Offspring Of Female Mice Research Articles

Effect of Lactational Low-Protein Diet on Skeletal Muscle during Adulthood and Ageing in Male and Female Mouse Offspring.

Sarcopenia is characterised by the loss of skeletal muscle mass and function, which leads to a high risk of increased morbidity and mortality. Maternal malnutrition has been linked to impaired development of skeletal muscle of the offspring; however, there are limited studies that report the long-term effect of a maternal low-protein diet during lactation on the ageing of skeletal muscles. This study aimed to examine how a maternal low-protein diet (LPD) during lactation affects skeletal muscle ageing in the offspring. Pups born from control mothers were lactated by mothers fed with an LPD. Post-weaning, mice were either maintained on an LPD or switched to a control, normal-protein diet (NPD). In males, an LPD mainly affected the size of the myofibres without a major effect on fibre number and led to reduced grip strength in ageing mice (24 months). Female mice from mothers on an LPD had a lower body and muscle weight at weaning but caught up with control mice at 3 months. During ageing, the muscle weight, myofibre number and survival rate of female pups were significantly affected. These findings highlight the effect of an LPD during lactation on skeletal muscle ageing, the lifespan of offspring and the importance of sexual dimorphism in response to dietary challenges.

The toxic effects and mechanisms of maternal exposure to Bisphenol F during gestation and lactation on lungs in female offspring mice

Epidemiologic studies suggest that prenatal exposure to bisphenols may increase the risk of respiratory disease in children. Bisphenol F (BPF), a member of the bisphenol family, is widely used in industrial production. However, the potential pulmonary toxic effects and mechanisms of BPF exposure on offspring remain unclear. In this study, maternal mice were exposed to 0, 40, 400, and 4000 μg/kg BPF during gestation and lactation. The results showed that an inflammatory response was observed in lungs of BPF-exposed female offspring mice, characterized by peribronchial inflammatory cell infiltration and an increase in the number of inflammatory cells in BALF. Subsequent transcriptome analysis identified a total of 685 differentially expressed genes (DEGs) were in lungs of female offspring mice exposed to high-dose BPF, with 526 upregulated genes and 159 downregulated genes. Among upregulated DEGs of top 10, most of the upregulated genes were associated with inflammatory responses. In addition, enrichment analysis showed that immunosuppression and oxidative damage were significantly enriched in lungs of female offspring mice, suggesting that BPF could induce immunosuppression and oxidative stress in lungs of female offspring mice. Overall, our findings provide mechanistic insights into the potential pulmonary toxicity associated with BPF exposure during gestation and lactation.

Cross-generational effects of dietary sea buckthorn on non-alcoholic fatty liver disease in offspring of obese female mice

Maternal obesity is a potential cause of non-alcoholic fatty liver disease (NAFLD) in the offspring. There is growing evidence that sea buckthorn plays an important role in protecting the liver. In this study, we established three dietary models of maternal to study the effects of different diets of maternal mice on the occurrence of NAFLD in their offspring and explored the underlying potential mechanisms. Studies have found that feeding sea buckthorn to maternal mice can improve liver steatosis and lipid deposition in the offspring. In addition, the expression of inflammation-related factors was reduced, the IκB/NF-κB pathway was inhibited, and inflammatory response was reduced in the offspring of maternal mice fed sea buckthorn. Furthermore, offspring exhibited increased antioxidant enzyme activity. Further, the results revealed that sea buckthorn inhibited glycolysis regulates AMPK/PKM2 activity, thereby reducing the occurrence of NAFLD. This study provides a novel strategy for treating NAFLD at the maternal level.

Fetal Origin of Abnormal Glucose Tolerance in Adult Offspring Induced by Maternal Bisphenol A Analogs Exposure.

