Function In Rat Offspring Research Articles

Sex-Specific Changes to Brain Fatty Acids, Plasmalogen, and Plasma Endocannabinoids in Offspring Exposed to Maternal and Postnatal High-Linoleic-Acid Diets.

Linoleic acid (LA) is required for neuronal development. We have previously demonstrated sex-specific changes in cardiovascular and hepatic function in rat offspring from mothers consuming a high-LA diet, with some effects associated with reduced LA concentration in the postnatal diet. At this time, the impact of a high-maternal-LA diet on offspring brain development and the potential for the postnatal diet to alter any adverse changes are unknown. Rat offspring from mothers fed low- (LLA) or high-LA (HLA) diets during pregnancy and lactation were weaned at postnatal day 25 (PN25) and fed LLA or HLA diets until sacrifice in adulthood (PN180). In the offspring's brains, the postnatal HLA diet increased docosapentaenoate in males. The maternal HLA diet increased LA, arachidonate, docosapentaenoate, C18:0 dimethylacetal (DMA), C16:0 DMA, C16:0 DMA/C16:0, and C18:0 DMA/C18:0, but decreased eoicosenoate, nervoniate, lignocerate, and oleate in males. Maternal and postnatal HLA diets reduced oleate and vaccenate and had an interaction effect on myristate, palmitoleate, and eicosapentaenoate in males. In females, maternal HLA diet increased eicosadienoate. Postnatal HLA diet increased stearate and docosapentaenoate. Maternal and postnatal HLA diets had an interaction effect on oleate, arachidate, and docosahexaenoic acid (DHA)/omega (n)-6 docosapentaenoic acid (DPA) in females. Postnatal HLA diet decreased DHA/n-6 DPA in males and females. Postnatal HLA diet increased plasma endocannabinoids (arachidonoyl ethanolamide and 2-arachidonoyl glycerol), as well as other N-acyl ethanolamides and testosterone. HLA diet alters brain fatty acids, plasma endocannabinoids, and plasmalogen concentrations in a development-specific and sex-specific manner.

Association between maternal hypothyroidism, baby birth weight, and adult cardiovascular disease risk: insights from ECG measurements.

Thyroid hormone (TH) deficiency during pregnancy may affect cardiovascular function in offspring rats. This study aimed to evaluate the effect of TH deficiency during gestation, on the electrocardiogram indices of young and middle-aged offspring of male rats. Eight female rats were equally divided into hypothyroid and control groups. The hypothyroid mothers received 0.025% 6-propyl-2-thiouracil (PTU) in drinking water throughout pregnancy, while control mothers consumed only tap water. Following birth, male rats from each group were observed for 4 months (young age) and 12 months (middle-aged). The group known as fetal hypothyroid (FH) consisted of rats born from hypothyroid mothers. The serum T4 and TSH concentrations from mothers and newborn male rats were assayed at the end of gestation. Lead II electrocardiogram (ECG) was recorded for 5 minutes using Power Lab, AD Instruments. There was a significant rise in the P wave voltage in young FH rats, whereas, it was decreased in middle-aged control and FH rats. The voltage of QRS decreased and its duration increased in the young and middle-aged FH rats compared to the corresponding control groups. Duration and voltage of the T wave were significantly altered in the young and middle-aged FH groups. PR and QT intervals significantly increased in the young and middle-aged FH groups compared to their controls. Maternal hypothyroidism affected the electrocardiogram indices of offspring rats, possibly signaling cardiovascular problems later in life.

Autophagy activation, histopathological damage, and altered renal epithelial sodium channel and Na+,K+‐ATPase gene expression in offspring kidney after in utero exposure to allethrin

