Prenatal immune activation leads to multiple changes in basal neurotransmitter levels in the adult brain: implications for brain disorders of neurodevelopmental origin such as schizophrenia

Maternal infection during pregnancy enhances the offspring's risk for severe neuropsychiatric disorders in later life, including schizophrenia. Recent attempts to model this association in animals provided further experimental evidence for a causal relationship between in-utero immune challenge and the postnatal emergence of a wide spectrum of behavioural, pharmacological and neuroanatomical dysfunctions implicated in schizophrenia. However, it still remains unknown whether the prenatal infection-induced changes in brain and behavioural functions may be associated with multiple changes at the neurochemical level. Here, we tested this hypothesis in a recently established mouse model of viral-like infection. Pregnant dams on gestation day 9 were exposed to viral mimetic polyriboinosinic-polyribocytidilic acid (PolyI:C, 5 mg/kg i.v.) or vehicle treatment, and basal neurotransmitter levels were then compared in the adult brains of animals born to PolyI:C- or vehicle-treated mothers by high-performance liquid chromatography on post-mortem tissue. We found that prenatal immune activation significantly increased the levels of dopamine and its major metabolites in the lateral globus pallidus and prefrontal cortex, whilst at the same time it decreased serotonin and its metabolite in the hippocampus, nucleus accumbens and lateral globus pallidus. In addition, a specific reduction of the inhibitory amino acid taurine in the hippocampus was noted in prenatally PolyI:C-exposed offspring relative to controls, whereas central glutamate and gamma-aminobutyric acid (GABA) content was largely unaffected by prenatal immune activation. Our results thus confirm that maternal immunological stimulation during early/middle pregnancy is sufficient to induce long-term changes in multiple neurotransmitter levels in the brains of adult offspring. This further supports the possibility that infection-mediated interference with early fetal brain development may predispose the developing organism to the emergence of neurochemical imbalances in adulthood, which may be critically involved in the precipitation of adult behavioural and pharmacological abnormalities after prenatal immune challenge.     

Chronic clozapine treatment improves prenatal infection-induced working memory deficits without influencing adult hippocampal neurogenesis

Background

Converging evidence indicates that prenatal exposure to immune challenge can induce long-term cognitive deficits relevant to schizophrenia. Such cognitive impairments may be related to deficient hippocampal neurogenesis at adult age.

Objectives

In the present study, we sought evidence for the possibility that chronic treatment with the reference atypical antipsychotic drug clozapine may improve prenatal infection-induced cognitive dysfunctions by stimulating adult hippocampal neurogenesis.

Methods

This hypothesis was tested in a well-established mouse model of prenatal immune challenge which is based on prenatal administration of the viral mimic, polyriboinosinic–polyribocytidilic acid (PolyI:C).

Results

We found that maternal PolyI:C (5 mg/kg, i.v.) exposure on gestation day 17 led to significant spatial working memory impairment and reduced hippocampal neurogenesis in the resulting offspring at adult age. The latter effect was apparent in postmortem immunohistochemical analyses of the cell proliferation marker bromodeoxyuridine and the microtubule-associated protein doublecortin, a marker of newborn neuronal cells. Chronic (3 weeks) administration of clozapine (5 mg/kg/day, i.p.) significantly improved the prenatal PolyI:C-induced working memory deficits, while at the same time, it negatively affected working memory performance in adult offspring born to control mothers. These bidirectional cognitive effects of clozapine were not paralleled by concomitant effects on adult hippocampal neurogenesis.

Conclusions

Our findings do not support the hypothesis that the atypical antipsychotic drug clozapine may influence cognitive functions by acting on adult neurogenesis in the hippocampus, regardless of whether the drug is administered to subjects with or without a neurodevelopmental predisposition to adult neuropathology.     

Effects of prenatal phencyclidine on 3H-PCP binding and PCP-induced motor activity and ataxia

Either phencyclidine hydrochloride (PCP) (5, 10, or 20 mg/kg) or saline was administered by subcutaneous injection to gravid CF-1 mice during either Mid (E6-15) or Late (E12-18) gestation. A nontreated control group (UTC) was left undisturbed during pregnancy. All treated and control litters were fostered at birth to untreated dams. Although postnatal challenge of PCP increased motor activity and ataxia in a dose-related manner, prenatal PCP had no effect on postnatal motor activity, ataxia or 3H-PCP binding. However, treatment period did have a significant effect on ataxia and 3H-PCP binding. In response to challenge doses of 5.0 and 7.5 mg/kg PCP, ataxia scores of the Late gestation offspring were significantly greater than the UTC offspring which in turn were significantly greater than the ataxia scores of the Mid gestation group. The results are discussed in relation to other animal and clinical reports of prenatal PCP exposure.     

