Prenatal cytokine exposure results in obesity and gender-specific programming

2001 ◽  
Vol 281 (2) ◽  
pp. E326-E334 ◽  
Author(s):  
Jovanna Dahlgren ◽  
Cecilia Nilsson ◽  
Eva Jennische ◽  
Hoi-Por Ho ◽  
Elias Eriksson ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Prenatal Exposure ◽  
Adult Life ◽  
Female Rats ◽  
Male Rats ◽  
Plasma Testosterone ◽  
Adult Age ◽  
Fat Depots ◽  
Tnf Α ◽  
Gender Specific

Prenatal events appear to program hormonal homeostasis, contributing to the development of somatic disorders at an adult age. The aim of this study was to examine whether maternal exposure to cytokines or to dexamethasone (Dxm) would be followed by hormonal consequences in the offspring at adult age. Pregnant rats were injected on days 8, 10, and 12 of gestation with either human interleukin-6 (IL-6) or tumor necrosis factor-α (TNF-α) or with Dxm. Control dams were injected with vehicle. All exposed offspring developed increased body weight ( P < 0.05–0.001), apparently due to an increase of 30–40% in adipose tissue weight ( P < 0.05–0.01). Corticosterone response to stress was increased in the IL-6 group ( P < 0.05–0.01). Dxm-treated male rats exhibited blunted Dexamethasone suppression test results. In male rats, insulin sensitivity was decreased after IL-6 exposure ( P < 0.01), whereas basal insulin was elevated in the TNF-α group ( P < 0.01). In female rats, plasma testosterone levels were higher in all exposed groups compared with controls ( P < 0.01–0.001), with the exception of Dxm-exposed offspring. Males in the TNF-α group showed decreased locomotor activity ( P < 0.05), and females in the IL-6 group showed increased locomotor activity ( P < 0.05). These results indicate that prenatal exposure to cytokines or Dxm leads to increased fat depots in both genders. In females, cytokine exposure was followed by a state of hyperandrogenicity. The results suggest that prenatal exposure to cytokines or Dxm can induce gender-specific programming of neuroendocrine regulation with consequences in adult life.

Disruption of the reproductive system and reproductive performance by administration of nonyiphenol to newborn rats

2000 ◽  
Vol 19 (5) ◽  
pp. 284-296 ◽  
Author(s):  
T Nagao ◽  
Y Saito ◽  
K Usumi ◽  
M Nakagomi ◽  
S Yoshimura ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Estrous Cycle ◽  
Reproductive Function ◽  
Female Rats ◽  
Male Rats ◽  
Plasma Testosterone ◽  
Male And Female ◽  
Testosterone Concentration ◽  
Male And Female Rats ◽  
Sperm Motion

A number of alkylphenolic compounds are used in a variety of commercial products and have been shown in in vitro studies to be weakly estrogenic, but few in vivo data are available addressing this issue in mammals. Human ex-posure to alkylphenols may occur not only from these environmental contaminants but also through contact with manufactured and metabolic breakdown products. The reproductive function of rats treated subcutaneously with nonylphenol (NP, 500 mg/kg/day) or 17Q3-estradiol (E2, 2 mg/kg/day) as a positive control, from postnatal days 1 to 5 was examined after puberty. In addition, masculine sexual behavior, sperm motion, plasma testosterone concentration and histopathological changes in the reproductive organs of the rats were examined. Furthermore, male rats were subjected to an open field test and wheel cage test to evaluate locomotor activity, and the estrous cycle was examined in female rats. All male and female rats exposed neonatally to NP or E2 showed macroscopic and/or microscopic altera-tions of the gonads. Females treated with NP or E2 showed an altered estrous cycle and abnormal reproductive function, while males treated with NP or E2 showed normal reproduc-tion. In males exposed neonatally to NP or E2, no abnorm-alities were observed in locomotor activity, sperm motion or plasma testosterone concentration. The results of this study indicate that early neonatal exposure to NP causes dysfunc-tion of postpubertal reproductive function in female rats, as well as disrupted development of gonads in male and female rats. More detailed studies are warranted to assess the possible risks to human and wildlife reproduction from exposure to NP and other environmental chemicals with estrogenic activity.

