Exposure Of Female Rats Research Articles

Chronic treatment with the antipsychotic lurasidone modulates the neuroinflammatory changes associated with the vulnerability to chronic mild stress exposure in female rats

Stress exposure is a key risk factor for the developmentof depressive-like conditions. However, despite the higher incidence of Major Depressive Disorder in the female population, classical stress-based experimental paradigms have primarily focused on males. In the present study, we used the well-established chronic mild stress (CMS) paradigm to investigate the development of anhedonia, a cardinal symptom of affective disorders, in the female animals and we also studied the potential effect of the antipsychotic drug lurasidone in normalizing the alterations brought about by stress exposure. We found that three weeks of CMS exposure produced a significant reduction of sucrose intake in 50% of the animals (vulnerable, CMS-V), whereas the others were resilient (CMS-R). The development of an anhedonic phenotype in CMS-V was associated with a significant elevation of different immune markers, such as Complement C3 and C4, and inflammatory cytokines, including INFß and Il1ß in dorsal and ventral hippocampus. Interestingly, sub-chronic treatment with the antipsychotic drug lurasidone was able to revert the anhedonic phenotype while normalizing most of the molecular alterations found in rats vulnerable to CMS exposure. This study extends the ability of lurasidone to normalize the anhedonic phenotype in CMS rats also to females. Moreover, we provide novel evidence on lurasidone’s potential effectiveness in treating mental disorders characterized by immune-inflammatory dysfunction.

Hypoactivity and neurochemical alterations in the basal ganglia of female Sprague-Dawley rats after repeated exposure to atrazine.

The herbicide atrazine (ATR) has been one of the most widely used herbicides worldwide. However, due to its indiscriminate use, it has been considered an environmental contaminant. Several studies have classified ATR as an endocrine disruptor, and it has been found to have neurotoxic effects on behavior, along with alterations in the dopaminergic, GABAergic, and glutamatergic systems in the basal ganglia of male rodents. These findings suggest that these neurotransmitter systems are targets of this herbicide. However, there are no studies evaluating the neurotoxicity of ATR in female rodents. Our study aimed to assess the effects of repeated IP injections of 100mg ATR/kg or a vehicle every other day for 2weeks (six injections) on the locomotor activity, content of monoamines, GABA, glutamate, and glutamine in the striatum, nucleus accumbens, ventral midbrain, and prefrontal cortex, and tyrosine hydroxylase (TH) protein levels in striatum and nucleus accumbens of female rats. Repeated 100mg ATR/kg injections immediately decreased all the locomotor activity parameters evaluated, and such hypoactivity persisted for at least 48h after the last ATR administration. The ATR administration increased dopamine and DOPAC content in the nucleus accumbens and the dopamine and DOPAC and serotonin and 5-HIAA content in the ventral midbrain. In contrast, the TH protein levels in the striatum and nucleus accumbens were similar between groups. Meanwhile, GABA, glutamine, and glutamate levels remained unaltered in all brain regions evaluated. The observed behavioral alterations could be associated with the monoamine changes presented by the rats. These data reveal that the nucleus accumbens and ventral midbrain are susceptible to repeated ATR exposure in female rats.

The Protective Effect of Gallic Acid Against Bisphenol A-Induced Ovarian Toxicity and Endocrine Disruption in Female Rats.

Purpose: This study aimed to investigate the protective effects of gallic acid (GA) against ovarian damage induced by bisphenol A (BPA) exposure in female rats. We evaluated whether GA can mitigate the adverse effects of BPA on ovarian structure, inflammatory markers, oxidative stress, apoptosis, and reproductive hormone levels. Methods: Thirty-two female rats were categorized into four groups: control, GA, BPA, and GA+BPA. Histopathological evaluations of ovarian tissue were performed using hematoxylin-eosin staining. The immunohistochemical analysis was conducted for inflammatory, oxidative DNA damage, and apoptotic markers (Tumor necrosis factor alpha [TNFα], cyclooxygenase-2 [COX2], interleukin-1 beta [IL-1β], 8-hydroxydeoxyguanosine [8-OHdG], and caspase 3). Oxidative stress was assessed by measuring malondialdehyde and superoxide dismutase levels. Furthermore, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen, and progesterone levels were quantified using enzyme-linked immunosorbent assay. Results: Histopathological outcomes revealed that BPA significantly induced follicular degeneration, which was effectively mitigated by GA treatment (P < 0.05). Immunohistochemical analysis highlighted the exacerbation of inflammatory responses and oxidative DNA damage and apoptosis (TNFα, COX-2, IL-1β, 8-OHdG, and caspase 3) in BPA-exposed tissues, which were reduced in the presence of GA (P < 0.05). The assessment of oxidative stress demonstrated that GA could significantly decrease lipid peroxidation and partially restore antioxidant defense mechanisms disrupted by BPA (P < 0.05). Hormonal profiling indicated that BPA exposure altered the levels of FSH, LH, estrogen, and progesterone, with GA treatment showing a capacity to modulate these changes, especially in progesterone levels (P < 0.05). Conclusions: The findings suggest that GA exhibits protective properties against BPA-induced ovarian damage through its antioxidative and anti-inflammatory activities, alongside its ability to modulate hormonal imbalances. This research underscores the therapeutic potential of GA in safeguarding reproductive health against environmental toxicants.