Prenatal exposure to a viral mimetic alters behavioural flexibility in male, but not female, rats

Current understanding of the etiology of neurodevelopmental disorders is limited; however, recent epidemiological studies demonstrate a strong correlation between prenatal infection during pregnancy and the development of schizophrenia in adult offspring. In particular, schizophrenia patients subjected to prenatal infection exhibit impairments in executive functions greater than schizophrenia patients not exposed to an infection while in utero. Acute prenatal treatment of rodents with the viral mimetic polyinosinic-polycytidylic acid (PolyI:C) induces behavioural and neuropathological alterations in the adult offspring similar to schizophrenia. However, impairments on tasks of executive function that involve the prefrontal cortex (PFC) have been rarely examined for the prenatal infection model. Hence, we investigated the effects of acute prenatal injection of PolyI:C (4.0 mg/kg, i.v., gestational day 15) on strategy set-shifting and reversal learning in an operant-based task. Our results show male, but not female, PolyI:C-treated adult offspring require more trials to reach criterion and perseverate during set-shifting. An opposite pattern was seen on the reversal day where the PolyI:C-treated male rats made fewer regressive errors. Females took more pre-training days and were slower to respond during the trials when compared to males regardless of prenatal treatment. The present findings validate the utility of the prenatal infection model for examining alterations of executive function, one of the most prominent cognitive symptoms of schizophrenia.     

Influence of prenatal maternal stress on the immunocompetence of the offspring.

To evaluate the effects of prenatal maternal stress on the development of humoral immunocompetence in the offspring and on their hormonal and immunologic responses to postnatal stress, gravid Sprague-Dawley rats were exposed daily on gestational days 15-21 to prenatal environmental stress [(PES) 15 unsignaled, inescapable electric foot-shocks (0.05 mA for 0.5 s)] or prenatal psychological stress [(PPS) pregnant rats were placed in the nonelectrified section of the apparatus and allowed to see, hear, and smell a nonpregnant partner being environmentally stressed]. Pregnant controls (PC) were placed in the apparatus for 30 min. Serum corticosterone (CCS) and immunoglobulin G (IgG) levels were measured in the offspring every 7 days from birth to postnatal day (PND) 28. On PND 29-33, offspring were environmentally stressed; hormonal and immune status were determined on PND 34. Levels of IgG were reduced in PES and PPS offspring on PND 0 and in PES offspring on PND 7 and 28. These changes were unrelated to differences in CCS and did not reflect altered maternal-pup interactions or nutritional factors. Postnatal stress was immunosuppressive in PC pups but did not alter immune parameters in PPS offspring. In PES females, postnatal stress was also immunosuppressive. However, in PES males with already reduced IgG levels postnatal stress enhanced immune function. These data provide the first experimental evidence that prenatal maternal stress can alter immune parameters in the rat offspring.     

Effect of prenatal waterpipe tobacco smoke on airway inflammation in murine model of asthma of adult offspring mice

Objective: Worldwide popularity of waterpipe tobacco smoking has increased, including in pregnant women. This study investigates the effect of prenatal waterpipe tobacco smoke (WTS) exposure on airway inflammation in a murine model of asthma of adult offspring mice.

Materials and methods: Pregnant BALB/c mice were exposed to fresh air or WTS, using a whole-body exposure system that mimics human use during WTS. Adult male offspring mice were divided into; (1) control (prenatal fresh air, postnatal ovalbumin sensitization and saline challenge), (2) postnatal Ova S/C (prenatal fresh air, postnatal ovalbumin sensitization and challenge (Ova S/C)), (3) prenatal WTS (prenatal WTS, postnatal ovalbumin sensitization and saline challenge) and (4) prenatal WTS?+?postnatal Ova S/C. Cells from the bronchoalveolar lavage fluid, cytokines, and oxidative stress markers (superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and thiobarbituric acid reactive substances (TBARS)) from lung homogenates were evaluated.