With the widespread use of bisphenol A (BPA) analogs, their health risks have attracted attention. The effects of maternal BPA analogs exposure on glucose homeostasis in adult offspring and the underlying fetal origins require further exploration. Herein, we exposed pregnant mice to two types of BPA analogs─BPB and BPAF; we evaluated glucose homeostasis in adult offspring and maternal-fetal glucose transport by testing intraperitoneal glucose tolerance, determining glucose and glycogen contents, conducting positron emission tomography (PET)/computed tomography (CT), detecting expression of placental nutrient transport factors, and assessing placental barrier status. We observed that adult female offspring maternally exposed to BPB and BPAF exhibited low fasting blood glucose in adulthood, with even abnormal glucose tolerance in the BPAF group. This phenomenon can be traced back to the elevated fetal glucose induced by the increased efficiency of placenta glucose transport in late pregnancy. On the other hand, the expression of genes associated with vascular development and glucose transport was significantly altered in the placenta in the BPAF group, potentially contributing to enhanced fetal glucose. These findings provide preliminary insights into potential mechanisms underlying the disturbance of glucose metabolism in adult female offspring mice induced by maternal exposure to BPA analogs.

Maternal and filial consumption of probiotics protects from acute stress-induced anxiety and loss of benevolent gut microbes.

The study aimed to determine the effects of probiotic consumption during pregnancy and lactation and post-weaning on acute stress-induced anxiety and gut beneficial microbiota of the female offspring mice.The female offspring mice were divided into several groups: intact, control (only stressed), PBS/dam (dams gavaged with PBS), PRO/dam (dams gavaged with probiotics), PRO/dam+off (both dams and offspring gavaged with probiotics), and PBS/dam+off (both dams and offspring gavaged with PBS)The probiotics chosen are mainly L. rhamnosus, B.breve, and B. longum (108 CFU/ml). Foot shock stress will be applied for one hour on the 43rd day after birth. Behavioral tests were conducted using the open field and elevated plus-maze. Corticosterone was measured by ELISA kit, and intestinal microflora with qPCR.The data showed that PRO/dam+off had more entries into open arms compared to the control group and decreased move distance and time spent in closed arms compared to the control group. However, there was no significant difference between the PRO/dam group and the control group. In the open field test, the control group spent less time in the inner zone compared to the intact group and in PRO/dam+off group. Corticosterone hormone was increased in the control group and was decreased in the PRO/dam+off. Bifidobacteria and Lactobacilli decreased in the control group in comparison to the intact group, and in the PRO/dam+off group increased compared with other groups. Maternal and filial supplementation with a multi-strain probiotic mixture increased levels of beneficial bacteria and reduced stress-induced anxiety in mice.

Gastrointestinal nematode infection during pregnancy and lactation enhances spatial reference memory and reduces indicators of anxiety-like behaviour in uninfected adult female mouse offspring.

Maternal bacterial and viral infections that induce neuroinflammation in the developing brain are associated with impaired cognitive function and increased anxiety in the offspring. In contrast, maternal infection with the immunoregulatory murine gastrointestinal (GI) nematode, Heligmosomoides bakeri, appears to benefit neurodevelopment as juvenile 2- and 3-week-old male and female offspring had enhanced spatial memory, which may be due to a Th2/Treg biased neuroimmune environment. Here, the impact of maternal H. bakeri infection during pregnancy and lactation on the spatial and anxiety-like behaviours of adult, 3-month-old uninfected male and female offspring was explored for the first time. It was observed that adult female offspring of H. bakeri-infected dams had enhanced spatial reference memory and reduced anxiety-like behaviour compared to females of uninfected dams. These effects were not observed in adult male offspring. Thus, the positive influence of a maternal GI nematode infection on spatial memory of juvenile offspring persists in adult female offspring.