Ameliorative mechanism of dietary vitamin d and magnesium on newborn’s pulmonary toxicity induced by cadmium

Cadmium (Cd) exposure in mothers can cause respiratory issues in newborns, but the exact toxicity mechanisms are not fully understood. Vitamin D deficiency in Cd-exposed rats is associated with increased cadmium accumulation in tissues. Finding a cost-effective medication that is vital for the body while also reducing the effects of poisoning is crucial in treating poisonings. To investigate the mechanisms of Cd-induced lung toxicity, we examined the impact of prolonged Cd exposure in female rats before pregnancy on newborn lung health, focusing on sera TNF-α level, lung P53, Foxo1 mRNA, and lung VEGF, and BMP-4 protein level. A total of 50 rats were divided into control, Cd, Cd+Vitamin D, Cd+Mg, and Cd + Vitamin D+Mg groups. Cd exposure resulted in higher serum TNF-α levels and a significant rise in P53 mRNA levels. Additionally, the occurrence of hemorrhage, inflammatory cell infiltration, and thickening of alveolar walls decreased following treatment with vitamin D + Mg. Although Cd did not affect the newborns' body weight, it did impair their lung function. These findings suggest that the Cd-induced increase in the P53 gene expression could be alleviated by vitamin D and Mg, along with the elevation of VEGF and BMP-4 proteins and Foxo1 gene expression. The study revealed that environmental toxins can sometimes harm molecules and proteins, leading to damage in critical fetal tissues. However, these issues can be mitigated through essential supplements. Structured AbstractThe increasing role of Cd in the erratic behavior of numerous biological and molecular entities, notably the development of fetal lung tissue, has made it beneficial to investigate the possible adverse effects of Cd exposure in pregnant mothers and fetal organ development, where instinctive molecular events occur. Researchers are encouraged to create new aspects of medications to reduce clinical symptoms and improve the quality of life due to exposure to metal toxins, particularly in industrialized countries. The present study aimed to evaluate histopathological and molecular modifications of fetal lungs caused by maternal Cd toxicosis and evaluate the possible ameliorating effects of vitamin D and Mg alone and in combination with fetal lung developmental abnormalities, followed by maternal toxin induction, which can be generalized to humans.Fifty female Wistar rats were purchased from the Pasteur Institute of Iran. To induce the model, cadmium at a dose of 2 mg/kg body weight was injected intraperitoneally into the female rats over 28 days before mating (5 days after injection in a week). Afterward, the female rats were randomly divided into type IV polycarbonate cages and mated with healthy male rats. The pregnancy was confirmed by observation of the vaginal plaque, which was subsequently observed, and the number of days of embryo formation was calculated. Subsequently, the pregnant rats were assigned to the following groups and received PBS, vitamin D, Mg, or vitamin D + Mg. At the end of the nine-day treatment period (the 6th day of pregnancy to the 14th day), the neonates were born vaginally, and their body weight and mortality were recorded. The P53 and Foxo1 gene expression levels in the left and right lobes of the homogenized lungs of the newborns in each group were assessed. TNF-alpha was detected in the sera collected from the newborns by ELISA. The isolated left and right lung tissues were homogenized in radioimmunoprecipitation assay (RIPA) buffer and the superior phase was collected to determine the total protein content by Lowry's method and VEGF and BMP-4 protein levels. The obtained lung samples from newborn rats were fixed in a 10% formalin solution for tissue processing. The fixed samples were embedded in paraffin, and serial paraffin sections were prepared for hematoxylin and eosin staining. This study is the first to examine how maternal Cd exposure affects fetal lung development and to estimate the impact of prescribing Mg and vitamin D during pregnancy. The present study assessed the effects of a repeated dose of Cd for 4 weeks before pregnancy on the lung development of newborn rats born to mothers treated with vitamin D and Mg. The results showed that the P53 gene was overexpressed in the model group, while Foxo1 gene expression was downregulated, negatively impacting the lung structure and developmental indices of the fetuses. Therefore, the intake of vitamin D and Mg may contribute to improving the various stages of Cd-induced lung injury by modulating lung inflammation and mucosal secretion while also positively influencing the number of surviving offspring.

