In Utero Exposure to Zika Virus Results in sex-Specific Memory Deficits and Neurological Alterations in Adult Mice.
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ABSTRACT: Summary statement
In utero exposure to ZIKV leads to decreased number of neurons in adult mice. Female mice exposed to ZIKV in utero exhibit lower levels of BDNF, a decrease in synaptic markers, memory deficits, and risk-taking behavior during adulthood.
SUBMITTER: Andrade TA
PROVIDER: S-EPMC9421007 | biostudies-literature | 2022 Jan-Dec
REPOSITORIES: biostudies-literature
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<i>In Utero</i> Exposure to Zika Virus Results in sex-Specific Memory Deficits and Neurological Alterations in Adult Mice.
Andrade Thiago A TA Fahel Julia S JS de Souza Jessica M JM Terra Ana C AC Souza Danielle G DG Costa Vivian V VV Teixeira Mauro M MM Bloise Enrrico E Ribeiro Fabiola M FM
ASN neuro 20220101
<h4>Summary statement</h4><i>In utero</i> exposure to ZIKV leads to decreased number of neurons in adult mice. Female mice exposed to ZIKV <i>in utero</i> exhibit lower levels of BDNF, a decrease in synaptic markers, memory deficits, and risk-taking behavior during adulthood. ...[more]
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Project description:IntroductionZika virus infection during pregnancy causes fetal microcephaly and brain damage. Congenital Zika syndrome (CZS) is characterized by systemic involvement with diffuse muscle impairment, a high frequency of arthrogryposis, and microphthalmia. Cardiac impairment in CZS has rarely been evaluated. Our study assessed morphology and biventricular cardiac function in children with CZS and advanced neurological dysfunction.MethodsThis cross-sectional study was conducted on 52 children with CZS (Zika group; ZG) and 25 healthy children (control group; CG) in Paraiba, Brazil. Clinical evaluation, electrocardiogram (EKG), and transthoracic echocardiogram (TTE) were performed on all children. Additionally, troponin I and natriuretic peptide type B (BNP) levels, the degree of cerebral palsy, and neuroimaging findings were assessed in the ZG group.ResultsThe median age of the study population was 5 years in both groups, and 40.4% (ZG) and 60% (CG) were female. The most prevalent electrocardiographic alteration was sinus arrhythmia in both the ZG (n = 9, 17.3%) and CG (n = 4, 16%). The morphological parameters adjusted for Z score were as follows: left ventricular (LV) end-diastolic diameter in ZG: -2.36 [-5.10, 2.63] vs. CG: -1.07 [-3.43, 0.61], p<0.001); ascending aorta (ZG: -0.09 [-2.08, 1.60] vs. CG: 0.43 [-1.47, 2.2], p = 0.021); basal diameter of the right ventricle (RV) (ZG: -2.34 [-4.90, 0.97] vs. CG: -0.96 [-2.21, 0.40], p<0.01); and pulmonary artery dimension (ZG: -2.13 [-5.99, 0.98] vs. CG: -0.24 [-2.53, 0.59], p<0.01). The ejection fractions (%) were 65.7 and 65.6 in the ZG and CG, respectively (p = 0.968). The left atrium volume indices (mL/m2) in the ZG and CG were 13.15 [6.80, 18.00] and 18.80 [5.90, 25.30] (p<0.01), respectively, and the right atrium volume indices (mL/m2) were 10.10 [4.90, 15.30] and 15.80 [4.10, 24.80] (p<0.01). The functional findings adjusted for Z score were as follows: lateral systolic excursion of the mitral annular plane (MAPSE) (ZG: 0.36 [-2.79, 4.71] vs. CG: 1.79 [-0.93, 4.5], p = 0.001); tricuspid annular plane systolic excursion (TAPSE) (ZG: -2.43 [-5.47, 5.09] vs. CG: 0.07 [-1.98, 3.64], p<0.001); and the S' of the RV (ZG: 1.20 [3.35, 2.90] vs. CG: -0.20 [-2.15, 1.50], p = 0.0121). No differences in biventricular strain measurements were observed between the groups. Troponin I and BNP levels were normal in in the ZG. Grade V cerebral palsy and subcortical calcification were found in 88.6% and 97.22% of children in the ZG group, respectively.ConclusionA reduction in cardiac dimensions and functional changes were found in CZS patients, based on the TAPSE, S' of the RV, and MAPSE, suggesting the importance of cardiac evaluation and follow-up in this group of patients.