Increased severity of alcoholic liver injury in female rats: role of oxidative stress, endotoxin, and chemokines

2001 ◽  
Vol 281 (6) ◽  
pp. G1348-G1356 ◽  
Author(s):  
Amin A. Nanji ◽  
Kalle Jokelainen ◽  
Maryam Fotouhinia ◽  
Amir Rahemtulla ◽  
Peter Thomas ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Liver Injury ◽  
Fish Oil ◽  
Nonheme Iron ◽  
Female Rats ◽  
Male Rats ◽  
Mrna Levels ◽  
Alcoholic Liver Injury ◽  
Tnf Α ◽  
Cox 2

Alcoholic liver injury is more severe and rapidly developing in women than men. To evaluate the reason(s) for these gender-related differences, we determined whether pathogenic mechanisms important in alcoholic liver injury in male rats were further upregulated in female rats. Male and age-matched female rats (7/group) were fed ethanol and a diet containing fish oil for 4 wk by intragastric infusion. Dextrose isocalorically replaced ethanol in control rats. We analyzed liver histopathology, lipid peroxidation, cytochrome P-450 (CYP)2E1 activity, nonheme iron, endotoxin, nuclear factor-κB (NF-κB) activation, and mRNA levels of cyclooxygenase-1 (COX-1) and COX-2, tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2). Alcohol-induced liver injury was more severe in female vs. male rats. Female rats had higher endotoxin, lipid peroxidation, and nonheme iron levels and increased NF-κB activation and upregulation of the chemokines MCP-1 and MIP-2. CYP2E1 activity and TNF-α and COX-2 levels were similar in male and female rats. Remarkably, female rats fed fish oil and dextrose also showed necrosis and inflammation. Our findings in ethanol-fed rats suggest that increased endotoxemia and lipid peroxidation in females stimulate NF-κB activation and chemokine production, enhancing liver injury. TNF-α and COX-2 upregulation are probably important in causing liver injury but do not explain gender-related differences.

scholarly journals Low-dose testosterone protects against renal ischemia-reperfusion injury by increasing renal IL-10-to-TNF-α ratio and attenuating T-cell infiltration

2016 ◽  
Vol 311 (2) ◽  
pp. F395-F403 ◽  
Author(s):  
Chetan N. Patil ◽  
Kedra Wallace ◽  
Babbette D. LaMarca ◽  
Mohadetheh Moulana ◽  
Arnaldo Lopez-Ruiz ◽  
...  
Keyword(s):  
T Cell ◽  
Low Dose ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Male Rats ◽  
Plasma Creatinine ◽  
Cell Infiltration ◽  
Plasma Testosterone ◽  
T Cell Infiltration ◽  
Tnf Α

Renal ischemia-reperfusion (I/R) in male rats causes reductions in plasma testosterone, and infusion of testosterone 3 h postreperfusion is protective. We tested the hypotheses that acute high doses of testosterone promote renal injury after I/R, and that acute low-dose testosterone is protective by the following: 1) increasing renal IL-10 and reducing TNF-α; 2) its effects on nitric oxide; and 3) reducing intrarenal T-cell infiltration. Rats were subjected to renal I/R, followed by intravenous infusion of vehicle or testosterone (20, 50, or 100 μg/kg) 3 h postreperfusion. Low-dose testosterone (20 μg/kg) reduced plasma creatinine, increased nitrate/nitrite excretion, increased intrarenal IL-10, and reduced intrarenal TNF-α, whereas 50 μg/kg testosterone failed to reduce plasma creatinine, increased IL-10, but failed to reduce TNF-α. A higher dose of testosterone (100 mg/kg) not only failed to reduce plasma creatinine, but significantly increased both IL-10 and TNF-α compared with other groups. Low-dose nitro-l-arginine methyl ester (1 mg·kg−1·day−1), given 2 days before I/R, prevented low-dose testosterone (20 μg/kg) from protecting against I/R injury, and was associated with lack of increase in intrarenal IL-10. Intrarenal CD4+ and CD8+ T cells were significantly increased with I/R, but were attenuated with low-dose testosterone, as were effector T helper 17 cells. The present studies suggest that acute, low-dose testosterone is protective against I/R AKI in males due to its effects on inflammation by reducing renal T-cell infiltration and by shifting the balance to favor anti-inflammatory cytokine production rather than proinflammatory cytokines.