Preconception opioids interact with mouse strain to alter morphine withdrawal in the next generation.

Transgenerational effects of preconception morphine exposure in female rats have been reported which suggest that epigenetic modifications triggered by female opioid exposure, even when that exposure ends several weeks prior to pregnancy, has significant ramifications for their future offspring. The current study compares two mouse strains with well-established genetic variation in their response to mu opioid receptor agonists, C57BL/6J (BL6) and 129S1/svlmJ (129) to determine whether genetic background modifies the impact of preconception opioid exposure. Adolescent females from both strains were injected daily with morphine for a total of 10 days using an increasing dosing regimen with controls receiving saline. Several weeks after their final injection, aged-matched BL6 and 129 morphine (Mor-F0) or saline (Sal-F0) females were mated with drug naïve males to generate Mor-F1 and Sal-F1 offspring, respectively. As adults, F1 mice were made morphine dependent using thrice daily morphine injections for 4 days. On day 5, mice were administered either saline or morphine followed 3 h later by naloxone. Behavioral and physiological signs of withdrawal were then measured. Regardless of strain or sex, morphine-dependent Mor-F1 mice had significantly lower levels of withdrawal-induced corticosterone but significantly higher glucose levels when compared to Sal-F1 controls. In contrast, both strain- and preconception opioid exposure effects on physical signs of morphine dependence were observed.

Impairments in expression of devaluation in a Pavlovian goal-tracking task, but not a free operant devaluation task, after fentanyl exposure in female rats

In laboratory animals, there are numerous demonstrations that past exposure to drugs of abuse can lead to devaluation impairments weeks after the final drug exposure, with the majority of these demonstrations examining effects of exposure to psychostimulants. There has been minimal investigation into whether prior exposure to opiates can lead to devaluation impairments. Here, we first trained female rats that two separate cuelights predicted two different foods and measured Pavlovian goal-tracking responses (Experiment 1) or trained female rats to press two levers to earn two different foods and measured this operant response (Experiment 2). In both experiments, we subsequently gave the rats injections of fentanyl twice daily for 6 days, and then tested rats for conditioned responses after satiation on one of the foods 48-h after the final injection. We found that rats were impaired in the expression of devaluation in the Pavlovian task after fentanyl exposure, but were unimpaired in the expression of devaluation in the operant task. The pattern of results is most consistent with an impairment in lateral orbitofrontal cortex function, but additional research is needed to determine the neurobiological cause of this pattern of results.

Lutein-loaded nanoparticles reverse oxidative stress, apoptosis, and autism spectrum disorder-like behaviors induced by prenatal valproic acid exposure in female rats

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction and repetitive behaviors. In this study, we assessed the effect of lutein-loaded nanoparticles on ASD-like behaviors induced by prenatal valproic acid (VPA) exposure in female offspring rats and the possible involvement of oxidative stress and apoptosis. Pregnant female Wistar rats received a single intraperitoneal injection of VPA (600 mg/kg), on the gestational day 12.5. The VPA-exposed female offspring rats were divided into two subgroups and received either lutein-loaded nanoparticles (5 mg/kg) or saline by oral gavage, for 14 days. The animals were submitted to the three-chamber test and open field to evaluate ASD-like behaviors. The hippocampus was removed for the determination of oxidative stress indicators (ROS; TBARS; SOD and Nrf2) and apoptosis biomarkers (Hsp-70; p38-MAPK; Bax and Bcl-2). The exposure to lutein-loaded nanoparticles reversed sociability deficit, social memory deficit, and anxiety-like and repetitive behaviors induced by VPA, and restored the oxidative stress indicators and apoptosis biomarkers in the hippocampus. This neurochemical effect must be associated with the reversal of ASD-like behaviors. These results provide evidence that lutein-loaded nanoparticles are an alternative treatment for VPA-induced behavioral damage in female rats and suggest the involvement of oxidative stress.