Maternal Limosilactobacillus reuteri rescues social and emotional recognition behavior in an environmental mouse model of autism

Introduction: Polybrominated diphenyl ethers (PBDEs) are thyroid disrupting chemicals with adverse neurodevelopmental effects in children. Our group has previously shown that PBDEs produce autism (ASD)-like traits (Kozlova et al. 2022 Arch Tox; PMID: 34687351) in combination with reduced hypothalamic oxytocin expression in developmentally exposed female mice offspring. Limosilactobacillus reuteri (LR) is a beneficial probiotic that can increase oxytocin and thyroid hormones (THs) in other ASD mouse models. Therefore, we hypothesized that LR would ameliorate PBDE-induced deficits in social behavior, oxytocin and thyroid status. Methods: C57BL/6N dams (n=8/group) were dosed with a commercial mixture of PBDE congeners, DE-71, at 0.1 mg/kg/d (DE-71), or corn oil vehicle control (VEH/CON) during preconception, gestation and lactation). Dams were gavaged with L. reuteri (LR) ATCC-PTA-6475 at 107-108 CFU/mL (gift of Biogaia, Sweden). Cohort 1 pups (C1) received LR via dam until weaning (PND 21). Cohort 2 pups (C2) continued to receive gavage of LR post-weaning, daily, through 6 mo of age. Results: Fecal microbiome analysis confirmed colonization of LR in dams after 25 doses and their offspring at postnatal day 22 and 40. Beta diversity PCoA using unweighted Unifrac revealed differences in microbial communities in 6 month old female (p<.05-.01) and male offspring (apparent) between DE-71 and VEH/CON (C2). LR treatment normalized DE-71-induced abnormal social novelty preference (30 min retention) in adult male (p<.01) and females (p<.05) and long-term social recognition memory (24 h retention) in adult C2 females (p<.001). Using an emotional recognition task DE-71-exposed C2 male and female offspring were unable to distinguish between emotional state of stimulus mice but LR supplementation normalized the DE-71-induced deficits in C2 males (p<.01) and females (p<.05). On a marble burying test DE-71 exposed offspring showed abnormally elevated scores compared to VEH/CON, which were normalized by LR treatment only in C1 females (p<.05). In females, maternal LR treatment ameliorated DE-71-induced locomotor hyperactivity in C1. Since social behavior involves discrimination between social odors we also investigated the effects of DE-71 and LR treatment on olfactory discrimination ability. LR treatment ameliorated DE-71 effects compared to VEH/CON, i.e., reduced dishabituation from social odor 1 to 2 in males and female (p<.0001). Single molecule in situ hybridization performed on paraventricular hypothalamic nucleus (PVN) sections revealed upregulation of thyroid hormone transporter monocarboxylate transporter 8 (Mct8) and downregulation of iodothyronine deiodinase 3 (Dio3) on oxytocin-positive neurons in DE-71 vs VEH/CON in C2 females. Dio3 expression was normalized in DE-71+LR. Conclusions: These results indicate that early life exposure to PBDEs alters thyroid hormone system genes in PVN neurons that express oxytocin, suggesting that PBDEs may alter ASD-relevant behavior via brain thyroid signaling. In addition, maternal LR supplementation provides normalization in a sex-dependent manner. This work is supported by a Danone North America Gut Microbiome, Yogurt and Probiotics Fellowship Grant and a University of California President's Pre-Professoriate Fellowship to E.V.K and an NIH/NIGMS R35GM124724 to A.H. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The 5-HT7 receptor antagonist SB 269970 ameliorates maternal fluoxetine exposure-induced impairment of synaptic plasticity in the prefrontal cortex of the offspring female mice

The use of a selective serotonin reuptake inhibitor fluoxetine in depression during pregnancy and the postpartum period might increase the risk of affective disorders and cognitive symptoms in progeny. In animal models, maternal exposure to fluoxetine throughout gestation and lactation negatively affects the behavior of the offspring. Little is known about the effects of maternal fluoxetine on synaptic transmission and plasticity in the offspring cerebral cortex. During pregnancy and lactation C57BL/6J mouse dams received fluoxetine (7.5 mg/kg/day) with drinking water. Female offspring mice received intraperitoneal injections of the selective 5-HT7 receptor antagonist SB 269970 (2.5 mg/kg) for 7 days. Whole-cell and field potential electrophysiological recordings were performed in the medial prefrontal cortex (mPFC) ex vivo brain slices. Perinatal exposure to fluoxetine resulted in decreased field potentials and impaired long-term potentiation (LTP) in layer II/III of the mPFC of female young adult offspring. Neither the intrinsic excitability nor spontaneous excitatory postsynaptic currents were altered in layer II/III mPFC pyramidal neurons. In mPFC slices obtained from fluoxetine-treated mice that were administered SB 269970 both field potentials and LTP magnitude were restored and did not differ from controls. Treatment of fluoxetine-exposed mice with a selective 5-HT7 receptor antagonist, SB 269970, normalizes synaptic transmission and restores the potential for plasticity in the mPFC of mice exposed in utero and postnatally to fluoxetine.

