Male Rat Offspring Research Articles

The low-expression programming of 11β-HSD2 mediates osteoporosis susceptibility induced by prenatal caffeine exposure in male offspring rats.

Prenatal caffeine exposure (PCE) can cause developmental toxicity of long bones in offspring, but the long-term effects and the underlying mechanism have not been fully clarified. Here, we investigated the effects of PCE peak bone mass accumulation and osteoporosis susceptibility in offspring and its intrauterine programming mechanism. Pregnant Wistar rats were administrated intragastrically with saline or caffeine (120 mg·kg-1 ·day-1 ) on gestational days 9-20. The serum and bone samples were collected from the fetal and postnatal offspring for bone mass, genes expression and corticosterone analysis. Then, rat bone marrow mesenchymal stem cells (BMSCs) were treated with corticosterone in vitro to confirm the molecular mechanism. PCE caused fetal bone dysplasia in male and female offspring. In adulthood, PCE reduced peak bone mass and increased osteoporosis susceptibility in male offspring but not in females. Meanwhile, PCE only decreased the H3K9ac and expression levels of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) before and after birth in the male offspring but not in the females. Moreover, the high level of corticosterone induced by PCE down-regulated the H3K9ac and expression levels of 11β-HSD2 through promoting glucocorticoid receptor (GR; NR3C1) into the nucleus of bone marrow mesenchymal stem cells (BMSCs) and recruiting histone deacetylase 11 (HDAC11) binding to 11β-HSD2 promoter region, which further enhanced the effect of corticosterone on suppressing osteogenic function of BMSCs. PCE caused osteoporosis susceptibility in male adult offspring, which attributed to the low-functional programming of 11β-HSD2 induced by corticosterone via GR/HDAC11 signalling.

Maternal Iron Deficiency Programs Offspring Cognition and Its Relationship with Gastrointestinal Microbiota and Metabolites.

Iron is an essential micronutrient for the brain development of the fetus. Altered intestinal microbiota might affect behavior and cognition through the so-called microbiota-gut-brain axis. We used a Sprague-Dawley rat model of a maternal low-iron diet to explore the changes in cognition, dorsal hippocampal brain-derived neurotrophic factor (BDNF) and related pathways, gut microbiota, and related metabolites in adult male offspring. We established maternal iron-deficient rats by feeding them a low-iron diet (2.9 mg/kg), while the control rats were fed a standard diet (52.3 mg/kg). We used a Morris water maze test to assess spatial learning and long-term memory. Western blot (WB) assays and a quantitative reverse-transcription polymerase chain reaction (qRT-PCR) were used to detect the BDNF concentration and related signaling pathways. We collected fecal samples for microbiota profiling and measured the concentrations of plasma short-chain fatty acids. The adult male offspring of maternal rats fed low-iron diets before pregnancy, during pregnancy and throughout the lactation period had (1) spatial deficits, (2) a decreased BDNF mRNA expression and protein concentrations, accompanied by a decreased TrkB protein abundance, (3) a decreased plasma acetate concentration, and (4) an enrichment of the Bacteroidaceae genus Bacteroides and Lachnospiraceae genus Marvinbryantia. Maternal iron deficiency leads to an offspring spatial deficit and is associated with alternations in gastrointestinal microbiota and metabolites.

Lentivirus-delivered ACE siRNA rescues the impaired peak bone mass accumulation caused by prenatal dexamethasone exposure in male offspring rats.

Angiotensin I converting enzyme (ACE) is a major component of the renin-angiotensin system (RAS). Our previous study demonstrated that activated bone RAS was associated with low peak bone mass induced by prenatal dexamethasone exposure (PDE) in male offspring rats. However, we did not determine whether the inhibition of ACE expression could rescue PDE-induced low peak bone mass. In the present study, we treated pregnant Wistar rats with dexamethasone (0.2mg/kg.d) on gestational days 9-20 and obtained eight weeks old male offspring rats. Some of the offspring rats from the PDE group were injected lentivirus delivered-ACE siRNA (LV-ACE siRNA) through the intra-bone marrow for 4weeks. We found that the intra-bone marrow injection of LV-ACE siRNA rescued the impaired peak bone mass accumulation caused by PDE in male offspring rats. Moreover, LV-ACE siRNA ameliorated PDE-induced inhibition of osteogenesis and alleviated PDE-induced RAS activation in the bone tissues in vivo. Our in vitro findings further confirmed that LV-ACE siRNA reversed the suppressed osteogenic differentiation caused by dexamethasone, which can be attributed to alleviated RAS activation. In conclusion, LV-ACE siRNA rescued impaired peak bone mass accumulation caused by PDE through alleviation of local bone RAS activation in male offspring rats.