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Project description:Pyrethroid pesticides have been suggested to be a cause of Parkinson disease and other neurodegenerative diseases. To investigate this, a cross-sectional study was conducted among 120 Bolivian public health vector program spray men, primarily exposed to pyrethroids. Pesticide exposure and central nervous system (CNS) symptoms were determined by a structured interview, whereas neuromotor and neurocognitive performance was assessed using the computerized Behavioral Assessment and Research System and CATSYS system. Individuals exposed to higher levels reported significantly more CNS symptoms (adjusted odds ratio per quintile of cumulative exposure = 2.01 [1.22-3.31]). There was no association seen between pyrethroid exposure and neuromotor performance. Higher spraying intensity was associated with significantly worse neurocognitive performance in structural equation models (adjusted β per quintile = -0.405 [-0.660 to -0.150]), and workers only exposed to pyrethroids performed worse than workers also exposed to other pesticides (adjusted β = -1.344 [-2.224 to -0.464]). Chronic pyrethroid exposure may cause deterioration in neurocognitive performance, and exposure control is recommended.
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Project description:BackgroundZika virus (ZIKV) infection during pregnancy can lead to congenital Zika syndrome (CZS) and may result in neurodevelopmental alterations in exposed children, with and without CZS. This study aimed to evaluate ZIKV infection during pregnancy as a risk factor for early and long-term adverse outcomes.MethodsThis retrospective-prospective, matched cohort study was conducted in Mato Grosso do Sul, Brazil. Mother-infant pairs exposed and unexposed to ZIKV during pregnancy were enrolled in the study from 2018 to 2022. Clinical and epidemiological data from the gestational period and neonatal evaluations were obtained from the Brazilian health surveillance system. Children were assessed for early (congenital anomalies) and long-term adverse outcomes (neurodevelopmental delay). Incidence risk ratio (IRR) and crude odds ratio (OR) were used to assess associations.ResultsThe risk of adverse outcomes in exposed children was nearly 3-fold higher (IRR, 2.7; 95% CI, 1.4-5.1) compared with the control group. The risk of motor (IRR, 3.4; 95% CI, 1.2-9.6) and cognitive delay (IRR, 4.7; 95% CI, 1.7-13.0) was significantly higher in exposed children. In 44% of pregnancies wherein maternal infection occurred in the first trimester, at least 1 adverse event was identified in the child, with 11.2-fold greater odds of adverse outcomes (OR, 11.2; 95% CI, 3.6-35.0) compared with children of mothers infected in the third trimester.ConclusionsChildren exposed to ZIKV in utero, even without CZS, demonstrate a greater risk for neurodevelopmental delay in early childhood, with the timing of maternal infection being a significant predictive risk factor.
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Project description:BackgroundNeurodevelopmental outcomes of asymptomatic children exposed to Zika virus (ZIKV) in utero are not well characterized.MethodsWe prospectively followed 129 newborns without evidence of congenital Zika syndrome (CZS) up to 24 months of age. Participants were classified as ZIKV exposed or ZIKV unexposed. The Mullen Scales of Early Learning (MSEL) was administered in the participants' homes at 6, 12, 15, 18, 21, and 24 months of age by trained psychologists. Sociodemographic data, medical history, and infant anthropometry at birth were collected at each home visit. Our primary outcome was the Mullen Early Learning Composite Score (ECL) at 24 months of age between our 2 exposure groups. Secondary outcomes were differences in MSEL subscales over time and at 24 months.ResultsOf 129 infants in whom exposure status could be ascertained, 32 (24.8%) met criteria for in utero ZIKV exposure and 97 (75.2%) did not. There were no differences in maternal age, maternal educational attainment, birthweight, or gestational age at birth between the 2 exposure groups. The adjusted means and standard errors (SEs) for the ELC score between the ZIKV-exposed children compared to ZIKV-unexposed children were 91.4 (SE, 3.1) vs 96.8 (SE, 2.4) at 12 months and 93.3 (SE, 2.9) vs 95.9 (SE, 2.3) at 24 months. In a longitudinal mixed model, infants born to mothers with an incident ZIKV infection (P = .01) and low-birthweight infants (<2500 g) (P = .006) had lower composite ECL scores.ConclusionsIn this prospective cohort of children without CZS, children with in utero ZIKV exposure had lower neurocognitive scores at 24 months.