Results: Prenatal WTS increased recruitment of cells in lungs and levels of SOD and catalase when compared to unexposed offspring’s. The levels of cytokines, GPx and TBARS were not affected by prenatal WTS. Prenatal WTS exposure and postnatal Ova S/C increased airway inflammation and activity of SOD compared to control and Ova S/C mice and reduced IL-18 levels compared to Ova S/C mice.

Discussion and conclusions: Prenatal exposure to WTS induced airway inflammation, further enhanced by a murine model of asthma in adult offspring. Prenatal exposure to WTS adversely affects the lung function of the offspring and careful strategies for increasing public awareness regarding the harmful effects of WTS during pregnancy is important.     

Tracing the development of psychosis and its prevention: what can be learned from animal models

Schizophrenia (SCZ) is a neurodevelopmental disorder manifested symptomatically after puberty whose pharmacotherapy remains unsatisfactory. In recent years, longitudinal structural neuroimaging studies have revealed that neuroanatomical aberrations occur in this disorder and in fact precede symptom onset, raising the exciting possibility that SCZ can be prevented. There is some evidence that treatment with atypical antipsychotic drugs (APDs) prior to the development of the full clinical phenotype reduces the risk of transition to psychosis, but results remain controversial. It remains unknown whether progressive structural brain aberrations can be halted. Given the diagnostic, ethical, clinical and methodological problems of pharmacological and imaging studies in patients, getting such information remains a major challenge. Animal neurodevelopmental models of SCZ are invaluable for investigating such questions because they capture the notion that the effects of early brain damage are progressive. In recent years, data derived from such models have converged on key neuropathological and behavioral deficits documented in SCZ attesting to their strong validity, and making them ideal tools for evaluating progression of pathology following in-utero insults as well as its prevention. We review here our recent studies that use longitudinal in vivo structural imaging to achieve this aim in the prenatal immune stimulation model that is based on the association of prenatal infection and increased risk for SCZ. Pregnant rats were injected on gestational day 15 with the viral mimic polyriboinosinic-polyribocytidylic acid (poly I:C) or saline. Male and female offspring were imaged and tested behaviorally on postnatal days (PNDs) 35, 46, 56, 70 and 90. In other experiments, offspring of poly I:C- and saline-treated dams received the atypical antipsychotic drugs (APDs) clozapine or risperidone in two developmental windows: PND 34-47 and PND 48-61, and underwent behavioral testing and imaging at adulthood. Prenatal poly I:C-induced interference with fetal brain development led to aberrant postnatal brain development as manifested in structural abnormalities in the hippocampus, the striatum, the prefrontal cortex and lateral ventricles (LV), as seen in SCZ. The specific trajectories were region-, age- and sex-specific, with females having delayed onset of pathology compared to males. Brain pathology was accompanied by development of behavioral abnormalities phenotypic of SCZ, attentional deficit and hypersensitivity to amphetamine, with same sex difference. Hippocampal volume loss and LV volume expansion as well as behavioral abnormalities were prevented in the offspring of poly I:C mothers who received clozapine or risperidone during the asymptomatic period of adolescence (PND 34-47). Administration at a later window, PNDs 48-61, exerted sex-, region- and drug- specific effects. Our data show that prenatal insult leads to progressive postnatal brain pathology, which gradually gives rise to "symptoms"; that treatment with atypical APDs can prevent both brain and behavioral pathology; and that the earlier the intervention, the more pathological outcomes can be prevented.     

Maternal age as a factor in determining the reproductive and behavioral outcome of rats prenatally exposed to ethanol