Prenatal diclofenac exposure delays pubertal development and induces behavioral changes in rats

Diclofenac is a non-steroidal anti-inflammatory drug widely used by the general population and, although generally contraindicated during pregnancy, it is also used by some pregnant women. This study investigated endocrine, reproductive and behavioral effects of diclofenac in male and female offspring rats exposed in utero from gestational days 10–20. Pregnant rats were treated with diclofenac at doses of 0.2, 1 and 5 mg/kg/day via oral gavage. Anogenital distance (AGD), number of nipples, and developmental landmarks of puberty onset - vaginal opening (VO), first estrus (FE) and preputial separation (PPS) – were evaluated in the offspring. At adulthood, behavioral and reproductive parameters were assessed. Male and female rats were tested in the elevated plus maze test to assess locomotor activity and anxiety-like behaviors, while male rats were also evaluated in the partner preference test. No significant effects were observed on AGD and number of nipples in both males and females. Diclofenac treatment induced an overall delay in developmental landmarks of puberty onset in male and female offspring, which reached statistical significance for PPS at the lowest diclofenac dose. Prenatal exposure to all tested doses abolished the preference of male rats for an estrous female, suggesting an impairment of brain masculinization. No changes were observed on male or female reproductive parameters at adulthood. Overall, our results indicate that prenatal exposure to therapeutically relevant doses of diclofenac may have an impact in the pubertal development of rats and negatively affect male partner preference behavior.

Influence of the maternal high-intensity-interval-training on the cardiac Sirt6 and lipid profile of the adult male offspring in rats.

The susceptibility to cardiovascular disease in offspring could be reduced prior to birth through maternal intervention, before and during pregnancy. We evaluated whether the initiation periods of maternal exercise in preconception and pregnancy periods induce beneficial effects in the adult male offspring. Thirty-two female rats were divided into control and exercise groups. The exercise groups involve exercise before pregnancy or the preconception periods, exercise during pregnancy, and exercise before and during pregnancy. The mothers in the exercise groups were run on the treadmill in different periods. Then the birth weight and weekly weight gain of male offspring were measured, and the blood and left ventricle tissue of samples were collected for analysis of the Sirtuin 6 (Sirt6) and insulin growth factor-2 (IGF-2) gene expression, serum levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), cholesterol (Cho), and triglycerides (TG). There was no significant difference in the birth weight of offspring groups (P = 0.246) while maternal HIIT only during pregnancy leads to reduce weekly weight gain of offspring. Our data showed that Sirt6 and IGF-2 gene expression was increased (P = 0.017) and decreased (P = 0.047) by maternal exercise prior to and during pregnancy, respectively. Also, the serum level of LDL (p = 0.002) and Cho (P = 0.007) were significantly decreased and maternal exercise leads to improves the running speed of the adult male offspring (p = 0.0176). This study suggests that maternal HIIT prior to and during pregnancy have positive intergenerational consequence in the health and physical readiness of offspring.

Waterpipe Tobacco Smoke Exposure during Lactation-Susceptibility of Reproductive Hormones and Oxidative Stress Parameters in Male Progeny Rats.

There is a growing evidence for the public health hazards associated with waterpipe tobacco smoking (WTS). While the adverse effects of WTS exposure during pregnancy on the offspring are widely reported, its impact during breastfeeding remains less understood. The effects of WTS exposure during lactation on the reproductive hormones and oxidative stress biomarkers of adult male progeny were examined. Lactating rats received either fresh air (controls) or mainstream WTS for 1h twice/day from day 4 to day 21 of lactation. The offspring was then followed up until week 20. The data indicated that WTS exposure in the lactating animals reduced the levels of follicle-stimulating hormone (FSH), prolactin (P < 0.05), luteinizing hormone (LH) (P = 0.1146), and estradiol (P = 0.0773) in the blood in male progeny.While the activities of testicular superoxide dismutase (SOD), glutathione peroxidase (GPx) and the levels of thiobarbituric acid reactive substances(TBARS) and blood levels of testosterone (P>0.05) remained unaltered, the activity of catalase increased significantly indicating an increased oxidant loadin the WTS exposed rats compared to the controls. WTS exposure during lactation impairs male reproductive hormonal profile, augments oxidative damage, and potentially affects male fertility in male offspring rats.

