Exposure Of Female Mice Research Articles

Deficits in Motor Function After Repeated Exertional Heat Stroke Exposure in Female Mice

Exertional Heat Stroke (EHS) is a life‐threatening illness that can result in a number of negative health outcomes. Once exposed to EHS, patients are considered to be at greater risk of subsequent EHS. In this study we hypothesized that a single EHS exposure would result in greater susceptibility to a second EHS, and that the consequences of EHS on skeletal muscle/motor function would be more profound. Twelve female mice were exposed to an initial EHS, allowed to rest for 2 weeks and then exposed to a second EHS and followed for 1 week. All mice reached symptom limitation (loss of consciousness) at lower maximum core temperatures (Tc, max) in their second EHS. Mice also had lower durations of unconsciousness after the second EHS. We evaluated motor function, before and after the EHS using behavior assessments including trunk curl, horizontal rotation response, catalepsy and a ‘weight test’ protocol. Mice showed a significant decrease in the strength (P = 0.0182) after the second EHS, as measured by the weight test protocol, an impaired rotation response (P = 0.0061), catalepsy (P = 0.0398) and trunk curl (P = .0001). These measures indicate reductions in strength and/or motor coordination. In conclusion, we identified that exposure to EHS increases the susceptibility to a second EHS with worsening outcomes in motor function after the second EHS. These data suggest that following a single exposure to EHS there is a prolonged period of increased vulnerability to EHS and greater potential risk of deficits in organ function.Support or Funding InformationSupported by the BK and Betty Stevens Endowment and a Fellowship from King Saud University, Saudi Arabia.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Baicalein, a flavonoid, causes prolonged estrus and suppressed fertility output upon prenatal exposure in female mice.

Baicalein (BC), a phytoestrogen of the flavonoid family shows beneficiary and adverse effects. Effect of BC on reproduction is still not understood. Reproductive toxic effects on female mice were tested in this study. Inseminated Wistar mice were divided into four groups and administered IP with 30, 60, and 90 mg/Kg body weight of BC on gestation days 11, 13, 15, and 17, and controls treated with DMSO. They were allowed to deliver pups and offspring were separated gender-wise on day 21. The stages of the estrus cycle and its lengthlengths of three successive cycles were measured from day 38 of young females. The mature female offspring of at 60 days age havewere cohabited with control males and the female reproductive endpoints and body weights of dams were measured. The BC exposure increased the length of the estrus cycle, especially the metestrus and diestrus phases were prolonged among other phases of the estrus cycle. Recorded significant reduction in the body weights (P<0.05) of prenatally BC exposed dams on 8 and 18 days of gestation. A significant increase in the conception time (P<0.0001), pre (53.42%) and post (8.82%) implantation loss, and resorptions (P=0.055), whereas a significant decrease in the number of implantations and live fetuses (P<0.0001) were found in BC exposed dams in a dose-dependent manner. Prenatal BC exposure prolonged the estrus cycle due to the augmented length of metestrus and diestrus phase, and is reportingreported for the first time. Female fertility output in mice is affected severely by prenatal BC exposure.

Longitudinal effects of developmental bisphenol A, variable diet, and physical activity on age-related methylation in blood.

Research indicates that environmental factors can alter DNA methylation, but the specific effects of environmental exposures on epigenetic aging remain unclear. Here, using a mouse model of human-relevant exposures, we tested the hypothesis that early-life exposure to bisphenol A (BPA), variable diet, and/or changes in physical activity would modify rates of age-related methylation at several target regions, as measured from longitudinal blood samples (2, 4, and 10 months old). DNA methylation was quantified at two repetitive elements (LINE-1, IAP), two imprinted genes (Igf2, H19), and one non-imprinted gene (Esr1) in isogenic mice developmentally exposed to Control, Control + BPA (50 µg/kg diet), Western high-fat diet (WHFD), or Western + BPA diets. In blood samples, Esr1 DNA methylation increased significantly with age, but no other investigated loci showed significant age-related methylation. LINE-1 and IAP both showed significant negative environmental deflection by WHFD exposure (P < 0.05). Esr1also showed significant negative environmental deflection by WHFD exposure in female mice (P = 0.02), but not male mice. Physical activity had a non-significant positive effect on age-related Esr1 methylation in female blood, suggesting that it may partially abrogate the effects of WHFD on the aging epigenome. These results suggest that developmental nutritional exposures can modify age-related DNA methylation patterns at a gene related to growth and development. As such, environmental deflection of the aging epigenome may help to explain the growing prevalence of chronic diseases in human populations.