Nulliparous Long-Evans rats were bred at one of four different ages and assigned to one of three treatment groups within each age condition. Maternal ages were 9, 18, 32, and 36 weeks. Treatment groups were ethanol (E), administered by gavage as 8 g/kg in two divided doses on days 10-14 of gestation, pair-fed (PF) controls, administered as an isocaloric sucrose solution by gavage on days 10-14 of gestation, and ad lib fed controls (C). All offspring were surrogate fostered shortly after delivery to untreated recently parturient dams. Litter sizes were standardized to 8 on the day of birth. Offspring were assessed longitudinally for growth, mortality, and behavior (olfaction, locomotor activity, maze learning, avoidance acquisition and startle). Approximately 85% of the 36 week old dams did not produce viable litters. In the remaining maternal age conditions, ethanol delayed offspring olfactory orientation and increased locomotor activity, the latter dissipating after 50-60 days of age. These ethanol-related effects occurred independent of maternal age condition. Maternal age, independent of ethanol, was a factor which reduced litter size and offspring weight up to 50 days, but produced few effects on behavior. The combination of maternal age and prenatal ethanol interacted to increase pregnancy loss (oldest maternal age), reduce offspring weight up to day 99 (oldest and middle maternal age), alter olfactory orientation performance (oldest and middle maternal age), reverse the typical ethanol-induced increase in activity for males in the figure-8 test (oldest maternal age group), shift the pattern of open-field activity, and change errors in a complex water maze. Not all of these interactions turned out to be specific to the ethanol X old maternal age condition. Several of the interactions occurred in both the old and middle maternal age conditions. The only effect of old maternal age that interacted strongly with ethanol was in their combined effects on reproduction. Here the combination of the two factors increased maternal mortality, the number of early pregnancy losses, and the number of litters where all members were dead or resorbed. It was concluded that short-term prenatal ethanol combined with advanced maternal age produces additive interactions on pregnancy success without affecting longer-term outcomes, while young maternal age showed no clear detrimental effects compared to the middle maternal age reference group.     

Chronic exposure to the opioid growth factor, [Met5]-enkephalin, during pregnancy: maternal and preweaning effects.

The opioid peptide, [Met(5)]-enkephalin (termed opioid growth factor, OGF), is an autocrine growth factor that serves as a constitutively active inhibitory agent. OGF crosses the placenta and depresses DNA synthesis in the fetus. The role of OGF in pregnancy and parturition, and the influence exerted on prenatal and neonatal features of the offspring, were studied in rats. Females received daily injections of 10 mg/kg OGF throughout gestation; all offspring were cross-fostered to lactating noninjected dams at birth. No effects on the length of gestation, course of pregnancy, behavior of the pregnant dam, maternal weight gain, or food and water intake throughout gestation were recorded in OGF-treated mothers. Moreover, nociceptive response in these females was not altered by chronic OGF exposure, and no signs of physical dependence or withdrawal could be observed following a challenge by the opioid antagonist naloxone. Litter size and the number of live births per litter of OGF-treated mothers were reduced by 25% from control subjects and a fourfold increase in stillborns was noted for mothers receiving OGF compared to control levels. Histopathologic analysis confirmed the stillborns to have died in utero. OGF-exposed neonates were normal in body weight and crown-to-rump length, but these pups were observed to be lethargic and cyanotic, and had subnormal weights of many organs. Body weights of 10-, 15-, and 21-day-old OGF-exposed rats were reduced 11-27% from control levels. Wet and dry organ weights of the rats maternally subjected to OGF were decreased from control values in six of the eight organs evaluated at 10 days. At weaning, some organs were subnormal in weight. These data lead us to hypothesize that a native opioid peptide-OGF-is integral to certain aspects of maternal, neonatal, and postnatal well-being, and that disruptions in this opioid peptide have serious repercussions on the course of pregnancy and fetal outcome.     

Effects of maternal exposure to di(2-ethylhexyl)phthalate (DEHP) during pregnancy on susceptibility to neonatal asthma

Di(2-ethylhexyl) phthalate (DEHP) is used as a plasticizer and is widely dispersed in the environment. In this study, we investigated the effects of maternal exposure to DEHP during pregnancy on neonatal asthma susceptibility using a murine model of asthma induced by ovalbumin (OVA). Pregnant BALB/c mice received DEHP from gestation day 13 to lactation day 21. Their offspring were sensitized on postnatal days (PNDs) 9 and 15 by intraperitoneal injection of 0.5 μg OVA with 200 μg aluminum hydroxide. On PNDs 22, 23 and 24, live pups received an airway challenge of OVA for 30 min. Offspring from pregnant mice that received DEHP showed reductions in inflammatory cell count, interleukin (IL)-4, IL-13, and eotaxin in their bronchoalveolar lavage fluid and in total immunoglobulin E and OVA-specific IgE in their plasma compared with offspring from pregnant mice that did not receive DEHP treatment. These results were consistent with histological analysis and immunoblotting. Maternal exposure to DEHP reduces airway inflammation and mucus production in offspring, with a decrease in inducible nitric oxide synthase (iNOS) in the lung tissue. This study suggests that maternal exposure to DEHP during pregnancy reduces asthmatic responses induced by OVA challenge in offspring. These effects were considered to be closely related to the suppression of Th2 immune responses and iNOS expression.     