Targeting on Gut Microbiota-Derived Metabolite Trimethylamine to Protect Adult Male Rat Offspring against Hypertension Programmed by Combined Maternal High-Fructose Intake and Dioxin Exposure.

Gut microbiota-dependent metabolites, in particular trimethylamine (TMA), are linked to hypertension. Maternal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure or consumption of food high in fructose (HFR) can induce hypertension in adult offspring. We examined whether 3,3-maternal dimethyl-1-butanol (DMB, an inhibitor of TMA formation) therapy can protect adult offspring against hypertension arising from combined HFR and TCDD exposure. Pregnant Sprague–Dawley rats received regular chow or chow supplemented with fructose (60% diet by weight) throughout pregnancy and lactation. Additionally, the pregnant dams received TCDD (200 ng/kg BW orally) or a corn oil vehicle on days 14 and 21 of gestation, and days 7 and 14 after birth. Some mother rats received 1% DMB in their drinking water throughout pregnancy and lactation. Six groups of male offspring were studied (n = 8 for each group): regular chow (CV), high-fructose diet (HFR), regular diet+TCDD exposure (CT), HFR+TCDD exposure (HRT), high-fructose diet+DMB treatment (HRD), and HFR+TCDD+DMB treatment (HRTD). Our data showed that TCDD exacerbates HFR-induced elevation of blood pressure in male adult offspring, which was prevented by maternal DMB administration. We observed that different maternal insults induced distinct enterotypes in adult offspring. The beneficial effects of DMB are related to alterations of gut microbiota, the increase in nitric oxide (NO) bioavailability, the balance of the renin-angiotensin system, and antagonization of aryl hydrocarbon receptor (AHR) signaling. Our findings cast new light on the role of early intervention targeting of the gut microbiota-dependent metabolite TMA, which may allow us to prevent the development of hypertension programmed by maternal excessive fructose intake and environmental dioxin exposure.

Maternal exposure to mixtures of dienestrol, linuron and flutamide. Part II: Endocrine-related gene expression assessment on male offspring rat testes

Exposure to endocrine-disrupting compounds (EDCs) during pregnancy and early development can lead to adverse developmental outcomes in offspring. One of the endpoints of concern is feminization. The present study aimed to investigate for any possible correlations with endocrine sensitive parameters in the testes of male rat offspring following dam exposure to three EDCs by assessing the expression of endocrine-related genes. Dienestrol (DIES) [0.37–6.25 μg/kg bw/day], linuron (LIN) [1.5–50 mg/kg bw/day], flutamide (FLU) [3.5–50 mg/kg bw/day] as well as their binary mixtures were administered to sexually mature female rats from gestation day (GD) 6 until postnatal day (PND) 21. Gene expression analysis of Star, Cyp11a1, Cyp17a1, Hsd3b2, Pgr and Insl3 was performed by RT-qPCR. Administration of the anti-androgen FLU alone significantly upregulated Cyp11a1 and Cyp17a1 gene expression while administration of LIN and DIES alone did not alter significantly gene expression. The effects of the binary mixtures on gene expression were not as marked as those seen after single compound administrations. Deregulation of Cyp17a1 in rat pup testis, following administration of FLU alone or in mixtures to dams, was significantly correlated with the observed feminization endpoints in male pups.

Perinatal fluoxetine treatment and dams\u2019 early life stress history have opposite effects on aggressive behavior while having little impact on sexual behavior of male rat offspring