Effects of continuous prenatal and postnatal global system for mobile communications electromagnetic waves (GSM-EMW) exposure on the oxidative stress biomarkers in female rat liver

In light of the increased use of communication technologies, the harm caused by continuous exposure to emitted radiation on pregnancy and developing newborns is among the public concerns. Using Sprague-Dawley rats, our study investigates the effects of 24 h/day prenatal and postnatal 900 MHz radiofrequency electromagnetic radiation (RF-EMR) exposure of female rats on liver oxidative stress (OS) and other hepatic parameters at postnatal days (PND) 1, 9, and 21. Our results showed that RF-EMR exposure led to an increase in oxidative stress status as indicated by a significant elevation in MDA level at PND9 and PND21, a decrease in catalase (CAT) activity at all ages, a reduction (PND1 and PND9) in catalase amounts and mRNA expression, in addition to a decrease in GPx activity at PND21 in the exposed group. Current findings also showed a significant increase in cytoSOD at PND9 and 21 and a reduction in mitoSOD at PND21 in the exposed groups compared to the control groups. However, significant increases in glutathione peroxidase (GPx) level and mitoSOD activity were observed at all studied ages. Furthermore, cytoSOD activity showed a significant reduction in PND1, whereas in PND9 the value of this parameter increased compared to the non-exposed group. Moreover, while SOD1 mRNA expression increased at PND1, it decreased at PND9 and 21. However, GPx1 expression was shown to be always decreased in the exposed group. In addition, at PND1 and 9, exposed rats showed a similar response on Akt1, nuclear factor erythroïd 2-related factor 2 (Nrf-2), and intercellular adhesion molecule-1 (ICAM-1) expression. Therefore, an increased oxidative stress status produced from a continuous (24 h/day) GSM-modulated 900 MHz radiofrequency electromagnetic radiation (RF-EMR) exposure during the prenatal and postnatal periods may result in adverse health effects during future life stages.

A Chinese herbs complex ameliorates gut microbiota dysbiosis induced by intermittent cold exposure in female rats.

Cold is a common source of stress in the alpine areas of northern China. It affects the microbial community, resulting in the invasion of pathogenic microorganisms and intestinal diseases. In recent years, studies have reported that Chinese herbal extracts and their fermentation broth have a significant beneficial effect on gut microbiota. This study aimed to investigate the probiotic effect of a self-designed Chinese herbs complex on the gut microbiota of rats exposed to cold. The rats were treated with intermittent cold exposure and Chinese herbs complex for 14 days, and the gut microbiota composition and other parameters were assayed. The 16s ribosomal DNA high-throughput sequencing and analysis confirmed that the Chinese herbs complex positively improved the gut microbiota. We found that cold exposure could lead to significant changes in the composition of gut microbiota, and affect the intestinal barrier and other physiological functions. The relative abundance of some probiotics in the genus such as Roseburia, Parasutterella, and Elusimicrobium in rats treated with Chinese herbs complex was significantly increased. Serum D-lactic acid (D-LA) and lipopolysaccharide (LPS) were increased in the cold exposure group and decreased in the Chinese herbs complex-treated group. Moreover, the Chinese herbs complex significantly increased the protein expression of occludin. In conclusion, the Chinese herbs complex is effective in restoring the gut microbiota caused by cold exposure, improving the function of the intestinal barrier, and may act as a prebiotic in combatting gut dysbiosis.

Hormonal profile changes induced by pesticide mixture exposure in female rats revealed by hair analysis.

Pesticide exposure has been associated with hormonal disruption in both animals and humans. However, there is limited knowledge of the combined effects of complex mixtures of pesticides on endogenous hormone levels. Here, we used hair analysis to assess the impact of a pesticide mixture comprising 19 components from multiple chemical classes at eight doses of 0-400μg/kg body weight (bw) three times per week per component on concentrations of 36 steroid and thyroid hormones in female rats over a 90-day exposure period. We detected 13 hormones in rat hair, namely estradiol (E2), androstenedione (AD), testosterone (T), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), pregnenolone (P5), progesterone (P4), 11-deoxycorticosterone (11-DOC), corticosterone (CORT), 3,3'-l-diiodothyronine (T2), 3,5,3'-l-triiodothyronine (T3), 3,3',5'-l-triiodothyronine (rT3), and 3,5,3',5'-l-tetraiodothyronine (T4). In comparison to the control group, hair E2 concentration was significantly lower in the two highest (200 and 400μg/kg bw) exposure groups, whereas hair DHEAS and CORT concentrations were significantly higher in the 40μg/kg bw and the highest exposure groups, respectively. Results from generalized additive models suggest that pesticide exposure resulted in monotonic dose responses in hair E2 concentration, CORT concentration and DHEA/CORT molar ratio but nonmonotonic dose responses in hair T concentration, DHEAS concentration, P4/P5 and DHEA/DHEAS molar ratios. The associations of E2, CORT and DHEA/CORT ratio with exposure intensity were confirmed by their significant linear relationships with hair concentrations of at least 23 of the 25 exposure biomarkers analyzed. Our results demonstrate that exposure to low levels of the pesticide mixture evaluated here can alter hair reproductive and adrenal hormones levels.

