Efecto de la Vitamina E en Células Peritubulares de Testículos de Ratones Mus musculus Tratados con Ácido Valproico Durante el Estado Fetal y Pubertad / Effect of Vitamin E on Peritubular Cells from Testis of Mus musculus Mice Treated with Valproic Acid During the Fetal Stage and Puberty

El ácido valproico (VPA) es un fármaco antiepiléptico teratógenico que, al ser administrado durante etapas tempranas del embarazo, puede producir alteraciones en el desarrollo embriofetal, las que se manifiestan tanto a nivel del sistema nervioso como del testículo. No obstante, se ha reportado que la administración de vitamina E (VE) podría revertir dichas alteraciones. El objetivo del presente estudio fue determinar el efecto protector de la VE a nivel testicular en fetos y ratones púberes expuestos a VPA durante la fase embrionaria de su desarrollo. Se utilizó un total de 30 ratones hembra adultas gestantes (Mus musculus) cepa BALB/c, las cuales se dividieron en 6 grupos. El estudio contempló el análisis de fetos machos a los 17,5 días post-coital (dpc) y machos juveniles a las 6 semanas post-natal. A los grupos 1 y 4 se les administró 0,3 mL de solución fisiológica (grupos control para 17,5 dpc y 6 semanas postnatal, respectivamente). A los grupos 2 y 5 se les suministró la cantidad de 600 mg/kg de VPA (grupos VPA), en tanto que a los grupos 3 y 6 se les aplicó la misma dosis de VPA complementada con 200 UI de VE (grupos VPA+VE). Se describió la histología normal y patológica del compartimento peritubular del testículo. En los grupos VPA se evidenció una degeneración de la pared peritubular, y atrofia de túbulos seminíferos, así como exfoliación de las células germinales. Por el contrario, en los grupos VPA+VE tales signos no fueron observados y la morfología presentó aspecto normal solo con algunas alteraciones focales. Estos resultados corroboran el hecho que la administración de VE contrarresta en parte, los efectos deletéreos que ocasiona el VPA.

SUMMARY: Valproic acid (VPA) is a teratogenic antiepileptic drug that, when administered during the early stages of pregnancy, can produce alterations in embryo-fetal development, which manifest both at the level of the nervous system and the testicle. However, it has been reported that the administration of vitamin E (VE) could reverse these alterations. The study aimed to determine the protective effect of VE at the testicular level in fetuses and pubertal mice exposed to VPA during the embryonic phase of their development. 30 pregnant adult female mice (Mus musculus) BALB/c strain were used, which were divided into 6 groups. The study included the analysis of male fetuses at 17.5 days post-coital (dpc) and juvenile males at 6 weeks post-natal. Groups 1 and 4 were administered 0.3 mL of physiological solution. Groups 2 and 5 were given 600 mg/kg of VPA (VPA groups), while groups 3 and 6 were given the same dose of VPA supplemented with 200 IU of VE (VPA+VE). The normal and pathological histology of the peritubular compartment of the testis was described. In the VPA groups, degeneration of the peritubular wall, and atrophy of the seminiferous tubules, as well as exfoliation of the germ cells, were evident. On the contrary, in the VPA+VE groups such signs were not observed and the morphology presented a normal appearance with only some focal alterations. These results corroborate the fact that the administration of VE partially counteracts the deleterious effects caused by VPA.

HDAC2 Inhibits Hippocampal Neurogenesis and Impairs the Cognitive Function in Prenatally Stressed Adult Offspring / HDAC2 Inhibe la Neurogénesis del Hipocampo y Afecta la Función Cognitiva en la Descendencia Adulta Estresada Prenatalmente