Chronic corticosterone administration effects on behavioral emotionality in female c57bl6 mice.

Understanding the pathophysiology of affective disorders and their treatment relies on the availability of experimental models that mimic aspects of the disease. Most of the studies on depressive disorders are conducted with male rodents, mostly because including females in protocols is more difficult. Indeed, there is a complex series of changes in the brain of females due to the estrous cycle, adding an important variability factor to the disease. However, twice as many women as men have a lifetime diagnosis of major depressive disorder (MDD), so we need to develop reliable female models of depression to improve our understanding of this disease. Here, we describe the effects of chronic corticosterone administration (CORT) on female mice, a procedure known to enhance behavioral emotionality in male mice. A dose-response study showed that 4 weeks of CORT exposure at 35 μg/ml in the drinking water enhanced the emotionality score of female mice, but with a very small size effect. Tests of longer treatment duration failed to potentiate the behavioral effects of CORT. As some steps of adult hippocampal neurogenesis are known to be sensitive to chronic CORT exposure, cell proliferation and survival, as well as neuronal maturation in the dentate gyrus of the hippocampus, analyses revealed no effect of chronic CORT exposure in female mice. Overall, this study showed that female C57BL6 mice are insensitive to chronic CORT as a way to model anxio-depressive-like behavior. (PsycINFO Database Record

Sunitinib Possible Sex-Divergent Therapeutic Outcomes.

Sunitinib is a tyrosine kinase inhibitor used for the treatment of renal cell carcinoma and metastatic brain tumors. Preclinical pharmacokinetic studies have shown higher sunitinib hepatic and brain exposure in female mice and higher sunitinib kidney concentrations in male mice. We explored whether sex-divergent tissue pharmacokinetics may anticipate sex-divergent therapeutic and toxicology responses in male and female patients. The review of the available scientific literature identified case reports, case series reports, clinical trials, and other studies associating sex with sunitinib outcomes. The results suggest male patients may respond better to renal cell carcinoma treatment and female patients may have better brain tumor treatment outcomes but a higher incidence of adverse events. Although more high-quality evidence is needed, these results, as anticipated by the preclinical data, may indicate possible sunitinib sex-divergent therapeutic outcomes in patients. In addition, we propose the systematic analysis of sex-based outcomes in clinical trial reports and their inclusion and review in the ethics committees and review boards to prevent, amongst others, patient burden in upcoming clinical trials.

Prenatal Nicotine Exposure Impairs the Proliferation of Neuronal Progenitors, Leading to Fewer Glutamatergic Neurons in the Medial Prefrontal Cortex.

Cigarette smoking during pregnancy is associated with various disabilities in the offspring such as attention deficit/hyperactivity disorder, learning disabilities, and persistent anxiety. We have reported that nicotine exposure in female mice during pregnancy, in particular from embryonic day 14 (E14) to postnatal day 0 (P0), induces long-lasting behavioral deficits in offspring. However, the mechanism by which prenatal nicotine exposure (PNE) affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that PNE disrupted the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and subventricular zones. In addition, using a cumulative 5-bromo-2'-deoxyuridine labeling assay, we evaluated the rate of cell cycle progression causing the impairment of neuronal progenitor proliferation, and uncovered anomalous cell cycle kinetics in mice with PNE. Accordingly, the density of glutamatergic neurons in the medial prefrontal cortex (medial PFC) was reduced, implying glutamatergic dysregulation. Mice with PNE exhibited behavioral impairments in attentional function and behavioral flexibility in adulthood, and the deficits were ameliorated by microinjection of D-cycloserine into the PFC. Collectively, our findings suggest that PNE affects the proliferation and maturation of progenitor cells to glutamatergic neuron during neurodevelopment in the medial PFC, which may be associated with cognitive deficits in the offspring.