Abstract P317: Sex Differences in the Hemodynamic and Sympathetic Responses to Centrally Administered Tumor Necrosis Factor-α in Rats

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Shun-Guang Wei ◽  
Yang Yu ◽  
Robert B Felder
Keyword(s):  
Heart Failure ◽  
Sex Differences ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Female Rats ◽  
Male Rats ◽  
Tnf Α ◽  
Estrogen Effect ◽  
Factor Α ◽  
Necrosis Factor

Introduction: Accumulating evidence indicates that sex differences exist in the clinical and experimental outcomes of various cardiovascular diseases. In addition to its protective effect on renin-angiotensin system activity, estrogen has an anti-inflammatory influence. The central actions of pro-inflammatory cytokines (PICs) contribute significantly to cardiovascular and autonomic dysfunction in hypertension and heart failure. In male adult rat, central administration of PICs induces substantial increases in blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA), and blocking PICs reduces sympathetic excitation in experimental models of hypertension and heart failure. Whether PICs have similar central sympatho-excitatory effects in the female rat remains unknown. Hypothesis: We hypothesized that female rats may be protected from the central cardiovascular and autonomic effects of PICs. Methods: Urethane anesthetized male and female Sprague Dawley rats (10-12 weeks) underwent an intracerebrovascular (ICV) injection of the prototypical PIC tumor necrosis factor-α (TNF-α, 100 ng). BP (mmHg), HR (beats/min) and RSNA (% change) responses were continuously recorded for 4-5 hours. Results: In male rats (n=6), ICV TNF-α induced a dramatic and long-lasting increase (*p<0.001 vs. baseline) in BP (23.1 ± 2.5*), HR (82 ± 8*) and RSNA (109.5 ± 4.3 %*), that began within 20-30 mins and peaked at 90-120 mins after ICV injection. In the female rats (n=6), ICV TNF-α elicited significantly (p<0.05) smaller increases (*p<0.001 vs. baseline) in BP (14.8 ± 1.8*), HR (55 ± 6*) and RSNA (78.5 ± 6.3*), compared with the male rats. Conclusion: These data demonstrate a sex difference in the cardiovascular and sympathetic responses to centrally administered PICs. Whether the observed differences can be explained by an estrogen effect on TNF-α signaling per se or by an estrogen effect on TNF-α-induced renin-angiotensin activity remains to be determined. However, a reduced response of female rats to central inflammation may be an important contributor to sex differences in pathophysiology of hypertension and heart failure.

Prenatal exposure to methylmercury alters locomotor activity of male but not female rats

1997 ◽  
Vol 117 (3) ◽  
pp. 428-436 ◽  
Author(s):  
A. D. Rossi ◽  
E. Ahlbom ◽  
S.-O. Ögren ◽  
P. Nicotera ◽  
S. Ceccatelli
Keyword(s):  
Locomotor Activity ◽  
Prenatal Exposure ◽  
Female Rats

Genotoxicity Evaluation in Severe or Mild Diabetic Pregnancy in Laboratory Animals

2012 ◽  
Vol 120 (05) ◽  
pp. 303-307 ◽  
Author(s):  
P.H. Lima ◽  
Y. Sinzato ◽  
R. Gelaleti ◽  
I.M. Calderon ◽  
M.V. Rudge ◽  
...  
Keyword(s):  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Adult Life ◽  
Female Rats ◽  
Male Rats ◽  
Laboratory Animals ◽  
Intravenous Route ◽  
Blood Samples ◽  
Severe Diabetes ◽  
Mild Diabetes

AbstractThis study aimed to evaluate the genotoxicity (DNA damage levels) in lymphocyte samples from pregnant Wistar rats with severe or mild diabetes and in whole blood samples from their newborns. Wistar female rats (1 and 90 days of age) and male rats (approximately 90 days of age) were used. The experiment consisted of 2 experimental groups (n=8 animals/group): 1) rats with severe diabetes, 2) rats with mild diabetes. For mild diabetes induction, the rats received streptozotocin (STZ) subcutaneously (100 mg/kg body weight) at day of birth, and those showing glycemia from 120 to 300 mg/dL in their adult life were included. For induction of severe diabetes, adult rats received 40 mg/kg STZ (intravenous route), and those showing glycemia > 300 mg/dL were included. At day 21 of pregnancy, the rats were anesthetized and euthanized for removal of maternal and fetal blood samples for determination of the oxidative DNA damage by applying Endo III and Fpg using the comet assay. Thus, the rats with mild diabetes and their offspring showed higher Fpg-sensitive sites, reflecting the damage resulting from hyperglycemia. The rats with severe diabetes and their offspring showed higher oxidative DNA damage detected by Fpg and Endo III-sensitive sites, showing general repercussions related to diabetes. The enzymatic treatment for DNA damage evidenced that the maternal repercussions of diabetes are associated with oxidative DNA damage of their newborn, which was not reflected using only the analysis of DNA damage free of the enzymes.