SUMMARY: The objective of this study was to investigate the mechanism of prenatal stress on the cognitive function of offspring, and clarify the change of histone deacetylase 2 (HDAC2) expression in hippocampal neurons of offspring. 16 pregnant SD rats were randomly divided into control group and stress group, with eight rats in each group. The stress group received restrained stress from 15 to 21 days of pregnancy, while the control group did not receive any treatment. Anxiety-like behavior and spatial memory, learning and memory ability were detected in open field, elevated plus maze, novel object recognition test, and Barnes maze. Nissl staining was used to detect the function of hippocampal neurons. Western blot was used to detect the expression of HDAC2 protein in hippocampal neurons of adult offspring. Immunofluorescence staining was used to detect the expression of HDAC2 protein and hippocampal neurogenesis. The learning and memory ability of adult offspring was decreased. The prenatal stress damaged the function of hippocampal neurons , the expression of HDAC2 was down-regulated, and the number of neurons was reduced. Maternal prenatal stress can down- regulate the expression of HDAC2 in the hippocampus of offspring, inhibits hippocampal neurogenesis and impairs the cognitive function.

El objetivo de este estudio fue investigar el mecanismo del estrés prenatal en la función cognitiva de la descendencia y aclarar el cambio de la expresión de la histona desacetilasa 2 (HDAC2) en las neuronas del hipocampo de la descendencia. 16 ratas SD preñadas se dividieron aleatoriamente en un grupo de control y un grupo de estrés, con ocho ratas en cada grupo. El grupo de estrés recibió estrés durante 15 a 21 días de pre, preñez, mientras que el grupo de control no recibió ningún tratamiento. El comportamiento similar a la ansiedad y la memoria espacial, el aprendizaje y la capacidad de memoria se detectaron en campo abierto, laberinto en cruz elevado, prueba de reconocimiento de objetos novedosos y laberinto de Barnes. La tinción de Nissl se utilizó para detectar la función de las neuronas del hipocampo. Se utilizó Western blot para detectar la expresión de la proteína HDAC2 en las neuronas del hipocampo de la descendencia adulta. La tinción de inmunofluorescencia se utilizó para detectar la expresión de la proteína HDAC2 y la neurogénesis del hipocampo. La capacidad de aprendizaje y memoria de la descendencia adulta se redujo. El estrés prenatal dañó la función de las neuronas del hipocampo, se reguló negativamente la expresión de HDAC2 y se redujo el número de neuronas. El estrés prenatal materno puede regular a la baja la expresión de HDAC2 en el hipocampo de la descendencia, inhibe la neurogénesis del hipocampo y deteriora la función cognitiva.

Meta-analysis of the correlation between prenatal steroid exposure and hypoglycemia in late preterm neonates / 中华儿科杂志

Objective: To systematically evaluate the correlation between prenatal steroid exposure and hypoglycemia in late preterm neonates. Methods: Eight databases in either Chinese or English, including PubMed, the Cochrane Library, Embase, Medline, Scopus, CNKI, Wanfang and VIP, were searched to extract the studies on the correlation between prenatal steroid exposure and hypoglycemia in late preterm neonates published from the establishment of each database to December 2022. The Meta-analysis was performed using Stata 14.0 statistical software. Results: A total of 9 studies were included in this Meta-analysis, including 6 retrospective cohort studies, 2 prospective cohort studies and 1 randomized controlled trial (RCT) study, involving 9 143 premature infants. The Meta-analysis showed that prenatal steroid exposure increased the risk of late preterm neonatal hypoglycemia (RR=1.55, 95%CI 1.25-1.91, P<0.001). The similar correlation between prenatal steroid exposure and hypoglycemia in late preterm neonates was all found in the following subgroups: North America (RR=1.57, 95%CI 1.37-1.80, P<0.001), enrolling pregnant women with gestational diabetes (RR=1.62, 95%CI 1.26-2.08, P<0.001), A-grade literature quality (RR=1.43, 95%CI 1.14-1.79, P=0.002), criteria for hypoglycemia ≤40 mg/dl (1 mg/dl=0.056 mmol/L, RR=1.49, 95%CI 1.28-1.73, P<0.001), sample size of 501-1 500 (RR=1.69, 95%CI 1.19-2.40, P=0.003) and >1 500 (RR=1.65, 95%CI 1.48-1.83, P<0.001), steroid injection dosage and frequency of 12 mg 2 times (RR=1.66, 95%CI 1.50-1.84, P<0.001), the time interval from antenatal corticosteroid administration to delivery of 24-47 h (RR=1.98, 95%CI 1.26-3.10, P=0.003), unadjusted gestational age (RR=1.78, 95%CI 1.02-3.10,P=0.043) and unadjusted birth weight (RR=1.80, 95%CI 1.22-2.66, P=0.003). Meta-regression results showed that steroid injection frequency and dose were the main sources of high heterogeneity among studies (P=0.030). Conclusion: Prenatal steroid exposure may be a risk factor for hypoglycemia in late preterm neonates.