RationaleMany depressed women continue antidepressant treatment during pregnancy. Selective serotonin reuptake inhibitor (SSRI) treatment during pregnancy increases the risk for abnormal social development of the child, including increased aggressive or defiant behavior, with unknown effects on sexual behavior.ObjectivesOur aim was to investigate the effects of perinatal SSRI treatment and maternal depression, both separately and combined, on aggressive and sexual behavior in male rat offspring.MethodsHeterozygous serotonin transporter (SERT± ) knockout dams exposed to early life stress (ELSD) were used as an animal model of maternal depression. Early life stress consisted of separating litters from their mother for 6 h a day on postnatal day (PND)2–15, resulting in a depressive-like phenotype in adulthood. Depressive-like dams were treated with fluoxetine (FLX, 10 mg/kg) or vehicle throughout pregnancy and lactation (gestational day 1 until PND 21). Male offspring were tested for aggressive and sexual behavior in adulthood. As lifelong reductions in SERT expression are known to alter behavioral outcome, offspring with normal (SERT+/+) and reduced (SERT± ) SERT expression were assessed.ResultsPerinatal FLX treatment reduced offensive behavior and the number of animals attacking and increased the latency to attack, especially in SERT+/+ offspring. Perinatal FLX treatment reduced the mounting frequency in SERT+/+ offspring. ELSD increased offensive behavior, without affecting sexual behavior in SERT± offspring.ConclusionsOverall, our research demonstrates that perinatal FLX treatment and ELSD have opposite effects on aggressive behavior, with little impact on sexual behavior of male offspring.

A low protein maternal diet during gestation has negative effects on male fertility markers in rats - A Systematic Review and Meta-analysis.

Research indicates that some adult diseases including reproductive pathologies are programmed in utero during foetal development. In particular, maternal low dietary protein, during the most critical developmental periods of male foetal development, may have a detrimental impact on male fertility through direct and epigenetic mechanisms. The aim of our study was to evaluate the impact of a gestational low protein diet on fertility markers in male offspring in rats through a systematic review and meta-analysis. A systematic search using PubMed, and EMBASE databases was performed and two investigators independently screened the 1,703 prospective articles. Eleven articles met the eligibility criteria. Outcome measures were pooled using random-effects models and expressed as mean differences (MDs) at 95% CIs for each study. The results reveal significant reduction in testis weight (MD (mean difference) -0.08g; -0.12, -0.42; p=.0001), epididymal sperm count (MD -35.34×106 cells; -52.15, -18.53; p=.0001), number of Sertoli cells (MD -7.27×106 (-13.92, -0.62; p=.03), testosterone (T) concentration (MD -0.29ng/ml; -0.48, -0.09; p=.004) and luteinising hormone (LH) concentration (MD of -0.24ng/ml; -0.45, 0.04; p=.02) in comparison with controls. In contrast, follicle-stimulating hormone (FSH) concentration (MD of 0.07ng/ml; -0.16, 0.29; p=.56) was not significantly different from controls. We conclude that low gestational dietary protein maternal intake potentially negatively impacts fertility in male progeny later in life. The mechanisms of action responsible for these phenomena remain unclear.

Maternal Immune Activation Sensitizes Male Offspring Rats to Lipopolysaccharide-Induced Microglial Deficits Involving the Dysfunction of CD200-CD200R and CX3CL1-CX3CR1 Systems.

Early life challenges resulting from maternal immune activation (MIA) may exert persistent effects on the offspring, including the development of psychiatric disorders, such as schizophrenia. Recent evidence has suggested that the adverse effects of MIA may be mediated by neuron–microglia crosstalk, particularly CX3CL1–CX3CR1 and CD200–CD200R dyads. Therefore, the present study assessed the behavioural parameters resembling schizophrenia-like symptoms in the adult male offspring of Sprague-Dawley rats that were exposed to MIA and to an additional acute lipopolysaccharide (LPS) challenge in adulthood, according to the “two-hit” hypothesis of schizophrenia. Simultaneously, we aimed to clarify the role of the CX3CL1–CX3CR1 and CD200–CD200R axes and microglial reactivity in the brains of adult offspring subjected to MIA and the “second hit” wit LPS. In the present study, MIA generated a range of behavioural changes in the adult male offspring, including increased exploratory activity and anxiety-like behaviours. The most intriguing finding was observed in the prepulse inhibition (PPI) test, where the deficit in the sensorimotor gating was age-dependent and present only in part of the rats. We were able to distinguish the occurrence of two groups: responsive and non-responsive (without the deficit). Concurrently, based on the results of the biochemical studies, MIA disrupted mainly the CD200–CD200R system, while the changes of the CX3CL1–CX3CR1 axis were less evident in the frontal cortex of adult non-responsive offspring. MIA markedly affected the immune regulators of the CD200–CD200R pathway as we observed an increase in cortical IL-6 release in the responsive group and IL-4 in the non-responsive offspring. Importantly, the “second hit” generated disturbances at the behavioural and biochemical levels mostly in the non-responsive adult animals. Those offspring were characterized both by disturbed PPI and “priming” microglia. Altogether, the exposure to MIA altered the immunomodulatory mechanisms, including the CD200–CD200R axis, in the brain and sensitized animals to subsequent immunological challenges, leading to the manifestation of schizophrenia-like alterations.