The goal of the current study was to determine the effects of the allethrin, as a pyrethroid-based insecticide, on kidney function in rat offspring. Sixty-day-old Wistar albino female rats were randomly allocated to three groups: control group and two allethrin-treated groups that were intragastrically administered with 34.2 or 68.5 mg/kg b.w. of allethrin starting from the day 6 of pregnancy until delivery. The results revealed that the high dose of allethrin (68.5 mg/kg) reduced the number of glomeruli. Results showed that the glomeruli diameter in animals treated with 34.2 mg/kg of allethrin significantly decreased when compared to the controls (p < 0.001) whereas at the dose of 68.5 mg/kg the glomeruli diameter was significantly higher than those of the control group (p < 0.05). Interestingly, the expression of the autophagic markers Beclin-1 and LC-3 was increased when compared to control indicating an induction of the autophagic mechanism. Furthermore, allethrin administration downregulated in a dose-dependent manner the expression of the epithelial sodium channel (ENaC) gene. The mRNA levels of Na+/K+- ATPase gene were significantly higher in the group treated with the low dose and significantly lower with the high dose, when compared to control. However, there was no effect of allethrin on the gene expression of NHE3 in both treated groups. Taken together, the findings of this study suggested that the exposure to allethrin might contribute to the nephrotoxicity by affecting the number and the diameter of glomeruli, causing histopathological alterations and inducing autophagic-related markers and affecting the mRNA levels of ENaC and Na+/ K + ATPase genes.

Allethrin Promotes Apoptosis and Autophagy Associated with the Oxidative Stress-Related PI3K/AKT/mTOR Signaling Pathway in Developing Rat Ovaries.

The increased concern regarding the reduction in female fertility and the impressive numbers of women undergoing fertility treatment support the existence of environmental factors beyond inappropriate programming of developing ovaries. Among these factors are pyrethroids, which are currently some of the most commonly used pesticides worldwide. The present study was performed to investigate the developmental effects of the pyrethroid-based insecticide allethrin on ovarian function in rat offspring in adulthood. We mainly focused on the roles of oxidative stress, apoptosis, autophagy and the related pathways in ovarian injury. Thirty-day-old Wistar albino female rats were intragastrically administered 0 (control), 34.2 or 68.5 mg/kg body weight allethrin after breeding from Day 6 of pregnancy until delivery. We found that allethrin-induced ovarian histopathological damage was accompanied by elevations in oxidative stress and apoptosis. Interestingly, the number of autophagosomes in allethrin-treated ovaries was higher, and this increase was correlated with the upregulated expression of genes and proteins related to the autophagic marker LC-3. Furthermore, allethrin downregulated the expression of PI3K, AKT and mTOR in allethrin-treated ovaries compared with control ovaries. Taken together, the findings of this study suggest that exposure to the pyrethroid-based insecticide allethrin adversely affects both the follicle structure and function in rat offspring during adulthood. Specifically, allethrin can induce excessive oxidative stress and defective autophagy-related apoptosis, probably through inactivation of the PI3K/AKT/mTOR signaling pathway, and these effects may contribute to ovarian dysfunction and impaired fertility in female offspring.

Low vs. High Wattage Vaping during Pregnancy Influences Vascular Function in Rat Offspring