Effect of Selenomethionine Supplementation in Food on the Excretion and Toxicity of Arsenic Exposure in Female Mice

Selenium (Se) is an essential component of several major metabolic pathways and controls immune function. Arsenic (As) is a human carcinogen with immunotoxic and genotoxic activities, functioning mainly by producing oxidative stress. Due to the ability of Se to interact with As and to possibly block its toxic effects, we investigated the impact of dietary Se-methionine (Se-Met) supplementation on the toxicity of As exposure in vivo in a mouse model. Sufficient and excess levels of Se-Met (0.2 and 2 ppm, respectively) were fed to C57BL/6N female mice exposed to sodium arsenite (3, 6 and 10 mg/kg) in tap water for 9 days. We observed that As exposure increased Se-Met excretion in the urine. Se-Met supplementation increased the relative liver weight and decreased the concentration of total liver proteins in animals exposed to 10 mg/kg of As. Se-Met supplementation maintained a normal pool of glutathione in the liver and increased glutathione peroxidase concentration, although the lipoperoxidation level was increased by Se-Met even without As exposure. Se-Met supplementation helped to maintain the CD4/CD8 ratio of lymphocytes in the spleen, although it increased the proportion of B cells. Se-Met supplementation prior to As exposure increased the secretion of interleukin-4, IL-12 and interferon-γ and the stimulation index of the spleen cells in in vitro assays. Se-Met intake improved the basal immunological parameters but did not reduce the damage caused by oxidative stress after low-dose As exposure.

Corticotropin-releasing factor modulation of forebrain GABAergic transmission has a pivotal role in the expression of anabolic steroid-induced anxiety in the female mouse.

Increased anxiety is commonly observed in individuals who illicitly administer anabolic androgenic steroids (AAS). Behavioral effects of steroid abuse have become an increasing concern in adults and adolescents of both sexes. The dorsolateral bed nucleus of the stria terminalis (dlBnST) has a critical role in the expression of diffuse anxiety and is a key site of action for the anxiogenic neuromodulator, corticotropin releasing factor (CRF). Here we demonstrate that chronic, but not acute, exposure of female mice during adolescence to AAS augments anxiety-like behaviors; effects that were blocked by central infusion of the CRF receptor type 1 antagonist, antalarmin. AAS treatment selectively increased action potential (AP) firing in neurons of the central amygdala (CeA) that project to the dlBnST, increased the frequency of GABA(A) receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in dlBnST target neurons, and decreased both c-FOS immunoreactivity (IR) and AP frequency in these postsynaptic cells. Acute application of antalarmin abrogated the enhancement of GABAergic inhibition induced by chronic AAS exposure whereas application of CRF to brain slices of naïve mice mimicked the actions of this treatment. These results, in concert with previous data demonstrating that chronic AAS treatment results in enhanced levels of CRF mRNA in the CeA and increased CRF-IR in the dlBnST neuropil, are consistent with a mechanism in which the enhanced anxiety elicited by chronic AAS exposure involves augmented inhibitory activity of CeA afferents to the dlBnST and CRF-dependent enhancement of GABAergic inhibition in this brain region.

Persistent trefoil factor 1 expression imprinted on mouse vaginal epithelium by neonatal estrogenization

Exposure of female mice to estrogenic substances during the neonatal period induces developmental defects in the reproductive tract such as estrogen-independent persistent proliferation of the vaginal epithelium, which often leads to carcinogenesis in adulthood. In this study, several estrogen-regulated genes have been identified in the neonatal mouse vagina by DNA microarray hybridization analysis. Among the genes up-regulated in the developing vagina by a high dose of estrogen, trefoil factor 1 (TFF1), a mucin-associated gastrointestinal growth factor, showed a unique expression pattern in accordance with the irreversible changes induced by neonatal estrogenization in the vagina. Vaginal expression of TFF1 mRNA was markedly increased by estrogen in neonatal mice but not in adults, and pronouncedly intensified expression of the gastrointestinal gene was observed in the vagina of neonatally estrogenized mice even at adulthood. The specific localization of TFF1 protein in the epithelium of neonatally estrogenized vagina was confirmed by immunohistochemistry. Moreover, without any obvious alteration in the expression of gel-forming mucin genes, the lumen of the neonatally estrogenized vagina became filled with periodic-acid-Schiff-stained mucinous gel, which was possibly caused by the overexpression of TFF1. Thus, estrogen acts directly on the developing vagina in the permanent induction of TFF1 gene expression, and the gene induction does not appear to be related to hypermethylation of the cis-promoter of the TFF1 gene. TFF1 may be a useful marker for developmental estrogenization syndrome of the mouse vagina.