Abstract 9869: Adverse Effects of Smoking/Vaping of Several Types of Tobacco Products and Marijuana on Cardiac Function and Platelet Aggregation

Tobacco and marijuana smoke contains ~7,000 chemicals that cause disorders in cardiac autonomic function, vascular biology, and platelet function. Along with marijuana, e-cigarettes (e-cigs) and heat-not-burn tobacco products (e.g., IQOS) are often viewed as being less harmful than smoking tobacco. However, there are many unknowns about how marijuana, e-cigs, and IQOS impact cardiovascular physiology and platelet function over the long term. To explore cardiovascular effects of smoking/vaping, we exposed conscious rats to single (one time) and multiple (one time daily for 10 days) pulsatile mainstream smoking/vaping of e-cigs (JUUL), IQOS (American and Russian HeatSticks), marijuana (~10% THC), and cannabinoid-depleted (“placebo”) marijuana, relative to regular tobacco (Marlboro Red) smoking and air controls. Cardiac function was assessed by echocardiography pre- and post- single exposure. Platelet aggregation was measured to determine changes in platelet response immediately post-single exposure and one day after the last of multiple exposures. Single exposure induced acute effects on echocardiographic function with reduced ventricular end-diastolic volume (EDV) in IQOS and marijuana groups of both genders (Fig. A), potentially indicating incomplete ventricular relaxation between heart beats after exposure. However, marijuana caused adjustments of end-systolic volume (ESV) and EDV without changes in ejection fraction (EF) in females, with smaller ESV and reduced EDV. Tobacco, marijuana, and placebo marijuana smoking immediately increased collagen-induced platelet aggregation post-single exposure in female rats. Tobacco smoking, JUUL, IQOS, and both kinds of marijuana significantly increased platelet aggregation post-multiple exposure as compared to air controls in mixed genders (Fig. B). P values ≤ 0.1 are shown. Conclusion: smoking/vaping causes clinically relevant adverse effects on cardiac function and platelet aggregation.

P–641 Pubertal high-fat diet interferes with the ovarian kisspeptin ligand and receptor expressions regulating female fertility

Abstract Study question Does chronic high-fat diet affect ovarian dysfunctions via changing of kisspeptin and kisspeptin receptor expressions? Summary answer Ovarian kisspeptin and kisspeptin receptor expressions are significantly affected by the chronic high-fat diet. What is known already Regarding the hypothalamic-pituitary-gonadal (HPG) roles of kisspeptin, it appears that it directly stimulates LH secretion from the pituitary, consecutively stimulates ovulation in the female. There are also studies showing that kisspeptins can increase GnRH release, serum FSH, LH, and testosterone (in vivo), and regulate ovulation in women who have reached sexual maturity through the central control of the HPG axis. Fatty acids can act as nutritional signals that regulate the HPG axis, and elevated levels of circulating saturated fatty acids associated with high-fat diet (HFD)-feeding has been shown to induce ovarian dysfunction. HFD consumption induces ovarian dysfunction in rodents. Study design, size, duration 4-week-old female rats obtained from Akdeniz University Experimental Animals Unit. Animals were kept in standard conditions; fed with control diet consisting of standard laboratory food (13.5% of total energy from oil) or HFD (60% of total energy from oil) for 8 weeks. Experimental procedures were performed at the age of 12 weeks (250–275 g live weight). Live weights and food consumption of the animals in both groups were calculated weekly and recorded during the experiment. Participants/materials, setting, methods At the end of the experimental period, the animals were sacrificed and tissues were obtained. Sections were taken from paraffin-embedded tissues. Immunohistochemical staining for KISS1 and GPR54 were performed in both groups’ ovaries. Tissue collecting, processing, and immunohistochemical staining were performed at the histology and embryology department of Akdeniz University Faculty of Medicine. Main results and the role of chance There was a significant increase in body weights of the HFD group during the experiment period compared to the control group. As a result of immunohistochemical staining, kisspeptin expression is specifically localized to the corpora lutea of the control ovaries. However, kisspeptin expression in the corpora lutea of the HFD ovaries was increased regardless of the ovarian follicles. KISS1R expression was located in the cytoplasm of oocytes. HFD group also expressed the KISS1R in the oocytes with increasing intensity. Limitations, reasons for caution The study design included pubertal age limit of the samples. The functional reproductive period in different mammal species should be considered. Wider implications of the findings: We suggest that chronic exposure of female rats to a high-fat diet may induce ovarian Kisspeptin expression while kisspeptin receptor expression is not affected in oocytes. Clinical implications should be considered. Trial registration number B.30.2.AKD.0.05.07.00/99

Inhibition of dipeptidyl peptidase-4 averts free fatty acids deposition in the hearts of oral estrogen-progestin contraceptive-induced hyperinsulinemic female rats.