Electronic cigarettes (e‐cigs) are being marketed as a healthier alternative to traditional cigarettes, yet the health consequences of e‐cig usage (also called vaping) are still being investigated. E‐cigs are easily customized for user preferences. For example, choice of flavors, nicotine concentration, and/or temperature (i.e. wattage) used to combust the e‐liquid can be selected in many devices. Emerging evidence suggest vaping during pregnancy impairs cerebral vascular function in rodent offspring. In this study, we sought to investigate the potential effects of changes in e‐cig device wattage (i.e. 5 watts vs 30 watts) with maternal vaping during pregnancy of vascular function in postnatal life of offspring. METHODS: Adult female Sprague Dawley rats were time‐mated to allow for maternal e‐cig exposure beginning on gestation day 2 until birth. Maternal vaping occurred for 1 h/day, 5 days/wk using a whole‐body chamber system. E‐cig aerosol was generation using D19 Joyetech atomizer with nicotine‐free (0 mg/mL) 50:50 VG:PG e‐liquid without flavoring. Puff topology was 83 ml with 5‐sec puff duration. Pregnant dams were randomly assigned to control (air‐exposed), 5 watt or 30‐watt exposure groups. Rat offspring (n=2/dam) were studied at 30‐, 90‐, and 180‐days after birth, where in vivo pulse wave velocity (an index of arterial stiffness) was assessed using VisualSonics Vevo 2100 ultrasound, thereafter animals were euthanized and thoracic aortas were excised, cleaned, and cut into 2mm rings for wire myography (DMT, AD instruments). Aortic rings were mounted and warmed in aerated Krebs‐Henseleit buffer solution. Vessel reactivity was measured using serial dilutions of methacholine [MCh 10‐9to 10‐5M] and sodium nitroprusside [SNP 10‐9 to 10‐5 M] to assess endothelial‐dependent vasodilation (EDD) and endothelium‐independent vasodilation (EID), respectively. RESULTS: At the 30‐days, max aortic EDD was not different between either 5W (79±17%, mean±SD) or 30W (86±4%) groups compared to controls (88±4%)(p&gt;0.36). At 90‐days, max aortic EDD was lower with 30W (58±18%, p&lt;0.001), but not 5W (78±4%, p=0.11) compared to controls (95±6%). Carotid PWV was elevated in 5W (3.49 m/s) and 30W (3.83 m/s) groups compared to controls (2.98 m/s, p&lt;0.05) suggesting 17‐29% increase in arterial stiffness. At 180 days, max aortic EDD was also lower with 30W (75±12%, p&lt;0.01), but not 5W (81±9x%, p=0.11) compared to controls (100±10%). Carotid PWV was elevated further in 5W (3.96 m/s) and 30W (4.29 m/s) groups compared to controls (3.13 m/s, p&lt;0.05) revealing 27‐37 % increase in arterial stiffness. Maximal aortic EID response (to SNP) was not different by wattage group or age. CONCLUSIONS: These findings show that e‐cig device power used during maternal vaping plays a role in increasing arterial stiffness and blunting EDD vascular function in the postnatal life of offspring with effects worsening with age. These data suggest vaping during pregnancy is not safe and has long‐lasting consequences to vascular health of progeny.

Sex differences and heritability of adrenal steroidogenesis in offspring rats induced by prenatal nicotine exposure

The epidemiological investigation has suggested prenatal nicotine exposure (PNE) induces multiorgan developmental toxicity and increases the risk of metabolic diseases in offspring. Our previous study found that the occurrence of fetal-originated diseases was associated with abnormal adrenal development in offspring. However, the long-term harmful effects on adrenal development in offspring induced by PNE remain unclear. Pregnant Wistar rats were injected subcutaneously with nicotine (2 mg/kg·d) from gestation day (GD) 9 to GD20 to obtain the adrenal gland from fetal and adult offspring rats of F1 and F2 generations. We found that the adrenal insulin-like growth factor 1 (IGF1) signaling pathway and steroidogenic function were increased in male while decreased in female of PNE fetal rats, which could extend into adulthood. Furthermore, the primary adrenal cells of fetal rats were treated with nicotine to observe the phenomena and clarify the possible mechanism of the sex difference. The results suggested that there are sex differences in IGF1 signaling pathway and steroidogenic function induced by PNE, which may be associated with sex differences in nAChRβ1 expression. In addition, the adrenal steroidogenic function was reduced in F2 offspring of F1 PNE female rats (regardless of mating with control or Male PNE rats). Therefore, the decrease of adrenal steroidogenic function in female offspring rats induced by PNE has maternal heritability. In conclusion, PNE could lead to sex differences and heritability of adrenal steroidogenic function in offspring rats.

The effect of selenium on learning disability due to maternal hyperthyroidism during lactation

Aim: Hyperthyroidism causes adverse changes in hippocampal-dependent learning and memory functions in developmental and adult periods. In the present study, the healing effect of selenium on learning disability in the offspring of mothers given L-thyroxine during lactation was investigated. Material and Methods:12 pregnant rats were used in the study. The pregnant rats were randomly assigned into three groups (n=8 per group): control group (CG), lactational hyperthyroid group (LHG), and lactational hyperthyroid + selenium group (LH+SeG) group. LHG consisted of male rat offspring from these mothers treated with L-thyroxine (0.2 mg kg–1 body mass, 1 mL) during lactation. LH+SeG was induced by selenium supplementation during 39-60 days after lactational hyperthyroid. The offspring of mother rats administered saline during the lactation period formed the control group (CG). Spatial learning and memory function were measured with the Morris water maze (n = 16 for each group). Measurements were made when offspring rats were 60-66 days old. Results: Post-hoc test with one-way ANOVA revealed that LHG group rats found the platform by traveling longer distances and swimming longer than the control group (p 0.005). There was no significant difference between the groups in terms of the time spent in the target quadrant in the probe trial (memory test). Conclusion: The study findings show that high thyroid hormone levels in mother rats during lactation have long-term negative effects on hippocampal-dependent learning function in offspring rats and selenium has a healing effect on these disorders.

