Deficits In Offspring Research Articles

Transgenerational impairment of hippocampal Akt-mTOR signaling and behavioral deficits in the offspring of mice that experience postpartum depression-like illness

Postpartum depression (PPD) has adverse effects on offspring and increases their vulnerability to psychiatric disorders such as depression. Akt-mTOR signaling in the hippocampus is implicated in depression but its role in the behavioral deficits in PPD offspring remains unknown. By using a prepregnancy stress model of PPD in which Balb/c females that experience chronic stress before pregnancy show long-lasting PPD-like behaviors, we tested depression-like behaviors in PPD offspring (PPD-F1) at juvenile and adult ages as well as in the second generation (PPD-F2) produced by cross of male PPD-F1 with naïve females. Hippocampal Akt-mTOR signaling was examined in the F1 and F2 generations of PPD, as well as in PPD-F1 mice treated with a single dose of the antidepressant ketamine. PPD-F1 showed depression-like behaviors at juvenile and adult stages, evidenced by reduced sucrose preference (SP), increased immobility time in the forced swim test (FST), and a longer latency to feed and reduced food consumption in the novelty suppressed feeding (NSF) test. PPD-F1 mice showed Akt-mTOR signaling deficiency in the hippocampus, with down-regulated expression of p-Akt, p-mTOR and p-p70S6K. A single dose of ketamine reversed the behavior deficits and the impairment in Akt-mTOR signaling in PPD-F1. Furthermore, the PPD-F2 mice remained deficient in the SP and NSF test and hippocampal Akt-mTOR signaling, although the performance in FST was normal. The present study demonstrated both long-term and transgenerational effects of PPD on the depression–like behaviors of offspring, and suggested impaired Akt-mTOR signaling may play a part.

Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring

Maternal obesity during pregnancy has been associated with increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD), in offspring. Here, we report that maternal high-fat diet (MHFD) induces a shift in microbial ecology that negatively impacts offspring social behavior. Social deficits and gut microbiota dysbiosis in MHFD offspring are prevented by co-housing with offspring of mothers on a regular diet (MRD) and transferable to germ-free mice. In addition, social interaction induces synaptic potentiation (LTP) in the ventral tegmental area (VTA) of MRD, but not MHFD offspring. Moreover, MHFD offspring had fewer oxytocin immunoreactive neurons in the hypothalamus. Using metagenomics and precision microbiota reconstitution, we identified a single commensal strain that corrects oxytocin levels, LTP, and social deficits in MHFD offspring. Our findings causally link maternal diet, gut microbial imbalance, VTA plasticity, and behavior and suggest that probiotic treatment may relieve specific behavioral abnormalities associated with neurodevelopmental disorders. VIDEO ABSTRACT.

Maternal Prenatal Psychological Distress and Preschool Cognitive Functioning: the Protective Role of Positive Parental Engagement.

Considerable animal research and available human studies suggest that psychological distress experienced by mothers during gestation is associated with later neurodevelopmental deficits in offspring; however, little research has examined potential protective factors that might mitigate this risk. The current study examined the impact of maternal prenatal psychological distress during pregnancy on cognitive outcomes in preschoolers (ages 2.5-5years) and positive parenting as a potential protective factor. Mother-child dyads (N = 162, mean child age = 44months, 49% female) were recruited from a longitudinal cohort of women who had previously participated in a study of maternal mood disorders during pregnancy. Maternal prenatal distress was assessed with multiple measures collected throughout pregnancy. During a follow-up visit, mothers were interviewed about their psychological symptoms since the birth of the child, parenting behaviors were recorded during a parent-child interaction, and children's cognitive abilities were measured using the Differential Ability Scales, 2nd Edition. Maternal prenatal distress significantly predicted lower general cognitive abilities; however, this relationship was strongest for children whose mothers exhibited low levels of positive engagement and not significant when mothers exhibited high levels of positive engagement. Results suggest that positive parental engagement can protect against the detrimental effects of maternal prenatal distress on preschoolers' cognitive abilities.