Diethylstilbestrol exposure during fetal development affects thymus: studies in fourteen-month-old mice

In utero exposure to diethylstilbestrol (DES) may have long-term immunological alterations after birth. It is hypothesized that in utero exposure to DES may pre-program the thymus to result in aberrant response to a subsequent adult exposure to an endocrine disrupting chemical. Pregnant mice at 14-days gestation were given either DES (0.25 μg; DES prenatal) or vehicle oil (Oil; Oil prenatal). One-year after birth, these mice were given a single dose of DES (DES adult) and thymii of these mice were studied two months later. DES prenatal/DES adult female mice had a significant decrease in thymocyte cellularity compared to female controls (Oil prenatal/DES adult). In contrast, male DES prenatal/DES adult mice had increased thymic mass and a trend towards increased thymocyte cellularity. There were no significant differences in the relative percentages of major thymocyte subsets, CD4 −CD8 −, CD4 +CD8 +, CD4 +CD8 −, CD4 −CD8 +, in either female or male DES prenatal/DES adult mice compared to their sex-matched controls. Nevertheless, thymocytes cultured in media alone showed increased percentage of apoptosis in CD4 +CD8 + subset from female DES prenatal/DES adult mice compared to similar cultures from sex-matched controls. Interestingly, the percentage of apoptosis of CD4 +CD8 + thymocytes in media-only cultures from DES prenatal/DES adult female mice was comparable to in vitro dexamethasone-exposed cultures from Oil prenatal/DES adult female mice. This pattern of increased apoptosis of female CD4 +CD8 + subset was not noticed in male DES prenatal/DES adult mice. This implies that prenatal DES exposure in female mice intrinsically alters the degree of apoptosis in CD4 +CD8 + thymocyte subset. Together, these data imply that prenatal DES exposure induces long-term thymic changes in a sex-related fashion.

Vitamin A prevents the irreversible proliferation of vaginal epithelium induced by neonatal injection of keratinocyte growth factor in mice.

Exposure of female mice to estrogen during the perinatal period results in estrogen-independent persistent proliferation and cornification of the vaginal epithelium when the animals become adults. However, the occurrence of such irreversible vaginal changes is blocked by concurrent vitamin A treatment. Neonatal exposure to keratinocyte growth factor (KGF), which is a paracrine mediator of epithelial-mesenchymal interactions, also induces the persistent proliferation and cornification of the vaginal epithelium in adult mice. This study was designed to examine whether concurrent administration of vitamin A inhibits the development of the irreversible vaginal changes in mice exposed neonatally to KGF. The vaginal epithelium in ovariectomized 35-day-old mice given 5 microg of KGF for 3 days after birth possessed a significantly larger number of layers and increased thickness as compared to that in control mice. Concurrent injections of 100 IU of vitamin A acetate inhibited the occurrence of the irreversible proliferation of the vaginal epithelium. These changes were equal to the results observed when 20 micro g of estrogen with or without vitamin A acetate was administered for 5 days after birth. Unlike the case of estrogen treatment, the effect of neonatal treatment with KGF seemed to appear after a latent period, since the vaginal epithelium did not show proliferation soon after the treatment. We discuss the inhibitory effect of VA on the irreversible vaginal changes induced by neonatal KGF treatment with reference to endocrine disruption by neonatal estrogen exposure.

Sexual maturation and fertility of male and female mice exposed prenatally and postnatally to trivalent and hexavalent chromium compounds.

