inheritance of significantly increased blood pressure in rat descendants, and that prenatal LPS exposure led to vascular remodeling and vasoconstrictor dysfunction in both thoracic aorta and superior mesenteric artery of adult F2 offspring. Furthermore, we revealed that PIE resulted in global alteration of DNA methylome in thoracic aorta of F2 offspring. Specifically, PIE led to the DNA hypomethylation of G beta gamma (Gβγ) signaling genes in both the F1 sperm and the F2 thoracic aorta, and activation of PI3K/Akt signaling was implicated in the pathologic changes and dysregulated vascular tone of aortic tissue in F2 LPS-P offspring. Our data demonstrate that PIE reprogrammed DNA methylome of cells from the germline/mature gametes contributes to the development of hypertension in F2 PIE offspring. This study broadens the current knowledge regarding the multi-generation effect of the cumulative early life environmental factors on the development of hypertension.     

Comparative effects of maternal prenatal and postnatal exposures to astemizole on reproductive parameters of rats

The prenatal and postnatal effects of administration of a nonsedative antihistamine H1, astemizole (ATZ), were compared. ATZ (10 mg/kg) was injected daily into female Wistar rats throughout pregnancy (prenatal treatment) or during the first 6 days of lactation (postnatal treatment). Neither treatment modified dam body weight. Prenatal exposure reduced offspring body weight and lead to a latter expression of the vaginal opening of female offspring. In addition, a long-term disruption of male reproductive behavior was observed, while female sexual behavior was not modified. The sexual activity index and the intromission frequency were increased in prenatally treated animals. Testes wet weight was reduced, but no modifications were detected in vas deferens or seminal vesicles. Postnatal treatment did not alter offspring body weight, open-field activity, sexual behavior and organ weight as well as did not delay testes descent but reduced the time until vaginal opening. Hypothalamic serotonin (5-HT), dopamine (DA) and noradrenaline (NA) as well as DA and NA metabolites were not modified by both prenatal and postnatal treatments. Increased striatal 3,4-dihydroxyphenylacetic acid (DOPAC) levels were observed after prenatal and postnatal treatments, while only postnatal 5-HT levels were increased. We propose that the present results indicate that prenatal ATZ exposure can have long-lasting organizational effects on reproductive behavior of male rats, while postnatal exposure to this drug did not alter mating behavior. In relation to female rats, prenatal and postnatal exposures to ATZ accelerated puberty but did not alter sexual behavior. Neurochemical data show that both treatments increased striatal dopaminergic system activity, suggesting a central ATZ effect after perinatal exposure.