Down-regulation of AMPK/PPARδ signalling promotes endoplasmic reticulum stress-induced endothelial dysfunction in adult rat offspring exposed to maternal diabetes.

Exposure to maternal diabetes is associated with increased prevalence of hypertension in the offspring. The mechanisms underlying the prenatal programming of hypertension remain unclear. Because endoplasmic reticulum (ER) stress plays a key role in vascular endothelial dysfunction in hypertension, we investigated whether aberrant ER stress causes endothelial dysfunction and high blood pressure in the offspring of dams with diabetes. Pregnant Sprague-Dawley rats were intraperitoneally injected with streptozotocin (35 mg/kg) or citrate buffer at Day 0 of gestation. Compared with control mother offspring (CMO), the diabetic mother offspring (DMO) had higher blood pressure and impaired endothelium-dependent relaxation in mesenteric arteries, accompanied by decreased AMPK phosphorylation and PPARδ expression, increased ER stress markers, and reactive oxygen species (ROS) levels. The inhibition of ER stress reversed these aberrant changes in DMO. Ex vivo treatment of mesenteric arteries with an AMPK agonist (A769662) or a PPARδ agonist (GW1516) improved the impaired EDR in DMO and reversed the tunicamycin-induced ER stress, ROS production, and EDR impairment in mesenteric arteries from CMO. The effects of A769662 were abolished by co-treatment with GSK0660 (PPARδ antagonist), whereas the effects of GW1516 were unaffected by Compound C (AMPK inhibitor). These results suggest an abnormal foetal programming of vascular endothelial function in offspring of rats with maternal diabetes that is associated with increased ER stress, which can be ascribed to down-regulation of AMPK/PPARδ signalling cascade.

Impact of intrauterine hypoxia on adolescent and adult cognitive function in rat offspring: sexual differences and the effects of spermidine intervention.

Intrauterine hypoxia (IUH) affects the growth and development of offspring. It remains unclear that how long the impact of IUH on cognitive function lasts and whether sexual differences exist. Spermidine (SPD) has shown to improve cognition, but its effect on the cognitive function of IUH offspring remains unknown. In the present study we investigated the influence of IUH on body weight and neurological, motor and cognitive function and the expression of APP, BACE1 and Tau5 proteins in brain tissues in 2- and 4-month-old IUH rat offspring, as well as the effects of SPD intervention on these parameters. IUH rat model was established by treating pregnant rats with intermittent hypoxia on gestational days 15-21, meanwhile pregnant rats were administered SPD (5 mg·kg-1·d-1;ip) for 7 days. Neurological deficits were assessed in the Longa scoring test; motor and cognitive functions were evaluated in coat hanger test and active avoidance test, respectively. We found that IUH decreased the body weight of rats in both sexes but merely impaired motor and cognitive function in female rats without changing neurological function in the rat offspring of either sex at 2 months of age. For 4-month-old offspring, IUH decreased body weight in males and impaired neurological function and increased cognitive function in both sexes. IUH did not affect APP, BACE1 or Tau5 protein expression in either the hippocampus or cortex of all offspring; however, it increased the cortical Tau5 level in 2-month-old female offspring. Surprisingly, SPD intervention prevented weight loss. SPD intervention reversed the motor and cognitive decline caused by IUH in 2-month-old female rat offspring. Taken together, IUH-induced cognitive decline in rat offspring is sex-dependent during puberty and can be recovered in adult rats. SPD intervention improves IUH-induced cognitive and neural function decline.

Effects of mild intrauterine hypoperfusion in the second trimester on memory and learning function in rat offspring.