Maternal glucose intolerance reduces offspring nephron endowment and increases glomerular volume in adult offspring.

Animal studies report a nephron deficit in offspring exposed to maternal diabetes, yet are limited to models of severe hyperglycaemia which do not reflect the typical clinical condition and which are associated with foetal growth restriction that may confound nephron endowment. We aimed to assess renal morphology and function in offspring of leptin receptor deficient mice (Leprdb /+) and hypothesized that exposure to impaired maternal glucose tolerance (IGT) would be detrimental to the developing kidney. Nephron endowment was assessed in offspring of C57BKS/J Leprdb /+ and +/+ mice at embryonic day (E)18 and postnatal day (PN)21 using design-based stereology. Transcutaneous measurement of renal function and total glomerular volume were assessed in 6-month-old offspring. Only +/+ offspring of Leprdb /+ dams were analysed. Compared with +/+ dams, Leprdb /+ dams had a 20% and 35% decrease in glucose tolerance prior to pregnancy and at E17.5 respectively. Offspring of IGT Leprdb /+ dams had approximately 15% fewer nephrons at E18.5 and PN21 than offspring of +/+ dams. There was no difference in offspring bodyweight. Despite normal renal function, total glomerular volume was 13% greater in 6-month-old offspring of IGT Leprdb /+ dams than in +/+ offspring. IGT throughout gestation resulted in a nephron deficit that was established early in renal development. Maternal IGT was associated with glomerular hypertrophy in adult offspring, likely a compensatory response to maintain normal renal function. Given the increasing prevalence of IGT, monitoring glucose from early in gestation may be important to prevent altered kidney morphology. Copyright © 2016 John Wiley & Sons, Ltd.

Nicotine ameliorates schizophrenia-like cognitive deficits induced by maternal LPS exposure: a study in rats.

ABSTRACTMaternal exposure to infectious agents is a predisposing factor for schizophrenia with associated cognitive deficits in offspring. A high incidence of smoking in these individuals in adulthood might be, at least in part, due to the cognitive-enhancing effects of nicotine. Here, we have used prenatal exposure to maternal lipopolysaccharide (LPS, bacterial endotoxin) at different time points as a model for cognitive deficits in schizophrenia to determine whether nicotine reverses any associated impairments. Pregnant rats were treated subcutaneously with LPS (0.5 mg/kg) at one of three neurodevelopmental time periods [gestation days (GD) 10-11, 15-16, 18-19]. Cognitive assessment in male offspring commenced in early adulthood [postnatal day (PND) 60] and included: prepulse inhibition (PPI), latent inhibition (LI) and delayed non-matching to sample (DNMTS). Following PND 100, daily nicotine injections (0.6 mg/kg, subcutaneously) were administered, and animals were re-tested in the same tasks (PND 110). Only maternal LPS exposure early during fetal neurodevelopment (GD 10-11) resulted in deficits in all tests compared to animals that had been prenatally exposed to saline at the same gestational time point. Repeated nicotine treatment led to global (PPI) and selective (LI) improvements in performance. Early but not later prenatal LPS exposure induced consistent deficits in cognitive tests with relevance for schizophrenia. Nicotine reversed the LPS-induced deficits in selective attention (LI) and induced a global enhancement of sensorimotor gating (PPI).