Early prenatal exposure to air pollutants and congenital heart disease: a nested case-control study

BACKGROUND@#Congenital heart disease (CHD) is one of the most common congenital malformations in humans. Inconsistent results emerged in the existed studies on associations between air pollution and congenital heart disease. The purpose of this study was to evaluate the association of gestational exposure to air pollutants with congenital heart disease, and to explore the critical exposure windows for congenital heart disease.@*METHODS@#The nested case-control study collected birth records and the following health data in Tianjin Women and Children's Health Center, China. All of the cases of congenital heart disease from 2013 to 2015 were selected matching five healthy controls for each case. Inverse distance weighting was used to estimate individual exposure based on daily air pollution data. Furthermore, the conditional logistic regression with distributed lag non-linear model was performed to identify the association between gestational exposure to air pollution and congenital heart disease.@*RESULTS@#A total of 8,748 mother-infant pairs were entered into the analysis, of which 1,458 infants suffered from congenital heart disease. For each 10 µg/m3 increase of gestational exposure to PM2.5, the ORs (95% confidence interval, 95%CI) ranged from 1.008 (1.001-1.016) to 1.013 (1.001-1.024) during the 1st-2nd gestation weeks. Similar weak but increased risks of congenital heart disease were associated with O3 exposure during the 1st week and SO2 exposure during 6th-7th weeks in the first trimester, while no significant findings for other air pollutants.@*CONCLUSIONS@#This study highlighted that gestational exposure to PM2.5, O3, and SO2 had lag effects on congenital heart disease. Our results support potential benefits for pregnancy women to the mitigation of air pollution exposure in the early stage, especially when a critical exposure time window of air pollutants may precede heart development.

Correlation analysis between prenatal exposure of per-/polyfluoroalkyl compounds and neonatal outcome / 中华预防医学杂志

Objective: To investigate the correlation between the prenatal exposure of per-/polyfluoroalkyl substances (PFASs) and the neonatal outcome. Methods: A total of 506 maternal infant cohort samples were collected in Hangzhou, Zhejiang province from 2020 to 2021. The exposure levels of seven PFASs in maternal serum before delivery were detected by solid-phase extraction-ultra performance liquid chromatography tandem mass spectrometry. Multivariable linear regression model was used to analyze the influence of prenatal exposure of PFASs on birth weight, birth length and Apgar score. Results: The maternal age, prenatal body mass index and gestation age were (31.3±4.3) years old, (26.7±3.2) kg/m2 and (265.0±28.3) days, respectively. The birth weight, birth length and scores of Apgar-1 and Apgar-5 were (3.1±0.8) kg, (49.3±2.9) cm, (9.88±0.47) points and (9.99±0.13) points, respectively. PFASs were widely distributed in maternal serum, with the highest concentration of (18.453±19.557) ng/ml, (6.756±9.379) ng/ml and (5.057±8.555) ng/ml for perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS) and 6∶2 chlorinated polyfluorinated ether sulfonate (Cl-PFESA), respectively. Maternal age, parity and delivery mode were associated with the exposure level of PFASs (P<0.05). Subgroup analysis showed that PFOS had negative effects on birth weight (β=-0.958), birth length (β=-0.073) and Apgar-5 score (β=-0.288) for neonates in the low birth weight (LBW) group. 6∶2 Cl-PFESA and 8∶2 Cl-PFESA inhibited the birth weight (β=-0.926; β=-0.552) and length (β=-0.074; β=-0.045) of newborn in the LBW group. In addition, 4∶2 fluorotelomer sulfonate (FTS) was associated with increased birth weight (β=0.111) and decreased Apgar-5 score (β=-0.030) in the normal weight group. Conclusion: Prenatal exposure to PFASs is associated with birth weight, birth length and Apgar-5 score. It is necessary to continue to pay attention to the impact of PFASs on fetal growth and development through maternal-fetal transmission.