Mild intrauterine hypoperfusion (MIUH) is a serious pathological event that affects the growth and development of fetuses and offspring. MIUH can lead to growth restriction, low birth weight, neurodevelopmental disorders, and other adverse clinical outcomes. To study the effects of MIUH on learning and memory function in offspring, a model of MIUH was established by placing a coil (length 2.5 mm, diameter 0.24 mm) on the uterine artery and ovarian uterine artery of Sprague-Dawley rats in the second trimester of pregnancy (day 17). Next, 120 mg/kg lithium chloride (the MIUH + Li group) or normal saline (the MIUH group) was injected intraperitoneally into these rats. In addition, 120 mg/kg lithium chloride (the Li group) or normal saline (the SHAM group) was injected intraperitoneally into pregnant rats without coil placement. The Morris water maze was used to detect changes in learning and memory ability in the offspring at 4 weeks after birth. In the MIUH group, the escape latency and journey length before reaching the platform were both increased, and the number of times that the platform was crossed and the activity time in the target quadrant within 90 seconds were both decreased compared with the SHAM group. Immunofluorescence double staining and western blot assays demonstrated that hippocampal nestin and Ki67 (both cell-proliferation-related proteins) expression was significantly downregulated in the MIUH group compared with the SHAM group. Furthermore, western blot assays were conducted to investigate changes in related signaling pathway proteins in the brains of offspring rats, and revealed that glycogen synthase kinase 3β (GSK3β) expression was upregulated and β-catenin expression was downregulated in the MIUH group compared with the SHAM group. In addition, compared with the MIUH group, the expression levels of p-GSK3β and β-catenin were upregulated in the MIUH + Li group. These results suggest that MIUH may affect learning and memory function in rat offspring by regulating the GSK3β signaling pathway. The experimental procedures were approved by Animal Ethics Committee of Shengjing Hospital of China Medical University (approval No. 2018PS07K) in June 2018.

Maternal exposure of triclosan cause intrauterine development restriction, delay in puberty installation and deregulation of testicular function in rat offspring

This study aimed to evaluate the effects of maternal exposure to triclosan (TCS), during gestation and lactation on physical development, puberty installation and testicular function of male offspring in puberty and sexual maturity. Sixteen pregnant Wistar rats were used and divided into four experimental groups: GI- they received corn oil daily by gavage; GII- they received 75 mg kg -1 day -1 of TCS; GIII- they received 150 mg kg -1 day -1 of TCS and GIV- they received 300 mg kg -1 day -1 of TCS during pregnancy and lactation. The mean weight of the treated rat’s offspring was lower in comparison to GI group. In the exposed offspring. A delay in puberty installation was observed following the exposure to triclosan. Regarding to the stages of the seminiferous epithelium in puberty, it was noticed an increase of the I-VI stages in GIV group, compared with to GI. In sexual maturity, it was observed an increase of VII-VIII, IX-XIII in contrast to a reduction of XIV stage in treated animals, comparing to GI. There was no difference in the number of Sertoli cells. We conclude that the maternal exposure to TCS during gestation and lactation causes restriction of the intrauterine development, delay in the puberty installation and deregulation in the seminiferous epithelium cycle.

Effects of perinatal di (2-ethylhexyl) phthalate exposure on thyroid function in rat offspring

Di (2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer in industry and displays the characteristics of an endocrine disruptor. Disorders of the maternal thyroid hormone (TH) during pregnancy can cause adverse effects on the fetus. We investigated the effects and possible mechanism of perinatal DEHP exposure on the thyroid function of pups. Pregnant female Wistar rats were randomly divided into four groups and received doses of DEHP of 0, 30, 300, 750 mg/kg/day by gavage at from gestational day (GD) 0 to postnatal day (PN) 21. The concentration of serum THs and the ultrastructure of thyroid follicular cells in the offspring were examined. Related protein level and gene expression of thyroid proteins in pups were analyzed by western blotting and real-time PCR. We found that DEHP significantly reduced total thyroxine (TT4) and increased thyroid stimulating hormone (TSH) in pups, while total triiodothyronine (TT3) showed no change. Thyroid follicular cells ultrastructure was damaged in DEHP exposed pups as viewed by electron microscopy. Furthermore, exposure to DEHP significantly increased protein and mRNA levels of thyroid transcription factor 1 (TTF-1), paired box 8 (PAX8), sodium iodide symporter (NIS) and thyroid peroxidase (TPO) in pups. In addition, levels of deiodinases of pups were also affected. These findings indicated that DEHP can disrupt thyroid function by damaging thyroid follicles and affecting TTF-1, PAX8, NIS, TPO and the deiodinase protein family.