Loss of Metabotropic Glutamate Receptor 5 Function on Peripheral Benzodiazepine Receptor in Mice Prenatally Exposed to LPS

Parental microglial induced neuroinflammation, triggered by bacterial- or viral infections, can induce neuropsychiatric disorders like schizophrenia and autism to offspring in animal models. Recent investigations suggest that microglia, the resident immune cells of the brain, provides a link between neurotransmission, immune cell activation, brain inflammation and neuronal dysfunction seen with the offspring. Relatively little is known about how reduction of brain inflammation and restoration of glial function are associated with diminution of brain degeneration and behavioral deficits in offspring. Increased mGluR5 expression and the long-lasting excitotoxic effects of the neurotoxin during brain development are associated with the glial dysfunctions. We investigated the relationship of mGluR5 and PBR and how they regulate glial function and inflammatory processes in mice prenatally exposed to LPS (120μg/kg, between gestational days 15 and 17), an inflammatory model of a psychiatric disorder. Using PET imaging, we showed that pharmacological activation of mGluR5 during 5 weeks reduced expression of classic inflammation marker PBR in many brain areas and that this molecular association was not present in LPS-exposed offspring. The post-mortem analysis revealed that the down regulation of PBR was mediated through activation of mGluR5 in astrocytes. In addition, we demonstrated that this interaction is defective in a mouse model of the psychiatric deficit offering a novel insight of mGluR5 involvement to brain related disorders and PBR related imaging studies. In conclusion, mGluR5 driven glutamatergic activity regulates astrocytic functions associated with PBR (cholesterol transport, neurosteroidogenesis, glial phenotype) during maturation and could be associated with neuropsychiatric disorders in offspring.

2-Cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride alters lipopolysaccharide-induced proinflammatory cytokines and neuronal morphology in mouse fetal brain

It is well documented that a maternal immune response to infection during pregnancy can cause neurodevelopmental damage. We demonstrate in our current study that maternally administered 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride (KHG26377), a novel thiazole derivative, prevents fetal malformations and neurodevelopmental deficits in offspring by blocking lipopolysaccharide (LPS)-induced inflammation. Administration of KHG26377 effectively regulated LPS-induced inflammatory markers and mediators such as soluble intercellular adhesion molecule-1, se-Selectin, macrophage chemoattractant protein-1, and cytokine-induced neutrophil chemoattractant-1 in the maternal serum. Furthermore, maternally administered KHG26377 showed an inhibitory effect on the LPS-induced developmental toxicity by selectively suppressing the TNF-α level in maternal serum, amniotic fluid, placenta, fetal liver, and fetal brain as well as by suppression of LPS-induced nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and myelin basic protein (MBP) levels in the fetal brain. In addition, pretreatment of neuronal cells with KHG26377 effectively reestablished the cell body morphology and microtubule-associated protein 2 (MAP2) staining compared to the LPS-treated group in cortex primary neuronal cultures. Although the clinical relevance of our findings remains to be determined, our results provide novel insights into KHG26377 as a possible therapeutic agent to protect fetuses against various inflammatory responses.

Experimental Malaria in Pregnancy Induces Neurocognitive Injury in Uninfected Offspring via a C5a-C5a Receptor Dependent Pathway

The in utero environment profoundly impacts childhood neurodevelopment and behaviour. A substantial proportion of pregnancies in Africa are at risk of malaria in pregnancy (MIP) however the impact of in utero exposure to MIP on fetal neurodevelopment is unknown. Complement activation, in particular C5a, may contribute to neuropathology and adverse outcomes during MIP. We used an experimental model of MIP and standardized neurocognitive testing, MRI, micro-CT and HPLC analysis of neurotransmitter levels, to test the hypothesis that in utero exposure to malaria alters neurodevelopment through a C5a-C5aR dependent pathway. We show that malaria-exposed offspring have persistent neurocognitive deficits in memory and affective-like behaviour compared to unexposed controls. These deficits were associated with reduced regional brain levels of major biogenic amines and BDNF that were rescued by disruption of C5a-C5aR signaling using genetic and functional approaches. Our results demonstrate that experimental MIP induces neurocognitive deficits in offspring and suggest novel targets for intervention.