Physiological regulation in cigarette exposed infants: an examination of potential moderators

The primary purpose of this study was to examine pathways from prenatal cigarette exposure to physiological regulation at 2 months of age. Specifically, we explored the possibility that any association between prenatal cigarette exposure and infant physiological regulation was moderated by fetal growth, prenatal or postnatal environmental tobacco smoke (ETS) exposure or maternal depressive symptomatology during pregnancy. We evaluated whether exposed infants who were also exposed to ETS after birth, were small for gestational age (SGA) or had mothers with higher depressive symptoms during pregnancy had the highest levels of physiological dysregulation. Respiratory sinus arrhythmia (RSA) was obtained from 234 (166 exposed and 68 nonexposed) infants during sleep. As expected, cigarette-exposed infants had significantly lower RSA than nonexposed infants. This association was not moderated by prenatal or postnatal ETS exposure, or maternal depressive symptomatology during pregnancy. However, small for gestational age status did moderate this association such that nonexposed infants who were not small for gestational age had a significantly higher RSA than nonexposed small for gestational age infants and exposed infants. These findings provide additional evidence that prenatal cigarette exposure is directly associated with dysregulation during infancy.     

Variations in maternal care alter GABA(A) receptor subunit expression in brain regions associated with fear.

Maternal care influences the development of stress reactivity in the offspring. These effects are accompanied by changes in corticotropin-releasing factor (CRF) expression in brain regions that regulate responses to stress. However, such effects appear secondary to those involving systems that normally serve to inhibit CRF expression and release. Thus, maternal care over the first week of life alters GABA(A) (gamma-aminobutyric acid)(A) receptor mRNA subunit expression. The adult offspring of mothers that exhibit increased levels of pup licking/grooming and arched back-nursing (high LG-ABN mothers) show increased alpha1 mRNA levels in the medial prefrontal cortex, the hippocampus as well as the basolateral and central regions, of the amygdala and increased gamma2 mRNA in the amygdala. Western blot analyses confirm these effects at the level of protein. In contrast, the offspring of low LG-ABN mothers showed increased levels of alpha3 and alpha4 subunit mRNAs. The results of an adoption study showed that the biological offspring of low LG-ABN mothers fostered shortly after birth to high LG-ABN dams showed the increased levels of both alpha1 and gamma2 mRNA expression in the amygdala in comparison to peers fostered to other low LG-ABN mothers (the reverse was true for the biological offspring of high LG-ABN mothers). These findings are consistent with earlier reports of the effects of maternal care on GABA(A)/benzodiazepine receptor binding and suggest that maternal care can permanently alter the subunit composition of the GABA(A) receptor complex in brain regions that regulate responses to stress.     

Attenuation of cocaine-induced genomic and functional responses in prenatal cocaine-exposed rabbits.

The effects of in utero cocaine exposure on cocaine-induced genomic and functional responses in postnatal life were examined. Pregnant Dutch Belted rabbits were injected intravenously, twice daily, with cocaine hydrochloride (4 mg/kg) or saline from day 8 through day 29 of pregnancy. Prenatally exposed kits were challenged with cocaine on postnatal day 20. In prenatal saline-exposed kits, cocaine induced time- and dose-dependent c-fos gene expression in both frontal cortex and striatum. Prenatal cocaine exposure reduced cocaine-induced c-fos responses by 35-58% in the frontal cortex and 37-41% in the striatum. Cocaine-induced functional responses that included head bobbing, seizure, and locomotor activity were also attenuated in prenatal cocaine-exposed kits. Cocaine-induced c-fos expression and functional responses were blocked by the D(1) dopamine receptor antagonist, SCH23390, or by the serotonin receptor antagonist, methysergide, but not by the D(2) dopamine receptor antagonist, L-sulpride. The results indicate that in utero cocaine exposure leads to diminished responses to cocaine challenge in the offspring, which may be mediated by prenatal cocaine-induced alterations in one or more components of the D(1) dopamine and/or serotonin receptor signaling systems during early postnatal life.     

Effects of prenatal exposure to cigarette smoke on offspring tumor susceptibility and associated immune mechanisms.