The effect of maternal and post-weaning low and high glycaemic index diets on glucose tolerance, fat deposition and hepatic function in rat offspring.

Clinical studies have reported beneficial effects of a maternal low glycaemic index (GI) diet on pregnancy and neonatal outcomes, but the impact of the diet on the offspring in later life, and the mechanisms underlying these effects, remain unclear. In this study, Albino Wistar rats were fed either a low GI (n=14) or high GI (n=14) diet during pregnancy and lactation and their offspring weaned onto either the low or high GI diet. Low GI dams had better glucose tolerance (AUC[glucose], 1322±55 v. 1523±72 mmol min/l, P&lt;0.05) and a lower proportion of visceral fat (19.0±2.9 v. 21.7±3.8% of total body fat, P&lt;0.05) compared to high GI dams. Female offspring of low GI dams had lower visceral adiposity (0.45±0.03 v. 0.53±0.03% body weight, P&lt;0.05) and higher glucose tolerance (AUC[glucose], 1243±29 v. 1351±39 mmol min/l, P&lt;0.05) at weaning, as well as lower hepatic PI3K-p85 mRNA at 12 weeks of age. No differences in glucose tolerance or hepatic gene expression were observed in male offspring, but the male low GI offspring did have reduced hepatic lipid content at weaning. These findings suggest that consuming a low GI diet during pregnancy and lactation can improve glucose tolerance and reduce visceral adiposity in the female offspring at weaning, and may potentially produce long-term reductions in the hepatic lipogenic capacity of these offspring.

Adult exercise effects on oxidative stress and reproductive programming in male offspring of obese rats.

Exercise improves health but few data are available regarding benefits of exercise in offspring exposed to developmental programming. There is currently a worldwide epidemic of obesity. Obesity in pregnant women predisposes offspring to obesity. Maternal obesity has well documented effects on offspring reproduction. Few studies address ability of offspring exercise to reduce adverse outcomes. We observed increased oxidative stress and impaired sperm function in rat offspring of obese mothers. We hypothesized that regular offspring exercise reverses adverse effects of maternal obesity on offspring sperm quality and fertility. Female Wistar rats ate chow (C) or high-energy, obesogenic diet (MO) from weaning through lactation, bred at postnatal day (PND) 120, and ate their pregnancy diet until weaning. All offspring ate C diet from weaning. Five male offspring (different litters) ran on a wheel for 15 min, 5 times/week from PND 330 to 450 and were euthanized at PND 450. Average distance run per session was lower in MO offspring who had higher body weight, adiposity index, and gonadal fat and showed increases in testicular oxidative stress biomarkers. Sperm from MO offspring had reduced antioxidant enzyme activity, lower sperm quality, and fertility. Exercise in MO offspring decreased testicular oxidative stress, increased sperm antioxidant activity and sperm quality, and improved fertility. Exercise intervention has beneficial effects on adiposity index, gonadal fat, oxidative stress markers, sperm quality, and fertility. Thus regular physical exercise in male MO offspring recuperates key male reproductive functions even at advanced age: it's never too late.

In utero exposure to prepregnancy maternal obesity and postweaning high-fat diet impair regulators of mitochondrial dynamics in rat placenta and offspring

The proportion of pregnant women who are obese at conception continues to rise. Compelling evidence suggests the intrauterine environment is an important determinant of offspring health. Maternal obesity and unhealthy diets are shown to promote metabolic programming in the offspring. Mitochondria are maternally inherited, and we have previously shown impaired mitochondrial function in rat offspring exposed to maternal obesity in utero. Mitochondrial health is maintained by mitochondrial dynamics, or the processes of fusion and fission, which serve to repair damaged mitochondria, remove irreparable mitochondria, and maintain mitochondrial morphology. An imbalance between fusion and fission has been associated with obesity, insulin resistance, and reproduction complications. In the present study, we examined the influence of maternal obesity and postweaning high-fat diet (HFD) on key regulators of mitochondrial fusion and fission in rat offspring at important developmental milestones which included postnatal day (PND)35 (2 wk HFD) and PND130 (∼16 wk HFD). Our results indicate HFD-fed offspring had reduced mRNA expression of presenilin-associated rhomboid-like (PARL), optic atrophy (OPA)1, mitofusin (Mfn)1, Mfn2, fission (Fis)1, and nuclear respiratory factor (Nrf)1 at PND35, while OPA1 and Mfn2 remained decreased at PND130. Putative transcriptional regulators of mitochondrial dynamics were reduced in rat placenta and offspring liver and skeletal muscle [peroxisome proliferator-activated receptor gamma coactivator (PGC1)α, PGC1β, and estrogen-related receptor (ERR)α], consistent with indirect calorimetry findings revealing reduced energy expenditure and impaired fat utilization. Overall, maternal obesity detrimentally alters mitochondrial targets that may contribute to impaired mitochondrial health and increased obesity susceptibility in later life.