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

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

Allergic fetal priming leads to developmental, behavioral and neurobiological changes in mice

The state of the mother's immune system during pregnancy has an important role in fetal development and disruptions in the balance of this system are associated with a range of neurologic, neuropsychiatric and neurodevelopmental disorders. Epidemiological and clinical reports reveal various clues that suggest a possible association between developmental neuropsychiatric disorders and family history of immune system dysfunction. Over the past three decades, analogous increases have been reported in both the incidence of neurodevelopmental disorders and immune-related disorders, particularly allergy and asthma, raising the question of whether allergic asthma and characteristics of various neurodevelopmental disorders share common causal links. We used a mouse model of maternal allergic asthma to test this novel hypothesis that early fetal priming with an allergenic exposure during gestation produces behavioral deficits in offspring. Mothers were primed with an exposure to ovalbumin (OVA) before pregnancy, then exposed to either aerosolized OVA or vehicle during gestation. Both male and female mice born to mothers exposed to aerosolized OVA during gestation exhibited altered developmental trajectories in weight and length, decreased sociability and increased marble-burying behavior. Moreover, offspring of OVA-exposed mothers were observed to have increased serotonin transporter protein levels in the cortex. These data demonstrate that behavioral and neurobiological effects can be elicited following early fetal priming with maternal allergic asthma and provide support that maternal allergic asthma may, in some cases, be a contributing factor to neurodevelopmental disorders.

Aberrant development of post-movement beta rebound in adolescents and young adults with fetal alcohol spectrum disorders.

Dependent on maternal (e.g. genetic, age) and exposure (frequency, quantity, and timing) variables, the effects of prenatal alcohol exposure on the developing fetus are known to vary widely, producing a broad range of morphological anomalies and neurocognitive deficits in offspring, referred to as fetal alcohol spectrum disorders (FASD). Maternal drinking during pregnancy remains a leading risk factor for the development of intellectual disabilities in the US. While few functional findings exist today that shed light on the mechanisms responsible for the observed impairments in individuals with FASD, animal models consistently report deleterious effects of early alcohol exposure on GABA-ergic inhibitory pathways. The post-motor beta rebound (PMBR), a transient increase of 15–30 Hz beta power in the motor cortex that follows the termination of movement, has been implicated as a neural signature of GABA-ergic inhibitory activity. Further, PMBR has been shown to be a reliable predictor of age in adolescents. The present study sought to investigate any differences in the development of PMBR between FASD and control groups. Beta event-related de-synchronization (ERD) and movement-related gamma synchronization (MRGS), although not clearly linked to brain maturation, were also examined. Twenty-two participants with FASD and 22 age and sex-matched controls (12–22 years old) underwent magnetoencephalography scans while performing an auditory oddball task, which required a button press in response to select target stimuli. The data surrounding the button presses were localized to the participants' motor cortices, and the time courses from the locations of the maximally evoked PMBR were subjected to wavelet analyses. The subsequent analysis of PMBR, ERD, and MRGS revealed a significant interaction between group and age in their effects on PMBR. While age had a significant effect on PMBR in the controls, no simple effects of age were detected in the FASD group. The FASD group additionally displayed decreased overall ERD levels. No group or age effects on MRGS were detected. The described findings provide further evidence for broad impairments in inhibitory processes in adolescents with FASD, possibly related to aberrant development of GABA-ergic pathways.

184: Implementing staff-administered TACER-3 alcohol screening in an antenatal clinic

TACER-3 is an adapted re-scoring of the T-ACE pregnancy alcohol screen. Our prior studies in a research setting showed that TACER-3 is more specific than T-ACE, better predicting risk drinking in pregnancy & alcohol-related neurobehavioral deficits in offspring. Though clinical use of the TACER-3 could result in better utilization of health care provider time by focusing effort on women drinking at fetal risk levels, surveys of ObGyns have shown repeatedly that few actually do formal screening, substantially under-identifying pregnancy risk drinking.