Front Cover: Prenatal High‐Salt Diet–Induced Metabolic Disorders via Decreasing Peroxisome Proliferator–Activated Receptor Gamma Coactivator 1α in Adult Male Rat Offspring

Front Cover: Prenatal High‐Salt Diet–Induced Metabolic Disorders via Decreasing Peroxisome Proliferator–Activated Receptor Gamma Coactivator 1α in Adult Male Rat Offspring

Protective effect of maternal exercise against amyloid-β neurotoxicity in the male rat offspring's cerebellum.

The Developmental Origins of Health and Disease (DOHaD) states that intrauterine maternal environment influences postnatal life by programming offspring's metabolism. Intrauterine milieu induced by exercise during pregnancy promotes long-lasting benefits to the offspring's health and seems to offer some resistance against chronic diseases in adult life. Alzheimer's disease is a public health concern with limited treatment options. In the present study, we assessed the potential of maternal exercise during pregnancy in long-term programming of young adult male rat offspring's cerebellar metabolism in conferring neuroprotection against amyloid-β (Aβ) neurotoxicity. Female Wistar rats were submitted to a swimming protocol 1 week prior mating and throughout pregnancy (five sessions/a week lasting 30 min). Aβ oligomers were infused bilaterally in the brain ventricles of 60-day-old male offspring. Fourteen days after surgery, we measured parameters related to redox state, mitochondrial function, and the immunocontent of proteins related to synaptic function. We found that maternal exercise during pregnancy attenuated several parameters in the offspring's male rat cerebellum, such as the reactive species rise, the increase of inducible nitric oxide synthase immunocontent and tau phosphorylation induced by Aβ oligomers, increased mitochondrial fission indicated by dynamin-related protein 1 (DRP1), and protein oxidation identified by carbonylation. Strikingly, we find that maternal exercise promotes changes in the rat offspring's cerebellum that are still evident in young adult life. These favorable neurochemical changes in offspring's cerebellum induced by maternal exercise may contribute to a protective phenotype against Aβ-induced neurotoxicity in young adult male rat offspring.

Addition of olive oil to diet of rats with mild pre-gestational diabetes impacts offspring β-cell development.

Maternal diabetes impairs fetal development and increases the risk of metabolic diseases in the offspring. Previously, we demonstrated that maternal dietary supplementation with 6% of olive oil prevents diabetes-induced embryo and fetal defects, in part, through the activation of peroxisome proliferator-activated receptors (PPARs). In this study, we examined the effects of this diet on neonatal and adult pancreatic development in male and female offspring of mothers affected with pre-gestational diabetes. A mild diabetic model was developed by injecting neonatal rats with streptozotocin (90 mg/kg). During pregnancy, these dams were fed a chow diet supplemented or not with 6% olive oil. Offspring pancreata was examined at day 2 and 5 months of age by immunohistochemistry followed by morphometric analysis to determine number of islets, α and β cell clusters and β-cell mass. At 5 months, male offspring of diabetic mothers had reduced β-cell mass that was prevented by maternal supplementation with olive oil. PPARα and PPARγ were localized mainly in α cells and PPARβ/δ in both α and β cells. Although Pparβ/δ and Pparγ RNA expression showed reduction in 5-month-old male offspring of diabetic rats, Pparβ/δ expression returned to control levels after olive-oil supplementation. Interestingly, in vitro exposure to oleic acid (major component of olive oil) and natural PPAR agonists such as LTB4, CPC and 15dPGJ2 also significantly increased expression of all Ppars in αTC1-6 cells. However, only oleic acid and 15dPGJ2 increased insulin and Pdx-1 expression in INS-1E cells suggesting a protective role in β-cells. Olive oil may be considered a dietary supplement to improve islet function in offspring of affected mothers with pre-gestational diabetes.