Disruption of paired-associate learning in rat offspring perinatally exposed to dioxins

The prevalence of cognitive abnormalities in children has partly been ascribed to environmental chemical exposure. Appropriate animal models and tools for evaluating higher brain function are required to examine this problem. A recently developed behavioral test in which rats learn six unique flavor-location pairs in a test arena was used to evaluate paired-associate learning, a hallmark of the higher cognitive function that is essential to language learning in humans. Pregnant Long-Evans rats were dosed by gavage with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) at a dose of 0, 200, or 800 ng/kg (referred as Control, TCDD-200, TCDD-800, TBDD-200, or TBDD-800, hereafter) on gestational day 15, and the offspring was tested during adulthood. Paired-associate learning was found to be impaired in the TCDD-200 and TBDD-200 groups, but not in either group exposed to 800 ng/kg, the observations of which were ensured by non-cued trials. As for the emotional aspect, during habituation, the TCDD-200 and TBDD-200 groups showed significantly longer latencies to enter the test arena from a start box than the Control, TCDD-800, and TBDD-800 groups, suggesting that the TCDD-200 and TBDD-200 groups manifested anxiety-like behavior. Thus, both the chlorinated dioxin and its brominated congener affected higher brain function to a similar extent in a nearly identical manner. Use of the behavioral test that can evaluate paired-associate learning in rats demonstrated that in utero and lactational exposure to not only TCDD but also TBDD perturbed higher brain function in rat offspring in a nonmonotonic manner.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-013-1161-y) contains supplementary material, which is available to authorized users.

Effects of High Fluoride and Low Iodine on Thyroid Function in Offspring Rats

Thirty-two Wistar rats were divided randomly into four groups of eight with six females and two males in each group. The rats were exposed to high fluoride drinking water (45 mg F− L−1 from 100 mg NaF L−1), low dietary iodine (0.0855 mg kg−1), or both together in order to assess the effects of these three regimens on the thyroid function of the offspring rats. After the animal model was established, the offspring rats were bred and 10-, 20-, 30-, 60-, and 90-d-old rats were used for the experiment. The treatments for the offspring rats were the same as those of their parents. In comparison with control rats, the relative thyroid glands were changed by three regimens, but the mean values of thyroid weight in the experimental groups saw no marked difference. Serum TT3 levels were increased in all stages in the low iodine (LI) group. In the high fluoride (HiF) group, increase in TT3 levels was observed except in 20-d-old rats. Decrease in TT3 at 20- and 90-d and increase in TT3 at 30- and 60-d were found in HiF+LI group. Serum TT4 levels first saw an increase, and then dropped in the LI and HiF+LI group. However, an increase in TT4 was found in the HiF group. The levels of TSH in serum rocketed at d 20, and then dropped in the next stages in experimental groups. The results suggested that thyroid disorder could be induced by high flroride in drinking water, low iodine diet, or both of them. Exposure time to fluoride or low iodine diet was one of the important factors that fluoride can induce the development of thyroid dyfunction.