87. T cell malfunction and a pro-inflammatory skew in autism spectrum disorders

Immune dysfunction is evident in many cases of autism spectrum disorders (ASD). Elevated levels of pro-inflammatory molecules, a deficiency and malfunction of T cells, and activated microglia in brain were detected in ASD. Whether a pro-inflammatory skew can cause ASD is unclear, but mounting evidence suggests that maternal immune activation (MIA) may contribute to the development of autistic features. MIA causes autistic-like behavioral deficits in offspring that can be prevented in mice by replacing their immune systems via bone marrow transplantation. We have identified that meningeal T cells, surrounding the brain, are necessary for normal brain function. Here we tested if malfunctioning T cells underlie behavioral dysfunction in ASD. We used multiple approaches to first deplete T cells in adult mice, and then assessed their behavior. We found that mice deficient or depleted of T cells have autistic-like dysfunction in multiple cognitive and social behavioral assays as well as an overall pro-inflammatory skew of their innate compartment (myeloid cells in the meninges and microglia). These data demonstrate that T cell malfunction in mice may be used to model behavioral abnormalities associated with ASD. We propose that in some cases of ASD, T cell malfunction leads to an unregulated pool of meningeal myeloid cells and microglia. This unleashes a pro-inflammatory environment that results in neuronal dysfunction and ultimately behavioral deficits in autism.

Hippocampal apoptosis involved in learning deficits in the offspring exposed to maternal high sucrose diets

The hippocampus plays a crucial role in learning and memory, and neuronal apoptosis in the hippocampus contributes to learning deficits. Metabolism problems in pregnancy related to excessive fuel consumption (e.g., high fat, high sugar) may influence cognitive and behavioral functions in the offspring by affecting developing brain cells. This study determined the influence of maternal high sucrose (HS) diets on behavior and hippocampal neurons in the young offspring. The ratio of brain weight to body weight in the offspring exposed to prenatal HS diets was significantly decreased; the Morris water maze showed that the offspring exposed to prenatal HS diets exhibited increased escape latencies and path length during navigation testing, while there were no changes in time spent in the target quadrant and number of target approaches. In the offspring exposed to prenatal HS, TUNEL-positive cells were significantly increased in CA1, CA2 and CA3 of the hippocampus; protein expression of insulin-like growth factor-I, PI3K and phosphorylated Akt was significantly decreased, while caspase-3 and N-methyl-d-aspartate receptors were significantly increased in the hippocampus, and there was no change in expression of Bcl-2 and Akt. The results demonstrated that prenatal HS diets could induce the spatial acquisition deficits in the young offspring associated with hippocampal apoptosis, and altered signaling factors for antiapoptosis in the hippocampus might play a critical role in cognition disorders in young children.

Chrna5 genotype determines the long-lasting effects of developmental in vivo nicotine exposure on prefrontal attention circuitry

Maternal smoking during pregnancy repeatedly exposes the developing fetus to nicotine and is linked with attention deficits in offspring. Corticothalamic neurons within layer VI of the medial prefrontal cortex are potential targets in the disruption of attention circuitry by nicotine, a process termed teratogenesis. These prefrontal layer VI neurons would be likely targets because they are developmentally excited and morphologically sculpted by a population of nicotinic acetylcholine receptors (nAChRs) that are sensitive to activation and/or desensitization by nicotine. The maturational effects of these α4β2* nAChRs and their susceptibility to desensitization are both profoundly altered by the incorporation of an α5 subunit, encoded by the chrna5 gene. Here, we investigate nicotine teratogenesis in layer VI neurons of wildtype and α5−/− mice. In vivo chronic nicotine exposure during development significantly modified apical dendrite morphology and nAChR currents, compared with vehicle control. The direction of the changes was dependent on chrna5 genotype. Surprisingly, neurons from wildtype mice treated with in vivo nicotine resembled those from α5−/− mice treated with vehicle, maintaining into adulthood a morphological phenotype characteristic of immature mice together with reduced nAChR currents. In α5−/− mice, however, developmental in vivo nicotine tended to normalize both adult morphology and nAChR currents. These findings suggest that chrna5 genotype can determine the effect of developmental in vivo nicotine on the prefrontal cortex. In wildtype mice, the lasting alterations to the morphology and nAChR activation of prefrontal layer VI neurons are teratogenic changes consistent with the attention deficits observed following developmental nicotine exposure.