Free fatty acid (FFA) deposition in non-adipose tissues such as the heart is a characteristic of insulin resistant states which feature hyperinsulinemia and dipeptidyl peptidase-4 (DPP-4) activation. Estrogen-progestin oral contraceptives (OC) treatment reportedly increased DPP-4 activity in rat tissue, and DPP-4 inhibitors have anti-diabetic and anti-inflammatory properties. This study aims to investigate the effects of DPP-4 inhibition on cardiac FFA deposition in estrogen-progestin-treated female rats. From our data, estrogen-progestin OC exposure in female rats led to elevated plasma insulin, cardiac DPP-4 activity, FFA and triglyceride (TG) accumulation, TG/high-density lipoprotein cholesterol (TG/HDL-C) ratio, adenosine deaminase/xanthine oxidase/uric acid pathway (ADA/XO/UA), lipid peroxidation, glycogen synthase activity, and alanine phosphatase; whereas cardiac glucose-6-phosphate dehydrogenase, Na+/K+-ATPase and nitric oxide (NO) were decreased. However, DPP-4 inhibition resulted in decreased plasma insulin, cardiac DPP-4 activity, FFA, TG, TG/HDL-C ratio, and alkaline phosphatase. These were accompanied by reduced ADA/XO/UA pathway, lipid peroxidation, and augmented NO and Na+/K+-ATPase in estrogen-progestin OC-treated rats. DPP-4 inhibition attenuated cardiac lipid deposition accompanied by reduced activity in the ADA/XO/UA pathway in estrogen-progestin OC-treated female rats. DPP-4 is therefore a plausible therapeutic target in cardiometabolic disorders.

Transgenerational effects on anxiety-like behavior following adolescent morphine exposure in female rats

Global opioid use and misuse remains high, despite efforts to decrease rates of prescribing and diversion. Chronic exposure to opioids, particularly during critical periods of development, can lead to long-lasting effects, including effects that may extend to future generations. Using a rodent model, we have demonstrated significant transgenerational effects of female adolescent morphine exposure, despite the absence of in utero drug exposure. While these effects have been observed in both sexes, effects on anxiety-like behavior were only observed in F1 females. The current study was designed to examine both inter- and transgenerational effects of adolescent morphine exposure on anxiety-like behavior. Female Sprague Dawley rats were administered increasing doses of morphine (5−25 mg/kg s.c.) or saline for 10 days during adolescence (PND30−39). Adult diestrous female offspring (MORF1 or SALF1) and grand offspring (F2) were tested for anxiety-like behavior using the elevated plus maze (EPM). F1 females cross-fostered to donor mothers were also examined. The results show that MORF1 and MORF2 females spend significantly more time on the open arms of the EPM compared to SALF1 controls, an effect that persisted in cross-fostered females. Additional studies demonstrate that this effect is estrous cycle dependent, as decreased anxiety-like behavior was observed in diestrus, while increased anxiety-like behavior was observed in estrus. These behavioral effects were not associated with any differences in circulating corticosterone either at baseline or following EPM testing. Thus, female adolescent morphine exposure alters the regulation of anxiety-like behavior in an estrous-dependent manner and this effect persists in the F2 generation.

Chronic irisin exposure decreases sexual incentive motivation in female rats

Irisin is a novel myokine/adipokine that is released into the circulation in response to types of exercise and increases energy expenditure. Disorders in the endocrine system related to reproduction, which occur due to the chronic or excessive exercise, cause a decrease in women's sexual desire. However, the role of irisin hormone on sexual desire in women has not been elucidated. We hypothesized that chronic irisin exposure would decrease sexual incentive motivation for male partners by affecting the endocrine system in female rats. We tested this by quantifying and comparing of both sexual incentive motivation and active investigation for sexual partner, and also changes in the serum hormone levels in chronically irisin-treated female rats. As a result, chronic irisin exposure decreased the time spent near the male rat, male preference ratio, and male investigation preference ratio. Furthermore, serum testosterone and progesterone levels significantly decreased and estradiol levels increased while kisspeptin-1 levels were not changed by chronic irisin exposure in female rats. These data indicate that chronic irisin exposure may cause low sexual incentive motivation for opposite-sex partners in female rats via changes in reproductive hormones. The results suggest that irisin hormone may play a role in decreased sexual desire due to long-term exercise in women.

Chronic Ethanol Exposure during Adolescence Increases Voluntary Ethanol Consumption in Adulthood in Female Sprague Dawley Rats.