Dextromethorphan affects ventilation differently in male and female rats

1996 ◽  
Vol 81 (5) ◽  
pp. 1911-1916 ◽  
Author(s):  
Evelyn H. Schlenker
Keyword(s):  
Oxygen Consumption ◽  
Aspartic Acid ◽  
Subcutaneous Administration ◽  
Female Rats ◽  
Male Rats ◽  
Male And Female ◽  
Time Points ◽  
Specific Effects ◽  
Male And Female Rats ◽  
Gender Specific

Schlenker, Evelyn H. Dextromethorphan affects ventilation differently in male and female rats. J. Appl. Physiol. 81(5): 1911–1916, 1996.—Subcutaneous administration of aspartic acid results in a long-lasting but reversible depression of ventilation in male but not in female rats. Aspartic acid acts on N-methyl-d-aspartate receptors. The present study tested the hypothesis that a noncompetitive N-methyl-d-aspartate-receptor antagonist, dextromethorphan (Dex), would depress ventilation in female rats and stimulate it in male rats. Moreover, Dex administered prior to aspartic acid should prevent the aspartic acid-induced depression of ventilation in male rats. In female rats, Dex caused a 30% depression of ventilation relative to saline at 5 and 10 mg/kg ( P < 0.01) but not at the highest dose (20 mg/kg). In male rats, Dex had no effect on ventilation. At a dose of 20 mg/kg, Dex depressed oxygen consumption to 50% of the saline value at all time points in female rats ( P < 0.001) and in male rats 45 and 60 min after administration. The time points when Dex depressed ventilation and oxygen consumption were different in female rats, suggesting that the depression of ventilation was not the result of a depression in oxygen consumption. During a hypercapnic challenge (7% CO2), female rats treated with 5 and 10 mg/kg of Dex exhibited a smaller increase in ventilatory response relative to saline treatment. At a dose of 20 mg/kg, the hypercapnic responsiveness of male rats was markedly stimulated (85.8 ± 8.95 ml/min) relative to saline (50.6 ± 9.14 ml/min; P < 0.001). Finally, Dex administered before aspartic acid prevented the aspartic acid-induced depression of ventilation in male rats. Thus, in rats, Dex has gender-specific effects on ventilation and these effects are not associated with changes in oxygen consumption.

scholarly journals Assessment of the Central Effects of Natural UraniumviaBehavioural Performances and the Cerebrospinal Fluid Metabolome

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
P. Lestaevel ◽  
S. Grison ◽  
G. Favé ◽  
C. Elie ◽  
B. Dhieux ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Drinking Water ◽  
Locomotor Activity ◽  
Brain Function ◽  
Spatial Working Memory ◽  
Natural Uranium ◽  
Female Rats ◽  
Male Rats ◽  
The Central Nervous System ◽  
And Control

Natural uranium (NU), a component of the earth’s crust, is not only a heavy metal but also an alpha particle emitter, with chemical and radiological toxicity. Populations may therefore be chronically exposed to NU through drinking water and food. Since the central nervous system is known to be sensitive to pollutants during its development, we assessed the effects on the behaviour and the cerebrospinal fluid (CSF) metabolome of rats exposed for 9 months from birth to NUvialactation and drinking water (1.5, 10, or 40 mg·L−1for male rats and 40 mg·L−1for female rats). Medium-term memory decreased in comparison to controls in male rats exposed to 1.5, 10, or 40 mg·L−1NU. In male rats, spatial working memory and anxiety- and depressive-like behaviour were only altered by exposure to 40 mg·L−1NU and any significant effect was observed on locomotor activity. In female rats exposed to NU, only locomotor activity was significantly increased in comparison with controls. LC-MS metabolomics of CSF discriminated the fingerprints of the male and/or female NU-exposed and control groups. This study suggests that exposure to environmental doses of NU from development to adulthood can have an impact on rat brain function.