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Project description:Exposure to fine ambient particulates (PM2.5) during gestation or neonatally has potent neurotoxic effects. While biological and behavioral data indicate a vulnerability to environmental pollutants across distinct neurodevelopmental windows, the behavioral consequences following exposure across the entire developmental period remain unknown. Moreover, several epidemiological studies support a link between developmental exposure to air pollution and an increased risk of later receiving a diagnosis of autism spectrum disorders (ASD), a neurodevelopmental disorder that persists throughout life. In the current study we sought to determine whether perinatal exposure to PM2.5 would reduce sociability and increase repetitive deficits in mice, two hallmark characteristics of ASD. Pregnant female B6C3F1 mice were exposed daily to concentrated ambient PM2.5 (CAPs) (135.8μg/m3) or filtered air (3.1μg/m3) throughout gestation followed by additional exposures to both dams and their litters from days 2-10 postpartum. Adult offspring were subsequently assessed for social and repetitive behaviors at 20 weeks of age. Daily perinatal exposure to CAPs significantly decreased sociability in male and female mice as measured by the social approach task; however, reductions in reciprocal social interaction and increased grooming behavior were only present in male offspring exposed to CAPs. These findings demonstrate that exposure to particulate air pollutants throughout early neurodevelopment induces long lasting behavioral deficits in a sex-dependent manner and may be an underlying cause of neurodevelopmental disorders such as ASD.
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Project description:ImportanceThe evolution of fetal brain injury by Zika virus (ZIKV) infection is not well described.ObjectivesTo perform longitudinal neuroimaging of fetuses and infants exposed to in utero maternal ZIKV infection using concomitant magnetic resonance imaging (MRI) and ultrasonography (US), as well as to determine the duration of viremia in pregnant women with ZIKV infection and whether the duration of viremia correlated with fetal and/or infant brain abnormalities.Design, setting, and participantsA cohort of 82 pregnant women with clinical criteria for probable ZIKV infection in Barranquilla, Colombia, and Washington, DC, were enrolled from June 15, 2016, through June 27, 2017, with Colombian women identified by community recruitment and physician referral and travel-related cases of American women recruited from a Congenital Zika Program.Interventions and exposuresWomen received 1 or more MRI and US examinations during the second and/or third trimesters. Postnatally, infants underwent brain MRI and cranial US. Blood samples were tested for ZIKV.Main outcomes and measuresThe neuroimaging studies were evaluated for brain injury and cerebral biometry.ResultsOf the 82 women, 80 were from Colombia and 2 were from the United States. In 3 of 82 cases (4%), fetal MRI demonstrated abnormalities consistent with congenital ZIKV infection. Two cases had heterotopias and malformations in cortical development and 1 case had a parietal encephalocele, Chiari II malformation, and microcephaly. In 1 case, US results remained normal despite fetal abnormalities detected on MRI. Prolonged maternal polymerase chain reaction positivity was present in 1 case. Of the remaining 79 cases with normal results of prenatal imaging, postnatal brain MRI was acquired in 53 infants and demonstrated mild abnormalities in 7 (13%). Fifty-seven infants underwent postnatal cranial US, which detected changes of lenticulostriate vasculopathy, choroid plexus cysts, germinolytic/subependymal cysts, and/or calcification in 21 infants (37%).Conclusions and relevanceIn a cohort of pregnant women with ZIKV infection, prenatal US examination appeared to detect all but 1 abnormal fetal case. Postnatal neuroimaging in infants who had normal prenatal imaging revealed new mild abnormalities. For most patients, prenatal and postnatal US may identify ZIKV-related brain injury.
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Project description:Zika virus (ZIKV) can cause various diseases in offspring after congenital infection. The purpose of this study was to identify disease phenotypes in pups exposed to ZIKV in utero. Female interferon-α/β, -γ receptor knockout mice (AG129) were infected intraperitoneally with ZIKV 7.5 days' post coitus (dpc). Viral RNA, antigen and infectious virus were detected in some, but not all, maternal and fetal tissues at various times during gestation. Fetuses of infected dams had significant intrauterine growth restriction (IUGR), which was more pronounced as females neared parturition. Pups born to infected dams were significantly smaller and had significantly shortened skull lengths, as determined by measurement with a caliper and by micro-CT analysis, as compared with age-matched controls. Growth rates of exposed pups after birth, however, was similar to sham-exposed offspring. Viral RNA was detected in pups of infected dams after birth. A lower survival rate was observed in neonates exposed to ZIKV in utero. A mortality rate of over 50%, attributed to consequences of ZIKV infection, occurred after birth in pups born to infected dams. A transient hearing loss was observed in some animals exposed to virus in utero. No motor deficits or cognitive deficits were detected using running wheel or viral paresis scoring assays. Abnormalities in offspring included smaller size, shorter skull length and increased neonatal mortality, while the only functional deficit we could detect was a low incidence of transient hearing loss.
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