Prenatal High-Salt Diet-Induced Metabolic Disorders via Decreasing Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1α in Adult Male Rat Offspring.

Although prenatal high-salt (HS) intake leads to physiological complications in the offspring, little is known regarding its effects on the offspring's glucose metabolism. Therefore, the objectives of this study are to determine the consequences of prenatal HS diet on the offspring's metabolism and to test a potential therapy. Pregnant rats are fed either a normal-salt (1% NaCl) or high-salt (8% NaCl) diet during the whole pregnancy. Experiments are conducted in five-month-old male offspring. It is found that the prenatal HS diet reduced the glucose tolerance and insulin sensitivity of the offspring. Additionally, there is down-regulation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Ppargc1a/PPARGC1A) at the transcript and protein level, which leads to decreased mitochondrial biogenesis and oxidative respiration in skeletal muscle. Moreover, the down-regulation of Ppargc1a is accompanied by decreases in the expression of glucose transporter type 4 (Glut4). With endurance exercise training, these changes are mitigated, which ultimately resulted in improved insulin resistance. These findings suggest that prenatal HS intake induces metabolic disorders via the decreased expression of Ppargc1a in the skeletal muscle of adult offspring, providing novel information concerning the mechanisms and early prevention of metabolic diseases of fetal origins.

Punicalagin Activates AMPK/PGC-1α/Nrf2 Cascade in Mice: The Potential Protective Effect against Prenatal Stress.

Prenatal stress is closely associated with poor health outcomes for offspring, yet the specific mechanisms and effective interventions remain limited. In the present study, both male and female rat offspring exposed to prenatal restraint stress (PRS) are confirmed to have impaired spatial learning and memory, accompanied by reduced AMP-activated protein kinase (AMPK) activity and decreased protein expression of mitochondrial biogenesis and antioxidant pathways in the hippocampus. Interestingly, a deficiency in the AMPK cascade also occurs in liver, heart, and adipose tissues, suggesting that the systemic deactivation of AMPK in the offspring is potentially attributed to increased maternal glucocorticoid levels under PRS. Punicalagin (PU), a major ellagitannin in pomegranate, is found to effectively induce mitochondrial biogenesis and phase II enzymes through activation of AMPK in both HT22 and primary hippocampal neurons, thereby inhibiting glutamate-induced cell viability and mitochondrial membrane potential loss. Meanwhile, the activation of AMPK cascade is also confirmed in mice administrated with PU for three days. Altogether, these results indicate that the systemic deficiency of the AMPK cascade can be the key factor that contributes to poor outcomes of PRS, and PU may be used as an effective maternal nutritional intervention.

Maternal Immune Activation Induces Neuroinflammation and Cortical Synaptic Deficits in the Adolescent Rat Offspring.

Maternal immune activation (MIA), induced by infection during pregnancy, is an important risk factor for neuro-developmental disorders, such as autism. Abnormal maternal cytokine signaling may affect fetal brain development and contribute to neurobiological and behavioral changes in the offspring. Here, we examined the effect of lipopolysaccharide-induced MIA on neuro-inflammatory changes, as well as synaptic morphology and key synaptic protein level in cerebral cortex of adolescent male rat offspring. Adolescent MIA offspring showed elevated blood cytokine levels, microglial activation, increased pro-inflammatory cytokines expression and increased oxidative stress in the cerebral cortex. Moreover, pathological changes in synaptic ultrastructure of MIA offspring was detected, along with presynaptic protein deficits and down-regulation of postsynaptic scaffolding proteins. Consequently, ability to unveil MIA-induced long-term alterations in synapses structure and protein level may have consequences on postnatal behavioral changes, associated with, and predisposed to, the development of neuropsychiatric disorders.

Intrauterine RAS programming alteration-mediated susceptibility and heritability of temporal lobe epilepsy in male offspring rats induced by prenatal dexamethasone exposure.