Epidemiologic evidence suggests that prenatal exposure to intact (unfractionated) cigarette smoke (CS) increases the incidence of cancer in the offspring. A toxicology study was carried out to examine the effects and underlying mechanisms of prenatal exposure to mainstream cigarette smoke (MCS) on offspring resistance to tumor challenge and surveillance mechanisms critical for the recognition and destruction of tumors. Pregnant B6C3F1 mice were exposed by inhalation to MCS for 5 days/week (4 h/day from gestational day 4 to parturition). Smoke-induced effects on offspring-host resistance to transplanted tumor cells; natural killer (NK) cell and cytotoxic T-lymphocyte (CTL) activity; cytokine levels; lymphoid organ immune cell subpopulations; and histology-were examined in 5-, 10- and 20-week-old male and female offspring. At a concentration of smoke roughly equivalent to smoking <1 pack of cigarettes/day, prenatally exposed male offspring challenged at 5 week of age with EL4 lymphoma cells demonstrated a greater than two-fold increase in tumor incidence (relative to age-/gender-matched air-exposed offspring); tumors in prenatally smoke-exposed pups also grew significantly faster. Cytotoxic T-lymphocyte activity in the smoke-exposed 5- and 10-week-old male pups was significantly less than that of the age- and gender-matched controls. No effects of prenatal CS exposure were observed on offspring NK activity, cytokine levels, lymphoid organ histology, or immune cell subpopulations. Results demonstrated that exposure of pregnant mice to a relevant dose of MCS decreased offspring resistance against transplanted tumor cells and persistently reduced CTL activity in prenatally exposed pups. This study provides biological plausibility for the epidemiologic data indicating that children of mothers who smoke during pregnancy have a greater risk of developing cancer in later life.     

Age- and gender-dependent impairments of neurobehaviors in mice whose mothers were exposed to lipopolysaccharide during pregnancy

Lipopolysaccharide (LPS)-induced intrauterine infection has been associated with neurodevelopmental injury in rodents. The purpose of the present study was to analyze the dynamic changes of neurobehaviors in mice whose mothers were exposed to LPS during pregnancy. The pregnant mice were intraperitoneally (i.p.) injected with LPS (8 μg/kg) daily from gestational day (gd) 8 to gd 15. A battery of neurobehavioral tasks was performed in mice at postnatal day (PND) 70, 200, 400 and 600. Results showed that the spatial learning and memory ability, determined by radial six-arm water maze (RAWM), were obviously impaired in two hundred-day-old female mice and four hundred-day-old male mice whose mothers were exposed to LPS during pregnancy. Open field test showed that the number of squares crossed and peripheral time, a marker of anxiety and exploration activity, were markedly increased in two hundred-day-old female mice following prenatal LPS exposure. In addition, prenatal LPS exposure significantly shortened the latency to the first grid crossing in six hundred-day-old female offspring. Moreover, sensorimotor impairment in the beam walking was observed in two hundred-day-old female mice whose mothers were exposed to LPS during pregnancy. Species-typical behavior examination showed that prenatal LPS exposure markedly increased weight burrowed in seventy-day-old male offspring and six hundred-day-old female offspring. Correspondingly, prenatal LPS exposure significantly reduced weight hoarded in two hundred-day-old female offspring. Taken together, these results suggest that prenatal LPS exposure induces neurobehavioral impairments at adulthood in an age- and gender-dependent manner.     

Effects of prenatal cigarette and marijuana exposure on drug use among offspring

The present study investigated whether maternal cigarette smoking and marijuana use during pregnancy were associated with an increased risk of initiation and daily/regular use of such substances among one hundred fifty-two 16- to 21-year-old adolescent offspring. The participants were from a low risk, predominately middle-class sample participating in an ongoing, longitudinal study. Findings indicated that offspring whose mothers reported smoking cigarettes during their pregnancy were more than twice as likely to have initiated cigarette smoking during adolescence than offspring of mothers who reported no smoking while pregnant. Offspring of mothers who reported using marijuana during pregnancy were at increased risk for both subsequent initiation of cigarette smoking (OR=2.58) and marijuana use (OR=2.76), as well as daily cigarette smoking (OR=2.36), as compared to offspring of whose mothers did not report using marijuana while pregnant. There was also evidence indicating that dose-response relationships existed between prenatal exposure to marijuana and offspring's use of cigarettes and marijuana. These associations were found to be more pronounced for males than females, and remained after consideration of potential confounds. Such results suggest that maternal cigarette smoking and marijuana use during pregnancy are risk factors for later smoking and marijuana use among adolescent offspring, and add to the weight of evidence that can be used in support of programs aimed at drug use prevention and cessation among women during pregnancy.     