Long-term effects of gestational diabetes mellitus on the pancreas of female mouse offspring.

Prolonged fetal exposure to hyperglycemia may increase the risk of developing abnormal glucose metabolism and type-2 diabetes during childhood, adolescence, and adulthood; however, the mechanisms by which gestational diabetes mellitus (GDM) predisposes offspring to metabolic disorders remain unknown. To quantify the nerve axons, macrophages, and vasculature in the pancreas from adult offspring born from mouse dams with GDM. GDM was induced by i.p. administration of streptozotocin (STZ) in ICR mouse dams. At 12 wk old, fasting blood glucose levels were determined in offspring. At 15 wk old, female offspring born from dams with and without GDM were sacrificed and pancreata were processed for immunohistochemistry. We quantified the density of sensory [calcitonin gene-related peptide (CGRP)] and tyrosine hydroxylase (TH) axons, blood vessels (endomucin), and macro-phages (CD68) in the splenic pancreas using confocal microscopy. Offspring mice born from STZ-treated dams had similar body weight and blood glucose values compared to offspring born from vehicle-treated dams. However, the density of CGRP+ and TH+ axons, endomucin+ blood vessels, and CD68+ macrophages in the exocrine pancreas was significantly greater in offspring from mothers with GDM vs control offspring. Likewise, the microvasculature in the islets was significantly greater, but not the number of macrophages within the islets of offspring born from dams with GDM compared to control mice. GDM induces neuronal, vascular, and inflammatory changes in the pancreas of adult progeny, which may partially explain the higher propensity for offspring of mothers with GDM to develop metabolic diseases.

Female offspring of mice perinatally exposed to benzophenone-3 showed early subfertility linked to a poor oocyte stockpile.

Previously, we found that the ultraviolet filter benzophenone-3 (BP3) causes fetal growth restriction in mice when is applied when implantation occurs (first week of gestation). However, whether BP3 can affect gestation and fertility after implantation period is unknown. We aimed to study the effects on reproductive physiology of the offspring caused by perinatal exposure to BP3. C57BL/6 pregnant mice were dermally exposed to 50mg BP3/kg bw.day or olive oil (vehicle) from gestation day 9 (gd9) to postnatal day 21 (pnd1). We observed no differences in mother's weights, duration of gestation, number of pups per mother, onset of puberty or sex ratio. The weights of the pups exposed to benzophenone-3 were transiently lower than those of the control. Estrous cycle was not affected by perinatal exposure to BP3. Besides, we performed a fertility assessment by continuous breeding protocol: at 10weeks of age, one F1 female and one F1 male mouse from each group was randomly chosen from each litter and housed together for a period of 6months. We noticed a reduction in the number of deliveries per mother among dams exposed to BP3 during the perinatal period. To see if this decreased fertility could be associated to an early onset of oocytes depletion, we estimated the ovarian reserve of germ cells. We found reduced number of oocytes and primordial follicles in BP3. In conclusion, perinatal exposure to BP3 leads to a decline in the reproductive capacity of female mice in a continuous breeding protocol linked to oocyte depletion.