scholarly journals Early life stress induces renal dysfunction in adult male rats but not female rats

2013 ◽  
Vol 304 (2) ◽  
pp. R121-R129 ◽  
Author(s):  
Analia S. Loria ◽  
Tatsuo Yamamoto ◽  
David M. Pollock ◽  
Jennifer S. Pollock
Keyword(s):  
Blood Pressure ◽  
Adult Male ◽  
Early Life ◽  
Female Rats ◽  
Male Rats ◽  
Plasma Testosterone ◽  
Ang Ii ◽  
Control Female ◽  
Induced Hypertension ◽  
And Control

Maternal separation (MatSep) is a model of behavioral stress during early life. We reported that MatSep exacerbates ANG II-induced hypertension in adult male rats. The aims of this study were to determine whether exposure to MatSep in female rats sensitizes blood pressure to ANG II infusion similar to male MatSep rats and to elucidate renal mechanisms involved in the response in MatSep rats. Wistar Kyoto (WKY) pups were exposed to MatSep 3 h/day from days 2 to 14, while control rats remained with their mothers. ANG II-induced mean arterial pressure (MAP; telemetry) was enhanced in female MatSep rats compared with control female rats but delayed compared with male MatSep rats. Creatinine clearance (Ccr) was reduced in male MatSep rats compared with control rats at baseline and after ANG II infusion. ANG II infusion significantly increased T cells in the renal cortex and greater histological damage in the interstitial arteries of male MatSep rats compared with control male rats. Plasma testosterone was greater and estradiol was lower in male MatSep rats compared with control rats with ANG II infusion. ANG II infusion failed to increase blood pressure in orchidectomized male MatSep and control rats. Female MatSep and control rats had similar Ccr, histological renal analysis, and sex hormones at baseline and after ANG II infusion. These data indicate that during ANG II-induced hypertension, MatSep sensitizes the renal phenotype in male but not female rats.

scholarly journals Developmental increases in plasma leptin binding activity and tissue Ob-Re mRNA expression in the rat

2005 ◽  
Vol 184 (3) ◽  
pp. 535-541 ◽  
Author(s):  
Jeremy T Smith ◽  
Peter J Mark ◽  
Brendan J Waddell
Keyword(s):  
Mrna Expression ◽  
Adult Life ◽  
Tissue Expression ◽  
Binding Activity ◽  
Female Rats ◽  
Male Rats ◽  
Target Cells ◽  
Male And Female Rats ◽  
Age Related ◽  
Plasma Leptin

Leptin’s actions are mediated via the long form of its receptor, Ob-Rb, but access to this receptor on target cells is also influenced by truncated leptin receptor isoforms Ob-Ra and Ob-Re. Plasma leptin binding activity is primarily attributed to Ob-Re, which can restrict leptin passage to extravascular tissue. In this study we investigated whether plasma leptin binding activity changes from fetal to adult life in male and female rats, and whether tissue expression of Ob-Re mRNA changes during development. Plasma leptin binding activity was low in the fetus and prepubertal rats but then increased in male rats by more than three-fold from pre- to post-puberty and by a further two-fold by 7 months of age. A more modest increase in plasma leptin binding activity was observed in females such that a clear sex difference became evident after puberty. There was also a reduction in hypothalamic Ob-Rb protein content between puberty and adult life in female rats. Combined with the higher levels of plasma leptin binding activity, this change in hypothalamic Ob-Rb expression is likely to lead to a more leptin-resistant state in aging females. To assess possible sources of circulating leptin binding activity, Ob-Re mRNA expression was measured by quantitative RT-PCR in several tissues from male rats soon after puberty and at 7 months of age. All tissues examined (testis, epididymis, adrenal, liver, adipose and spleen) expressed Ob-Re mRNA, and there was a dramatic, age-related increase in expression (> 300-fold) in the spleen. These data show that, in addition to the developmental increase in hypothalamic Ob-Rb expression previously reported, plasma leptin binding activity increases several fold from fetal to adult life in the rat. This suggests that the actions of leptin depend not only on its synthesis in adipose tissue and Ob-Rb expression in target cells, but also on factors that regulate tissue expression of Ob-Re and thus leptin transport within plasma.

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