Research progress on effects of intergenerational transmission on allergic disease susceptibility in offspring北大核心CSCD

过敏性疾病是由机体对抗原所产生的异常免疫反应引发的疾病,近年来儿童过敏性疾病的患病率呈上升趋势,已经成为当今社会迫切解决的公共卫生问题之一。最近临床数据和研究表明,代际传递因素与儿童患过敏性疾病的易感性有关,母代在孕前或孕期遭受一些不利因素可能会使其子代患过敏性疾病的易感性增强。因此识别早期危险因素(即母代危险因素)对于儿童过敏性疾病的预防具有重要意义。目前在代际传递背景下影响子代过敏性疾病易感性的研究取得了一定的进展,关于其分子生物学机制已有初步探究,该文针对母代遭受不利因素对子代患过敏性疾病的易感性的影响进行综述,以期在代际传递背景下为儿童过敏性疾病的预防提供新的方法和思路。     

Response model analysis for cross-fostering studies: Prenatal versus postnatal effects on offspring exposed to methylmercury dicyandiamide

Quantitation of prenatal versus postnatal effects in offspring derived from treated mothers requires both cross-fostering procedures and a cogent method of data analysis. An explicit statement of the manner in which the treatments (independent variables) combine to produce the observed development parameters (dependent variables) is defined as the response model. We present the response model approach to analysis of these cross-fostering designs and the application of multiple regression to their solution. Pregnant 129/SvSl mice received single ip injections of 0, 4, or 8 mg/kg of methylmercury dicyandiamide (MeHg) on Day 7, 9, or 12 of gestation. Fostering and cross-fostering procedures were carried out at birth to partition the effects of prenatal and postnatal exposure on two parameters: survival and weight gain. A linear response model is presented to aid in: (1) conceptualizing the cross-fostering process; (2) quantitating the effects of treatment day, maternal dose, and the fostering process; and (3) providing the basis for statistical analysis. A multiple regression method is described to provide analysis of variance, solution for model parameters, and a guide in model simplification and statistical testing. Cross-fostering procedures permitted partitioning of adverse effects into prenatal and postnatal components. Effects of prenatal exposure to MeHg were about twice as large as postnatal and were greatest when administered late in the period of organogenesis. The dose response was approximately linear (proportional) in weight and logarithmic in survival. Thus, doses of MeHg which had no apparent effect on pregnant female mice did result in reduced survival to weaning and weight gain of offspring.     

Effects of silver nanoparticles prenatal exposure on rat offspring development

Many types of nanocomposites employed in food packaging are based on silver nanoparticles (AgNP) because of their antibacterial properties, which can increase food shelf-life. As the commercialization of AgNP products has been expanding, the released of such nanoparticles in the environment has caused enormous concern, once they can pose potential risks to the environment and human beings. For instance, exposure of the maternal environment to nanomaterials during pregnancy may impact the health of the dam, fetus and offspring. In this context, here we investigated the effects of prenatal exposure of AgNP on the pregnancy outcomes of dams and postnatal development of their offspring. Pregnant Wistar rats were exposed to distinct AgNP concentrations (0, 1, 3 and 5 μg/kg/day) from beginning to the end of pregnancy. At parturition, newborns were observed regarding clinical signs of toxicity and survival rate. The offspring was examined by evaluating developmental endpoints. A delay in time for vaginal opening and testes descent were detected in the offspring exposed to AgNP during embryonic development. Our results indicate that prenatal exposure to AgNP can compromise neonatal rats’ postnatal development, especially the reproductive features.     

Use of barusiban in a novel study design for evaluation of tocolytic agents in pregnant and neonatal monkeys, including behavioural and immunological endpoints

The oxytocin receptor antagonist barusiban, currently being developed for treatment of preterm labour, was investigated in pregnant cynomolgus monkeys with a 9-month postnatal follow-up of their offspring. The nature of barusiban, its indication, and the potential exposure of pre- and postnatal infants entailed the design of a unique protocol to investigate all aspects of maternal and offspring well-being. Barusiban was administered to the mothers from gestation day 85 until delivery with daily subcutaneous dosages up to 2.5 mg/kg body weight/day. There were no test article-related effects seen in the mothers at any time during the study. The postnatal examination of offspring included routine toxicological parameters, as well as specialised investigation of the immune, cardiovascular, renal and central nervous systems, including a full behavioural assessment. A full pathology examination of offspring was performed at the end of the 9-month postnatal period. No adverse infant findings occurred.