Delay and Impairment in Brain Development and Function in Rat Offspring After Maternal Exposure to Methylmercury

Maternal exposure to the neurotoxin methylmercury (MeHg) has been shown to have adverse effects on neural development of the offspring in man. Little is known about the underlying mechanisms by which MeHg affects the developing brain. To explore the neurodevelopmental defects and the underlying mechanism associated with MeHg exposure, the cerebellum and cerebrum of Wistar rat pups were analyzed by [(18)F]FDG PET functional imaging, field potential analysis, and microarray gene expression profiling. Female rat pups were exposed to MeHg via maternal diet during intrauterinal and lactational period (from gestational day 6 to postnatal day (PND)10), and their brain tissues were sampled for the analysis at weaning (PND18-21) and adulthood (PND61-70). The [(18)F]FDG PET imaging and field potential analysis suggested a delay in brain activity and impaired neural function by MeHg. Genome-wide transcriptome analysis substantiated these findings by showing (1) a delay in the onset of gene expression related to neural development, and (2) alterations in pathways related to both structural and functional aspects of nervous system development. The latter included changes in gene expression of developmental regulators, developmental phase-associated genes, small GTPase signaling molecules, and representatives of all processes required for synaptic transmission. These findings were observed at dose levels at which only marginal changes in conventional developmental toxicity endpoints were detected. Therefore, the approaches applied in this study are promising in terms of yielding increased sensitivity compared with classical developmental toxicity tests.

Effect of maternal excessive iodine intake on neurodevelopment and cognitive function in rat offspring

BackgroundIodine deficiency and iodine excess are both associated with adverse health consequences. Iodine deficiency during pregnancy leads to insufficient maternal thyroid hormone, subsequently causing irreversible adverse effects on the neurological and cognitive functions of the offspring. The results of our previous epidemiological study suggested that mild iodine excess might increase the prevalence of subclinical hypothyroidism. In the present study, female Wistar rats maintained on low-iodine grain were randomly assigned to three groups based on iodated water concentration: low iodine (LI, 1.2 μg/d), normal iodine (NI, 5–6 μg/d), and 3-fold high iodine (3HI, 15–16 μg/d). The present study investigated whether higher-than-normal iodine intake (3HI) by rats from before pregnancy until breastfeeding affects the postnatal (PN) neurodevelopment (PN7 and PN45) of their offspring during particularly sensitive periods in brain development.ResultsAfter 12 weeks of treatment (before pregnancy), iodine concentrations in urine and thyroid tissue and circulating thyroxine of adult females correlated with iodine intake. Brain-derived neurotrophic factor (BDNF) expression in the hippocampi of pups on PN7 and PN45 was decreased in 3HI group compared to the NI controls (P < 0.05, all) On PN7 and PN45, the BDNF levels of the 3HI pups were 83.5% and 88.8%, respectively, that of the NI pups. In addition, the 3HI group had a higher neuroendocrine-specific protein A (NSP-A) level than the NI controls on PN7 (P < 0.05). NSP-A levels of the 3HI pups were 117.0% that of the NI pups. No significant difference was observed in the expressions of c-Fos or c-Jun in the hippocampal CA1 region of the 3HI group compared to the controls (P > 0.05). Results from the Morris water maze test revealed that pups of the 3HI group had mild learning and spatial memory deficits.ConclusionsThe neurodevelopmental and cognitive deficits of the 3HI pups were mild and temporary, likely related to the changes in hippocampal protein expressions of BDNF and NSP-A.

Effect of isoflurane anesthesia during early pregnancy on cognitive function of offspring rats

Objective To investigate the effect of isoflurane anesthesia during early pregnancy on the cognitive function of offspring rats.Methods Thirty SD rats at 5-7 day gestation were randomly divided into 3 groups ( n =10 each):control group (group C) and 2 isoflurane groups (groups Ⅰ1,Ⅰ2).Groups Ⅰ1 and Ⅰ2 inhaled 1.4％ isoflurane in O2 for 4 and 8 h respectively while group C inhaled 95 ％ O2 for 8 h.At 20 and 30 days after birth,offspring rats from 5 pregnant rats were tested for learning and memory abilities using Morris water maze.The offsprings were sacrificed at 7 days after test and their hippocampi were isolated for determination of N-methyl-D-aspartate receptor subunit 2B (NR2B) mRNA and protein expression.Results There were no significant differences in the results of Morris water maze test and NR2B mRNA and protein expression among the three groups.Conclusion Isoflurane anesthesia during early pregnancy has no effect on the cognitive function of the offspring rats. Key words: Isoflurane; Pregnancy trimester,first; Cognition disorders