Cuscuta chinensis flavonoids alleviate ovarian damage in offspring female mice induced by BPA exposure during pregnancy by regulating the central carbon metabolism pathway

Pregnancy is a sensitive window period for bisphenol A (BPA) exposure. BPA can pass through the placenta and cause reproductive damage in offspring female mice. Even BPA that is not metabolized during lactation can be passed through milk. Cuscuta chinensis flavonoids (CCFs) can alleviate reproductive damage caused by BPA, but the mechanism of action is unclear. To investigate the potential mitigating impact of CCFs on ovarian damage resulting from BPA exposure during pregnancy, we administered BPA and CCFs to pregnant mice during the gestational period spanning from 0.5 to 17.5 days. Aseptic collection of serum and ovaries from female mice was conducted on postnatal day 21 (PND21). Serum hormone levels and tissue receptor levels were quantified utilizing ELISA and PCR, while ovaries underwent sequencing and analysis through transcriptomics and metabolomics techniques. Additionally, the assessment of ovarian oxidative stress levels was carried out as part of the comprehensive analysis. The results showed that CCFs administration mitigated the adverse effects induced by BPA exposure on ovarian index, hormone levels, receptor expression, and mRNA expression levels in female offspring mice. The joint analysis of transcriptome and metabolome revealed 48 enriched pathways in positive ion mode and 44 enriched pathways in negative ion mode. Among them, the central carbon metabolism pathway is significantly regulated by BPA and CCFs. The screened sequencing results were verified through qPCR and biochemical kits. In this study, CCFs may participate in the central carbon metabolism pathway by reducing the expression of Kit proto-oncogene (Kit), hexokinase 1 gene (Hk1) and pyruvate kinase M (Pkm) mRNA and increasing the expression of h-ras proto-oncogene (Hras), sirtuin 3 (Sirt3), sirtuin 6 (Sirt6) and TP53 induced glycolysis regulatory phosphatase gene (Tigar) mRNA, thereby resisting the effects of BPA on the body. At the same time, the metabolic levels of D-Fructose 1,6-bisphosphate and L-Asparagine tend to be stable. Moreover, CCFs demonstrated a capacity to diminish the BPA-induced escalation in reactive oxygen species (ROS) and malondialdehyde (MDA). Simultaneously, it exhibited the ability to elevate levels of glutathione (GSH) and catalase (CAT), thereby effectively preventing peroxidation. In summary, CCFs alleviate BPA-induced ovarian damage in offspring female mice by regulating the central carbon metabolism pathway. This study will improve the information on BPA reproductive damage antagonist drugs and provide a theoretical basis for protecting animal reproductive health.

Effects of Varied Sulfamethazine Dosage and Exposure Durations on Offspring Mice.

The development of antibiotics was a turning point in the history of medicine; however, their misuse and overuse have contributed to the current global epidemic of antibiotic resistance. According to epidemiological studies, early antibiotic exposure increases the risk of immunological and metabolic disorders. This study investigated the effects of exposure to different doses of sulfamethazine (SMZ) on offspring mice and compared the effects of exposure to SMZ on offspring mice in prenatal and early postnatal periods and continuous periods. Furthermore, the effects of SMZ exposure on the gut microbiota of offspring mice were analyzed using metagenome. According to the results, continuous exposure to high-dose SMZ caused weight gain in mice. IL-6, IL-17A, and IL-10 levels in the female offspring significantly increased after high-dose SMZ exposure. In addition, there was a significant gender difference in the impact of SMZ exposure on the gut microbiota of offspring: Continuous high-dose SMZ exposure significantly decreased the relative abundance of Ligilactobacillus murinus, Limosilactobacillus reuteri, Lactobacillus johnsonii, and Bifidobacterium pseudolongum (p < 0.05) in female offspring mice; however, these significant changes were not observed in male offspring mice.