Prenatal pyrethroid pesticides exposure and neurodevelopment of 2-year-old children: a birth cohort study / 中华预防医学杂志

Objective: To investigate the influence and critical windows of prenatal exposure to pyrethroid pesticides (PYRs) on neurodevelopment of 2-year-old children. Methods: The subjects of this study were derived from the Xuanwei Birth Cohort. A total of 482 pregnant women who participated in the rural district of Xuanwei birth cohort from January 2016 to December 2018 were included. Maternal urinary concentrations of PYRs metabolites during 8-12 gestational weeks, 20-23 gestational weeks and 32-35 gestational weeks were measured with ultra high performance liquid chromatography system coupled with a tandem mass spectrometry detector. Child neurodevelopment was evaluated with the Bayley Scales of Infant and Toddler Development-Third Edition at 2 years of age. Multivariate linear regression models and binary logistic regression models were used to assess the association between PYRs exposure during pregnancy and children's neurodevelopment. Results: A total of 360 mother-child pairs had complete data on maternal urinary PYRs metabolites detection and children's neurodevelopment assessment. The detection rate of any one PYRs metabolites during the first, second and third trimester were 93.6% (337/360), 90.8% (327/360) and 94.2% (339/360), respectively. The neurodevelopmental scores of Cognitive, Language, Motor, Social-Emotional, and Adaptive Behavior of 2-year-old children were (102.3±18.9), (100.2±16.3), (102.0±20.3), (107.8±23.3) and (85.8±18.6) points, respectively. After controlling for confounding factors, 4-fluoro-3-phenoxybenzoic acid (4F3PBA, one of PYRs metabolites) exposure in the first trimester reduced Motor (β=-5.02, 95%CI: -9.08, -0.97) and Adaptive Behavior (β=-4.12, 95%CI:-7.92, -0.32) scores of 2-year-old children, and increased risk of developmental delay of adaptive behavior (OR=2.07, 95%CI:1.13-3.82). Conclusion: PYRs exposure during the first trimester of pregnancy may affect neurodevelopment of 2-year-old children, and the first trimester may be the critical window.

Mechanism of valproic acid-induced dendritic spine and synaptic impairment in the prefrontal cortex for causing core autistic symptoms in mice / 南方医科大学学报

OBJECTIVE@#To investigate the mechanism of valproic acid (VPA) -induced impairment of the dendritic spines and synapses in the prefrontal cortex (PFC) for causing core symptoms of autism spectrum disorder (ASD) in mice.@*METHODS@#Female C57 mice were subjected to injections of saline or VPA on gestational days 10 and 12, and the male offspring mice in the two groups were used as the normal control group and ASD model group (n=10), respectively. Another 20 male mice with fetal exposure to VPA were randomized into two groups for stereotactic injection of DMSO or Wortmannin into the PFC (n=10). Open field test, juvenile play test and 3-chamber test were used to evaluate autistic behaviors of the mice. The density of dendrite spines in the PFC was observed with Golgi staining. Western blotting and immunofluorescence staining were used to detect the expressions of p-PI3K, PI3K, p-AKT, AKT, p-mTOR, mTOR and the synaptic proteins PSD95, p-Syn, and Syn in the PFC of the mice.@*RESULTS@#Compared with the normal control mice, the mice with fetal exposure to VPA exhibited obvious autism-like behaviors with significantly decreased density of total, mushroom and stubby dendritic spines (P < 0.05) and increased filopodia dendritic spines (P < 0.05) in the PFC. The VPA-exposed mice also showed significantly increased expressions of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR (P < 0.01) and lowered expressions of PSD95 and p-Syn/Syn in the PFC (P < 0.05 or 0.001). Wortmannin injection into the PFC obviously improved the ASD-like phenotype and dendritic spine development, down-regulated PI3K/Akt/mTOR signaling pathway and up-regulated the synaptic proteins in VPA-exposed mice.@*CONCLUSION@#In male mice with fetal exposure to VPA, excessive activation of PI3K/Akt/mTOR signaling pathway and decreased expressions of the synaptic proteins PSD95 and p-Syn cause dendritic spine damage and synaptic development disturbance in the PFC, which eventually leads to ASD-like phenotype.