Early alcohol use is a major concern due to the dramatic rise in alcohol use during adolescence. In humans, adolescent males and females consume alcohol at equivalent rates; however, in adulthood males are more likely to consume harmful levels of alcohol. In animal models, the long-term dose-dependent and sex-dependent effects of alcohol exposure during adolescence have not been readily assessed relative to exposure that is initiated in adulthood. The purpose of the present set of experiments was to determine if adolescent exposure to chronic ethanol would predispose male and female rats to greater ethanol intake in adulthood when compared to animals that were not exposed to chronic ethanol exposure until early adulthood. Male and female rats were chronically administered 0.75 g/kg or 1.5 g/kg ethanol or saline for 21 days during adolescence (postnatal day (PND) 30–50) or adulthood (PND 60–80). All rats subsequently underwent 14-days of abstinence (PND 51–64 or PND 81–94, respectively). Finally, all rats were given 30-min daily access to saccharin-sweetened ethanol or saccharin alone from PND 65–80 for adolescent-exposed rats and PND 95–110 for adult-exposed rats. Exposure to 0.75 g/kg ethanol did not alter ethanol or saccharin intake in adolescent-exposed or adult-exposed rats, regardless of sex. In contrast, chronic exposure to the higher 1.5 g/kg dose during adolescence increased ethanol intake in adulthood in female rats. However, there was no change in saccharin intake in animals exposed to 1.5 g/kg ethanol during adolescence or adulthood, regardless of sex. Additionally, there were no clear age- and ethanol-dependent changes in duration of loss of righting reflex and blood ethanol concentrations to a challenge administration of a higher dose of ethanol. The results of the present set of experiments indicate chronic exposure to a high dose of ethanol during adolescence in female rats did indeed predispose rats to consume more ethanol in adulthood. Given that these effects were only observed in adolescent-exposed female rats, these results support a unique vulnerability to the long-term consequences of adolescent ethanol exposure in female rats, an effect that is not merely mediated by the sweetener used in the ethanol solution.

Effect of subacute combined oral exposure of titanium dioxide nanoparticles and glucose on blood glucose homeostasis in young SD rats

To explore the effect of combined oral exposure of titanium dioxide nanoparticles(TiO_2 NPs) and glucose on blood glucose homeostasis in young SD rats. Eighty 4-week-old young SD rats were randomly divided into 8 groups(10 rats in each group, half male and half female). The rats were exposed to TiO_2 NPs through intragastric administration at 0, 2, 10 and 50 mg/kg with or without 1. 8 g/kg glucose daily for 30 days. Blood glucose was monitored weekly during the experiment. Oral glucose tolerance test(OGTT) was carried out after subacute exposure(30 days), and the biomarkers related to blood glucose homeostasis were detected, including the contents of glycosylated serum protein(GSP), glycosylated hemoglobin(HbA1 c), insulin, C-peptide and glucagon. At the same time, the pancreatic pathology of rats was observed. TiO_2 NPs were anatase crystals, closely spherical shape, with an average particle size of(24±5)nm. Exposure of TiO_2 NPs alone had little effect on blood glucose homeostasis. Blood glucose decreased on the 16 th exposure day at dose of 10 mg/kg TiO_2 NPs, and postprandial blood glucose(2 h) decreased after 30 days of TiO_2 NPs exposure at doses of 2 and 50 mg/kg in male rats(P&lt;0. 05). The combined effect of oral exposure of TiO_2 NPs and glucose on blood glucose homeostasis was more obvious than that of TiO_2 NPs alone. Blood glucose decreased on the 9 th exposure day at dose of 10 mg/kg TiO_2 NPs+glucose in female rats, and postprandial blood glucose(2 h) decreased at dose of 2 and 50 mg/kg TiO_2 NPs+glucose after 30 days of exposure in male rats(P&lt;0. 05). Blood glucose decreased on the 9 th day after 10 mg/kg TiO_2 NPs+glucose exposure in female rats. The glycosylated serum protein decreased and postprandial blood glucose(30 and 60 min) as well as the area under curve of OGTT increased in male rats after 30 days of exposure(P&lt;0. 05). The changes of blood glucose-regulating hormones were only found after the combined exposure of 10 mg/kg TiO_2 NPs+glucose for 30 days, including the decrease of insulin in female rats, as well as the decrease of insulin and the increase of glucagon in male rats(P&lt;0. 05). The interaction analysis showed that TiO_2 NPs and glucose had significant synergistic effect on postprandial blood glucose(60 min) in male rats(P&lt;0. 05). No abnormality was found in the pathological observation of pancreas in rats of experimental groups. Subacute combined oral exposure of TiO_2 NPs and glucose could affect the blood glucose homeostasis of young SD rats, resultsing in temporary hypoglycemia and impaired glucose tolerance, as well as adaptive changes of blood glucose-regulating hormones. The male rats were more sensitive. Compared with the exposure of TiO_2 NPs alone, the combined exposure of TiO_2 NPs and glucose induced more significant effects. Significant synergistic effect between them occurred on postprandial blood glucose.