Female mice prenatally exposed to valproic acid exhibit complex and prolonged social behavior deficits

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized mainly by deficits in social communication and stereotyped and restricted behavior and interests with a male to female bias of 4.2/1. Social behavior in ASD animal models is commonly analyzed in males, and seldomly in females, using the widely implemented three-chambers test procedure. Here, we implemented a novel procedure, the Live Mouse Tracker (LMT), combining artificial intelligence, machine learning procedures and behavioral measures. We used it on mice that were prenatally exposed to valproic acid (VPA) (450 mg/kg) at embryonic day 12.5, a widely recognized and potent ASD model that we had previously extensively characterized. We focused on female mice offspring, in which social deficits have been rarely documented when using the 3-CT procedure. We recorded several parameters related to social behavior in these mice, continuously for three days in groups of four female mice. Comparisons were made on groups of 4 female mice with the same treatment (4 saline or 4 VPA) or with different treatments (3 saline and 1 VPA). We report that VPA females show several types of social deficits, which are different in nature and magnitude in relation with time. When VPA mice were placed in the LMT alongside saline mice, their social deficits showed significant improvement as early as 1 h from the start of the experiment, lasting up to 3 days throughout the duration of the experiment. Our findings suggest that ASD may be underdiagnosed in females. They also imply that ASD-related social deficits can be ameliorated by the presence of typical individuals.

Protective Effects of Perinatal Resveratrol on Bisphenol A Exposure-Induced Cardiovascular Alterations and Hepatic Steatosis in Adult Offspring Mice: A Histopathological Study

Perinatal bisphenol A (BPA) exposure promotes the risk of cardiovascular diseases in adulthood. Currently, there is a dire need to develop new therapeutic strategies and options to treat the adverse fetal programming consequences of this exposure. The present study explored the protective effects of perinatal resveratrol (Rsv) administration on BPA exposure-induced adverse cardiovascular changes and hepatic steatosis in adult offspring mice. Pregnant apolipoprotein E-deficient mice were exposed to BPA in drinking water (1 μg/mL) or to both BPA (1 μg/mL) and Rsv (oral; 20 mg kg−1 day−1) during the gestation and lactation periods. Tissues from the heart, liver, left kidney, and brachiocephalic artery from adult offspring (20 weeks old) were processed for staining with H and E, Masson’s trichrome, and Verhoeff–van Gieson and subsequent histology analysis. In both female and male mice who received Rsv supplementation, the following changes were observed in the brachiocephalic arterial wall: (a) a reduction in the BPA exposure-induced increased thickness ratio of the tunica intima to tunica media from 1.3 ± 1.1 µm to 0.5 ± 0.37 µm (p = 0.027) and 0.72 ± 0.58 µm to 0.29 ± 0.25 µm (p = 0.038), respectively, (b) a reduction in the number of elastic lamina breaks (p &lt; 0.05), and (c) the prevention of the BPA exposure-induced progression of atherosclerotic lesions. Further, it also reduced the BPA exposure-induced increased left ventricular thickness by 135 µm and 131 µm in female and male offspring, respectively. The BPA exposure-induced hepatic steatosis score was also significantly reduced with Rsv treatment in female offspring mice (p = 0.02). Renal cortical cytoplasmic vacuolation was identified in both BPA and/or Rsv-treated groups. Our findings suggest that Rsv could be a potential protective candidate against perinatal BPA exposure-induced cardiovascular changes and hepatic steatosis.

Maternal folic acid supplementation does not impact skeletal muscle function and metabolism in male and female CD-1 mouse offspring.

Folic acid fortification of all white flour, enriched pasta, and cornmeal products became mandatory in Canada to reduce risk of neural tube defects at birth. Furthermore, Health Canada and the Society of Obstetricians and Gynaecologists of Canada recommend women take daily prenatal folic acid supplements in addition to folic acid fortified foods during pregnancy. However, the influence of maternal folic acid supplementation on offspring development, specifically the highly abundant and metabolically active skeletal muscle, is currently unknown. Thus, the purpose of this study was to determine the effect of supplemental folic acid (four times higher than normal dietary consumption), in utero and throughout suckling on muscle size, function, and metabolism in male and female CD-1 mouse offspring. The major findings were that maternal exposure to supplemental folic acid (i) had no impact on postpartum growth rates or muscle mass in female and male offspring, (ii) had no impact on skeletal muscle contractile kinetics in females and male offspring, and (iii) increased maximal phosphofructokinase activity in extensor digitorum longus of female and male offspring. These findings suggest that exposure to folic acid supplementation in utero and throughout suckling at levels four times higher than recommended had minimal effect on skeletal muscle size, function, and metabolism regardless of sex. Future research is needed explore the underlying biological pathways and mechanisms affected by folic acid supplementation during pregnancy and lactation on offspring skeletal muscle tissue, specifically in humans.