Partial temporal lobe epilepsy (TLE) has an intrauterine developmental origin. This study was aimed at elucidating the heritable effects and programming mechanism of TLE in offspring rats induced by prenatal dexamethasone exposure (PDE). Pregnant Wistar rats were injected subcutaneously with dexamethasone (0.2mg/kgday) from gestational day9 to 20. The F1 and F2 generations of male offspring were administered lithium pilocarpine (LiPC) for electroencephalography and video monitoring in epilepsy or behavioral tests. Results showed that the PDE + LiPC group exhibited TLE susceptibility, which continued throughout F2 generation. Expression of hippocampal glucocorticoid receptor (GR), CCAAT enhancer-binding protein α (C/EBPα), intrauterine renin-angiotensin system (RAS) classical pathway related genes, the H3K27ac level in angiotensin-converting enzyme (ACE) promoter, as well as high mobility group box 1 (HMGB1) and toll-like receptor 4 (TLR4) were increased, but glutamate dehydrogenase (GLUD) 1/2 expression were decreased, accompanied by increased glutamate levels in PDE fetal and adult rats, as well as in F1 and F2 offspring of the PDE + LiPC group. These consistent changes were also observed by treating the H19-7 fetal hippocampal cell line with dexamethasone and were reversed by GR inhibitor (RU486) and ACE inhibitor (enalaprilat). Our results confirmed that PDE-induced H3K27ac enrichment in the ACE promoter and enhanced the RAS classic pathway via activating GR-C/EBPα-p300 in utero, which caused changes of the HMGB1 pathway and glutamate excitatory damage. Intrauterine programming mediated by abnormal histone modification of hippocampal ACE could continue to adulthood and even F2 generation, which induced the heritability of TLE in male offspring rats.

Prenatal urban traffic noise exposure impairs spatial learning and memory and reduces glucocorticoid receptor expression in the hippocampus of male rat offspring.

Exposure to noise stress during early life may permanently affect the structure and function of the central nervous system. The aim of this study was to evaluate the effects of prenatal exposure to urban traffic noise on the spatial learning and memory of the rats' offspring and the expression of glucocorticoid receptors (GRs) in their hippocampi. Three g\roups of pregnant rats were exposed to recorded urban traffic noise for 1, 2 or 4 h/day during the last week of pregnancy. At the age of 45 days, their male offspring were introduced to the Morris water maze (MWM) for assessment of spatial learning and memory. The corticosterone levels were measured in the offspring's sera by radioimmunoassay, and the relative expression of glucocorticoid and mineralocorticoid receptors (MRs) in their hippocampi was evaluated via RT-PCR. Facing urban traffic noise for 2 and 4 h/day during the third trimester of pregnancy caused the offspring to spend more time and to travel a larger distance than the controls to find the target platform. Analogously, these two groups were inferior to their control counterparts in the probe test. Also, prenatal noise stress elevated the corticosterone concentration in the sera of the rats' offspring and dose-dependently decreased the relative expression of the mRNA of both GRs and MRs in their hippocampi. Urban traffic noise exposure during the last trimester of pregnancy impairs spatial learning and memory of rat offspring and reduces GRs and MRs gene expression in the hippocampus.

In utero and lactational exposure to triclocarban: Age-associated changes in reproductive parameters of male rat offspring

Triclocarban (TCC) is an antimicrobial compound, widely used in personal care products, such as soaps, toothpaste, and shampoo. This agent is incompletely removed by wastewater treatment and represents an environmental contaminant. Studies show that TCC has been associated with some endocrine disruptions. In vitro, TCC demonstrated potent androgen-augmenting activity and aromatase inhibition. In this sense, exposure during critical periods of development (gestation and lactation) could lead to some adverse health outcomes in offspring. Therefore, the present study evaluated if maternal exposure to three different doses of TCC could interfere in the reproductive parameters of male offspring. Pregnant female Wistar rats were separated into four groups: vehicle Control (CTR); TCC 0.3 mg/kg (TCC 0.3); TCC 1.5 mg/kg (TCC 1.5); TCC 3.0 mg/kg (TCC 3.0). Dams were treated daily by oral gavage from gestational day 0 to lactational day 21. The males were evaluated in different timepoint: infancy (PND 21), puberty (PND 50) and adult life (PND 90–120). The histomorphometric analysis of testis and testosterone level were assessed on PND 21, 50, 120; sexual behavior and sperm parameters at adulthood. In the TCC 3.0 group, a decrease in the testis interstitial volume and an increase in testosterone levels were observed on PND 21. Moreover, there was a decrease in the diameter of the seminiferous tubules on PND 50, and a decrease in sexual competency in adulthood. These results suggest that exposure to a human relevant dose of TCC may interfere with reproduction and could have implications for human health.