Dexamethasone increases renal free fatty acids and xanthine oxidase activity in female rats: could there be any gestational impact?

Dexamethasone (DEX) is used for various conditions in female and even during pregnancy. We tested the hypothesis that DEX exposure in female rats would lead to renal free fatty acid (FFA) accumulation with elevated xanthine oxidase (XO) activity that would be aggravated by pregnancy. Twenty-four female rats (n = 6/group) were randomly assigned to non-pregnant (NPR), DEX-exposed non-pregnant (NPR + DEX), pregnant (PRE) and DEX-exposed pregnant (PRE + DEX), respectively. NPR and PRE rats received vehicle (po) while NPR + DEX and PRE + DEX groups received DEX (0.2 mg/kg; po), between gestational days 14 and 19. Data showed that DEX exposure caused increased plasma creatinine, urea, renal FFA accumulation, lipid peroxidation, aminotranferases, depressed glutathione, increased activity of XO, and elevated uric acid in both pregnant and non-pregnant rats. The findings of this study indicate that DEX exposure would cause renal FFA accumulation and glutathione depletion that are accompanied by increased activity of XO/uric acid independently of gestation. The study also implies that DEX-induced renal damage could be worsened by gestation.

Thyroid-disrupting effects of chlorpyrifos in female Wistar rats

Thousands of chemicals are released into the environment daily, arousing great scientific interest because they can influence the overall function of living organisms. The indiscriminate use of pesticides, especially organophosphate, confers important risks to both public and environmental health. Previous studies showed that chlorpyrifos (CPF) acts as an endocrine disruptor. Nevertheless, CPF is still widely used in many countries. Thus, we evaluated the thyroid-disrupting effects of CPF after short-term low-dose oral exposure in female Wistar rats. A total of 48 female Wistar rats were divided into five experimental groups (n = 8/group) that were treated orally by gavage with vehicle (control) and chlorpyrifos (0.01, 0.1, 1, and 10 mg/kg) for 5 days. Clinical signs of toxicity were observed throughout treatment. On day 6, the animals were weighed. Serum samples were obtained to measure levels of thyroid hormones, alanine aminotransferase, aspartate aminotransferase, bilirubin, glutamyl transpeptidase, and estradiol. The animals were then euthanized by deep anesthesia with isoflurane. The thyroid gland, liver, spleen, and kidneys were collected to determine relative organ weight and perform histopathological analyses. We observed a significant increase in total triiodothyronine (T3) levels in all CPF treatment groups, even at very low doses that corresponded to the Acceptable Daily Intake. Only the highest dose tested significantly increased both total and free T3 levels. In the group that received the highest dose of CPF, thyroid follicles had irregular contours and few or no colloids. The present results indicated that short-term low-dose CPF exposure in female rats induced significant thyroid-disrupting effects.

Subacute co-exposure to low doses of ruthenium(III) changes the distribution, excretion and biological effects of silver ions in rats

Environmental contextAlthough ruthenium is a technology-critical element used in several new industries, little is known about its environmental impact or possible human health risks. We report a toxicological evaluation of laboratory animals during co-exposure to ruthenium and silver. We identified interactions between the two elements that could lead to unwanted biological effects. AbstractRuthenium is one of the rarest metals on Earth that is classified as a technology-critical element (TCE). Silver, however, is well known for its antibacterial and immunostimulant properties. The increasing use of Ru and Ag in medicine and daily life makes simultaneous exposure possible, with unknown pharmacokinetic or toxicological consequences for the human organism. Thus, the present study investigated the influence of co-exposure to RuIII on the subacute toxicity of Ag ions in rats after repeated daily administration for 28 days of low doses by oral gavage. The subacute toxicity was investigated by the evaluation of several biochemical and hematological parameters, evaluation of specific oxidative stress biomarkers from liver and kidney, and histopathological investigation of liver and kidney tissue samples after 28 days of exposure in female rats. In addition, Ag and Ru concentrations were determined by inductively coupled plasma mass spectrometry (ICP-MS) in urine, liver and kidney parenchyma in male rats. The obtained results showed that co-exposure to low doses of RuIII and Ag did not produce any significant biochemical, hematological or histopathological alterations in the treated female rat groups, except for an increased red cell distribution width (RDW) value. A decrease of urinary excretion of Ag and of the Ag concentration in kidneys was observed in the male rat group co-exposed to RuIII and Ag. This is the first invivo study investigating the toxic effect of co-exposure to low doses of Ag and Ru ions, and the obtained results may justify further research on this subject, mainly on the investigation of possible competitive mechanisms.