Isradipine therapy in Cacna1dIle772Met/+ mice ameliorates primary aldosteronism and neurologic abnormalities.

Somatic gain-of-function mutations in the L-type calcium channel CaV1.3 (CACNA1D gene) cause adrenal aldosterone-producing adenomas and micronodules. De novo germline mutations are found in a syndrome of primary aldosteronism, seizures, and neurologic abnormalities (PASNA) as well as in autism spectrum disorder. Using CRISPR/Cas9, we here generated mice with a Cacna1d gain-of-function mutation found in both adenomas and PASNA syndrome (Cacna1dIle772Met/+). These mice show reduced body weight and increased mortality from weaning to approximately 100 days of age. Male mice do not breed, likely due to neuromotor impairment, and the offspring of female mice die perinatally, likely due to lack of maternal care. Mice generated by in vitro fertilization showed elevated intracellular calcium in the aldosterone-producing zona glomerulosa, an elevated aldosterone/renin ratio, and persistently elevated serum aldosterone on a high-salt diet as signs of primary aldosteronism. Anesthesia with ketamine and xylazine induced tonic-clonic seizures. Neurologic abnormalities included hyperlocomotion, impaired performance in the rotarod test, impaired nest building, and slight changes in social behavior. Intracellular calcium in the zona glomerulosa, aldosterone levels, and rotarod performance responded to treatment with the calcium channel blocker isradipine, with implications for the therapy of patients with aldosterone-producing lesions and with PASNA syndrome.

Impact of maternal dietary folic acid or choline dietary deficiencies on vascular function in young and middle-aged female mouse offspring after ischemic stroke.

Adequate maternal dietary levels of one-carbon metabolites, such as folic acid and choline, play an important role in the closure of the neural tube in utero; however, the impact of deficiencies in one-carbon (1C) metabolism on offspring neurological function after birth remain undefined. Stroke is one of the leading causes of death and disability globally. The aim of our study was to determine the impact of maternal 1C nutritional deficiencies on cerebral and peripheral blood flow after ischemic stroke in adult female offspring. In this study, female mice were placed on either control (CD)-, folic acid (FADD)-, or choline (ChDD)-deficient diets before pregnancy. Female offspring were weaned onto a CD for the duration of the study. Ischemic stroke was induced in offspring and after 6 wk cerebral and peripheral blood flow velocity was measured using ultrasound imaging. Our data showed that 11.5-mo-old female offspring from ChDD mothers had reduced blood flow in the posterior cerebral artery compared with controls. In peripheral blood flow velocity measurements, we report an aging effect. These results emphasize the importance of maternal 1C diet in early life neuro-programming on long-term vasculature health.NEW & NOTEWORTHY We demonstrate that a maternal dietary deficiency in one-carbon (1C) metabolites result in reduced cerebral blood flow in adult female offspring after ischemic stroke, but the long-term effects are not present. This result points to the key role of the maternal diet in early life neuroprogramming, while emphasizing its effects on both fetal development and long-term cerebrovascular health.

Maternal Obesity and Kawasaki Disease-like Vasculitis: A New Perspective on Cardiovascular Injury and Inflammatory Response in Offspring Male Mice.