Binge toluene exposure in pregnancy and pre-weaning developmental consequences in rats

Binge Toluene Exposure in Pregnancy and Pre-weaning Developmental Consequences in Rats. Bowen, S.E. and Hannigan, J.H. The persistent rate of abuse of inhaled organic solvents, especially among women of child-bearing age, raises the risk for teratogenic effects of maternal toluene abuse. In this study, timed-pregnant Sprague Dawley rats were exposed from Gestation Day (GD) 8 to GD20 to 12,000 or 8000 parts per million (ppm) toluene, or 0ppm (controls) for 30min twice daily, 60min total daily exposure. Pups were assessed from postnatal day (PN) 4 to PN21 using a developmental battery measuring growth (i.e., body weight), maturational milestones (e.g., eye opening & incisor eruption), and biobehavioral development (e.g., negative geotaxis & surface righting). Pups exposed in utero to 12,000ppm or 8000ppm toluene weighed significantly less than the non-exposed control pups beginning at PN4 and PN12 (respectively) until PN21. Toluene resulted in significant increases in an index of poor perinatal outcome, specifically a composite of malformations, defined “runting” and neonatal death. No significant delays were observed in reaching maturational milestones. The results reveal that brief, repeated, prenatal exposure to high concentrations of toluene can cause growth retardation and malformations in rats. A comparison of the present, conservative results with findings in previous studies implies that binge patterns of toluene exposure in pregnant rats modeling human solvent abuse can result in developmental and morphological deficits in offspring. These results do not exclude the possibility that maternal toxicity as well as teratogenic effects of toluene may contribute to outcomes. The results suggest that abuse of inhaled organic solvents like toluene may result in similar early developmental outcomes in humans.

Preliminary study on the intergerational effect of postnatal malnutrition on attention

Early malnutrition has been associated with attention deficits across the lifespan. Limited studies exist on the intergenerational effects of malnutrition and, to our knowledge, none specifically address attention. In the current study, we assessed Barbadian adults (17–26y) whose mothers had been followed for 40y in the Barbados Nutrition Study (N=31). Eleven had mothers who suffered from a single episode of moderate‐ severe postnatal malnutrition in the first year of life (MAL). The remaining 20 were offspring of healthy mothers (CON) matched to the MAL group by age, sex, and handedness in childhood. The Conners Adult ADHD Rating Scale‐S:SV was used to identify inattention, hyperactivity, ADHD symptoms and DSM‐IV clinical index scores. Parental malnutrition effects were analyzed across factors, adjusting for childhood standard of living of the parent (SAS PROC MIXED). Mean scores were higher in the MAL offspring when compared with CON offspring, connoting more attention deficits. Significant main effects of nutrition were present for DSM‐IV clinical index scores (F=6.10, p<0.05). We concluded that postnatal malnutrition is associated with attention deficits in offspring of individuals exposed to postnatal malnutrition, though these offspring themselves were never malnourished. Studies in a larger sample are needed to identify biological and environmental mechanisms underlying these differences.Grant Funding Source: NIH HD060986