The reproductive toxicity of trivalent and hexavalent chromium compounds was investigated in male and female mice exposed to 1000 ppm chromium chloride and potassium dichromate via their mother during gestational and lactational periods. Fertility was reduced in male offspring exposed to either trivalent or hexavalent chromium compounds. Body weights and weights of testes, seminal vesicles and preputial glands were reduced in trivalent-exposed male offspring. The exposure of female mice offspring to trivalent and hexavalent chromium compounds delayed sexual maturation. Fertility was reduced in female offspring exposed to either trivalent or hexavalent chromium compounds. The exposure of female mice to hexavalent chromium compound reduced the number of implantations and viable fetuses respectively. Body weight and weights of ovaries and uteri were reduced in trivalent-exposed female offspring. The results indicate that under our experimental conditions, the exposure of male and female mice offspring to either trivalent or hexavalent chromium compounds during gestational and lactational periods impair reproductive functions and fertility in adulthood.

Stage of susceptibility to carcinogenicity of prenatal dietary fat exposure tested by blastocyst transfer.

A previous experiment with exposure of female mice to a diet high in fat from 4 weeks of age through to the end of pregnancy demonstrated a substantial increase in the frequency of reproductive system tumors in their female offspring. Over this wide period of exposure, one or more specific periods of sensitivity to the carcinogenic effects of dietary fat should exist. To test whether a high fat diet affects maternal germ cells and/or zygote development through to blastocyst formation, two blastocyst transfer experiments were performed. Blastocysts from a dam on high fat were transferred to a pseudopregnant dam on low fat. The reverse type of transfer was performed for contrast. These experiments did not reveal any significant effect of dietary fat on maternal germ cells or zygote development.

Exposure of female mice to nocodazole 1 h after mating results in abnormal chromosome numbers and early death among conceptuses

Exposure of female mice to nocodazole 1 h after mating results in abnormal chromosome numbers and early death among conceptuses

The effect of exposure regimen and duration on benzene-induced bone-marrow damage in mice: I. Sex comparison in DBA/2 mice

In the mouse, the concurrent evaluation of micronuclei frequencies in peripheral blood polychromatic erythrocytes (PCE) and normochromatic erythrocytes (NCE) permits an assessment of both recently-induced and chronically-accumulated bone-marrow damage. This assay system was used to evaluate on a weekly basis the effect of exposure duration (1–13 weeks, 6 h per day) and exposure regimen (Regimen 1:5 exposure days per week; Regimen 2:3 exposure days per week) on the ability of 300 ppm benzene to induce genotoxic damage in the bone marrow of male and female DBA/2 mice. In addition, an analysis of the percentage of PCE in peripheral blood was used to evaluate benzene-induced alterations in the rate of erythropoiesis. Exposure to benzene induced a marked increased in the frequency of micronucleated PCE (MN-PCE), an effect which was considerably greater in male mice than in female mice. In both sexes, the induction of MN-PCE was independent of exposure regiment and of exposure duration. Exposure to benzene also resulted in an exposure duration-dependent increase in the frequency of MN-PCE. The frequency of MN-NCE increased more slowly in female than in male mice and, within each sex, more slowly in Regimen 2 animals. Apparent steady-state conditions for MN-NCE frequencies were attained by about the fifth week of exposure in female mice exposed by either regimen and in male exposed by Regimen 2. Steady-state conditions for MN-NCE frequencies in male mice exposed to benzene by Regimen 1 did not occur during the duration of the study. An analysis of %PCE data revealed an initial severe depression in the rate of erythropoiesis in both sexes, with the return in the production of PCE to control levels being dependent on both sex and exposure regimen. Suppression of PCE production occurred throughout the course of the study in Regimen 2 males, while the percentage of PCE returned to control levels sporadically after 5 weeks in Regimen 1 males and within 5 weeks in females, regardless of regimen. Thus, while the sex-dependent induction of genotoxic damage by multiple exposures to benzene over a 13-week period was independent of exposure regimen and duration, the induction of cytotoxic damage was both sex- and regimen-dependent. The most severe depression of erythropoiesis occurred in male DBA/2 mice exposed to benzene by the more intermittent regimen (i.e., 3 days/week versus 5 days/week). The results of this study underscores the complexity of the peripheral blood micronucleus assay and emphasizes the utility of evaluating micronucleated PCE and micronucleated NCE frequencies and the percentage of PCE in the same animals across time in multiple exposure situations.