Maternal obesity affects the risk of cardiovascular disease and inflammatory response in offspring. However, the impact of maternal obesity on offspring with Kawasaki disease (KD), the leading cause of childhood acquired heart disease, is still an understudied area. This study aimed to elucidate the impact of maternal obesity on offspring in KD-like vasculitis and the underlying mechanisms. Offspring of obese female mice and normal diet dams were randomly divided into two subgroups. The pups were injected intraperitoneally with either Candida albicans water-soluble fraction (CAWS) or phosphate buffered saline (PBS) to establish the obesity (OB)-CAWS group, OB group, wild type (WT)-CAWS group, and WT group. Their weight was monitored during the study. After four weeks, echocardiography was applied to obtain the alternation of cardiac structures. Mouse cytokine panel, Hematoxylin-Eosin (HE) staining, western blot, and real-time qPCR were used to study the pathological changes and protein and RNA expression alternations. Based on the study of pathology, serology and molecular biology, maternal obesity lead to more severe vasculitis and induced altered cardiac structure in the offspring mice and promoted the expression of pro-inflammatory cytokines through activating the NF-κB signaling pathway. Maternal obesity aggravated the inflammatory response of offspring mice in KD-like vasculitis.

Postpartum scarcity-adversity inflicts sex-specific cerebellar adaptations and reward behaviors in adolescence

Early life adversity in the form of poor postnatal care is a major developmental stressor impacting behavior later in life. Previous studies have shown the impact of early life stress on neurobehavioral abnormalities. Specifically, research has demonstrated how limited bedding and nesting (LBN) materials can cause behavioral deficits in adulthood. There is, however, a limited understanding of how LBN influences sex-specific neurobehavioral adaptation in adolescence, a developmental stage susceptible to psychiatric diseases including substance use disorder. LBN and stress-naive c57BL/6 adolescent male and female mouse offspring were tested for a battery of behaviors including open field, novel object recognition, elevated plus maze, social preference, and morphine-induced conditioned place preference. There was a significant sex-specific deficit in social preference in male mice exposed to LBN compared to stress-naïve counterparts and both LBN males and females had a higher preference towards the drug-paired chamber in the morphine-induced conditioned place preference test. These behavioral deficits were concomitant with sex-specific increases in the transcription factor, Klf9 in the deep cerebellar nuclei (DCN) of males. Further, mRNA levels of the circadian gene Bmal1, which is known to be transcriptionally regulated by Klf9, were decreased in the DCN. Since Bmal1 has recently been implicated in extracellular matrix modulation, we examined perineuronal nets (PNN) and observed depleted PNN in the DCN of males but not female LBN mice. Overall, we provide a novel understanding of how postpartum adversity impinges on the cerebellar extracellular matrix homeostasis, likely, through disruption of the circadian axis by Klf9 that might underlie sex-specific behavioral adaptations in adolescence.

Long-term effects of streptozotocin-induced gestational diabetes mellitus on mechanical sensitivity and intraepidermal nerve fibers in female and male mice offspring

While the long-term complications of gestational diabetes mellitus (GDM) in the cardiovascular, endocrine, and central nervous systems from offspring have been widely studied, less is known about the long-term outcomes of GDM on the peripheral nervous system. Thus, here we assessed the mechanical sensitivity and density of nerve fibers of the hind paw from middle-aged offspring born from dams with GDM. GDM was induced by the intraperitoneal administration of streptozotocin (STZ) in mouse dams. Mechanical sensitivity in male and female offspring was bi-weekly evaluated from week 18 to week 40 of age. At 40 weeks old, offspring were sacrificed and glabrous hind paw skin was processed for immunohistochemistry to determine the density of intraepidermal CGRP and PGP9.5 positive nerve fibers. Offspring mice born from STZ-treated dams had significantly greater mechanical sensitivity from 18 to 40 weeks of age compared to offspring born from vehicle-treated dams (control group). The density of intraepidermal CGRP+ and PGP9.5+ nerve fibers were significantly lower in the hind paw skin of female but not male offspring, born from STZ-treated dams versus the control group. These results suggest that GDM has long-term sex-dependent complications on the nociceptive system. Further studies are necessary to elucidate the mechanisms underlying the GDM-induced long-term consequences.