Altered neuroendocrine status at the onset of CNS lupus-like disease

Neuropsychiatric (NP) manifestations and brain atrophy are common, etiologically unexplained complications of the systemic autoimmune disease lupus erythematosus (SLE). Similar to patients with NP SLE, behavioral deficits and neurodegeneration occur in aged, lupus-prone MRL/lpr mice. In order to gain a better understanding of the time course and nature of CNS involvement, we compare the neuro-immuno-endocrine profiles of two lupus-prone MRL/lpr stocks, which differ in disease onset and severity. Mice from stock 485 (characterized by early lupus-like manifestations) display blunted responsiveness to palatable solutions and impaired nocturnal activity as early as 7 weeks of age. They also have increased IgG in cerebrospinal fluid (CSF) before high serum autoantibody levels and splenomegaly are detected. Moreover, when compared to age-matched 6825 controls, 485 mice exhibit elevated serum corticosterone, enlarged left adrenal gland, and enhanced haematoxylin/eosin staining in the hypothalamic paraventricular nucleus. Swimming speed and novel object exploration become impaired only when more severe peripheral manifestations are documented in 17 week-old 485 mice. The obtained results suggest that performance deficits during the prodromal phase of NP SLE-like disease are associated with autoantibodies in CSF and asymmetric activation of the hypothalamus-pituitary-adrenal axis. Subsequent deterioration in behavioral performance evolves alongside systemic autoimmunity and inflammation. Although a leaky blood-CSF barrier is a possible explanation, one may hypothesize that, similar to neonatal lupus, maternal antibodies to brain antigens cross blood-placental barrier during embryogenesis and induce early endocrine and behavioral deficits in offspring.

Effects of Low-Dose Drinking Water Arsenic on Mouse Fetal and Postnatal Growth and Development

BackgroundArsenic (As) exposure is a significant worldwide environmental health concern. Chronic exposure via contaminated drinking water has been associated with an increased incidence of a number of diseases, including reproductive and developmental effects. The goal of this study was to identify adverse outcomes in a mouse model of early life exposure to low-dose drinking water As (10 ppb, current U.S. EPA Maximum Contaminant Level).Methodology and FindingsC57B6/J pups were exposed to 10 ppb As, via the dam in her drinking water, either in utero and/or during the postnatal period. Birth outcomes, the growth of the F1 offspring, and health of the dams were assessed by a variety of measurements. Birth outcomes including litter weight, number of pups, and gestational length were unaffected. However, exposure during the in utero and postnatal period resulted in significant growth deficits in the offspring after birth, which was principally a result of decreased nutrients in the dam's breast milk. Cross-fostering of the pups reversed the growth deficit. Arsenic exposed dams displayed altered liver and breast milk triglyceride levels and serum profiles during pregnancy and lactation. The growth deficits in the F1 offspring resolved following separation from the dam and cessation of exposure in male mice, but did not resolve in female mice up to six weeks of age.Conclusions/SignificanceExposure to As at the current U.S. drinking water standard during critical windows of development induces a number of adverse health outcomes for both the dam and offspring. Such effects may contribute to the increased disease risks observed in human populations.

Amelioration Of Congenital Toxoplasmosis Effects By Maternal Immune Stimulation

In mice, peri‐conceptual maternal immune stimulation can reduce the incidence and severity of structural birth defects caused by a wide variety of physical and chemical agents. Maternal immune mediated protection against malformations caused by an infectious agent has not previously been examined. We investigated the ability of interferon gamma (IFN) to protect against birth defects caused by the parasite Toxoplasma gondii. We assessed structural and behavioral deficits in offspring of control, Toxo only, IFN only, and IFN+Toxo treated mice. Offspring were assessed structurally on prenatal day 17 and functionally at 4 and 8 weeks of age using the Barnes maze, motor activity and function observational battery assessments. Infection with T. gondii reduced fetal viability to 23%; however, viability was increased to 58% in dams treated with IFN prior to infection. Congenital toxoplasmosis decreased memory and learning at 4 weeks of age. Treatment of dams with IFN altered spatial memory, coordination and processing of stimuli. By 8 weeks of age, all the deficits observed at 4 weeks had disappeared for both sexes, but male T. gondii infected mice acquired deficits involving spatial memory and rate of learning. IFN treatment prior to infection eliminated negative effects of congenital toxoplasmosis in male offspring. Supported by the Harvey Peters Foundation.