Anatomía del cuerpo calloso en ratas sometidas a estrés prenatal crónico / Anatomy of corpus callosum in rats submitted to chronic prenatal stress

RESUMEN: El cuerpo calloso (CC), es la mayor comisura de sustancia blanca del encéfalo de los mamíferos placentados, constituida por numerosos haces de fibras transversales que conectan áreas corticales de ambos hemisferios cerebrales. Por otro lado, el estrés se define como una respuesta general del organismo ante demandas externas o internas, inicialmente amenazantes, que consiste en movilizar recursos fisiológicos y psicológicos para poderlas afrontar. Dada la importancia del cuerpo calloso en las conexiones cortico-corticales, el objetivo del presente estudio, fue evaluar el efecto en ratas, de un estrés prenatal crónico por inmovilización, sobre la anatomía macroscópica del CC. Se utilizaron seis ratas preñadas de la cepa Wistar de 250 g, de las cuales tres fueron sometidas, a partir del octavo día postconcepción, a una restricción de movimiento por diez días (2h/día). Posteriormente, las madres prosiguieron su gestación, parto y lactancia. Al nacimiento, las camadas fueron ajustadas a seis crías machos por madre (n=36), destetadas a los 21 días y sacrificadas a los 45-52 días de edad. Los encéfalos fueron seccionados a través de la cisura interhemisférica y ambos hemisferios fotografiados por su cara medial. Las imágenes fueron digitalizadas y analizadas mediante el programa Scion Image®, para la medición del área total, parciales (tercio anterior, medio, posterior y quinto posterior) y perímetro callosal. Es así como, el estrés prenatal por inmovilización, afectó significativamente (p<0,01), la morfología macroscópica del cuerpo calloso. Evidenciándose una disminución del área total, áreas parciales y perímetro callosal, en los animales sometidos a restricción prenatal. Estableciendo una relación directa entre número de axones y área callosal e inversa entre diámetro y densidad axonal; lo observado podría tener incidencia en la transferencia interhemisférica.

SUMMARY: The Corpus Callosum (CC) is the largest white matter commissure in the brain of placental mammals, consisting of numerous transverse fiber bundles that connect cortical areas of both cerebral hemispheres. On the other hand, stress is defined as a general response of the organism to external or internal demands, initially threatening, which consists of mobilizing physiological and psychological resources to be able to face them. Given the importance of CC in cortico-cortical connections, the aim of the present study, was to evaluate the effect of chronic pre-natal immobilization stress on the macroscopic anatomy of CC in rats. Six 250g pregnant rats of the Wistar strain were used, of which three were subjected, starting on the eighth post-conception day, to movement restriction for ten days (2h/day). Subsequently, the mothers continued their gestation, delivery and lactation. At birth, litters were adjusted to six male offspring per mother (n=36), which were weaned at 21 days and slaughtered at 45-52 days of age. The brains were fixed, and later sectioned through the interhemispheric fissure and both hemispheres photographed by their medial aspect. The images were digitized and analyzed using the Scion Image® program, for the measurement of the total area, partial area (ante- rior, middle and posterior thirds, as well as posterior fifth) and callosal perimeter. Thus, prenatal stress due to immobilization significantly affected (p<0.01), the macroscopic morphology of the CC. Evidence shows a decrease in the total area, partial areas and callosal perimeter in the animals subjected to prenatal restraint, as compared to normal animals. Establishing a direct relationship between number of axons and callosal area and an inverse relationship between diameter and axonal density, what was observed may have an impact on interhemispheric transfer.

Can Prenatal and Postnatal Cell Phone Exposure Increase Adverse Maternal, Infant and Child Outcomes? / A exposição pré-natal e pós-natal a telefones celulares pode aumentar os resultados adversos para mães, bebês e crianças?

Abstract Objective To determine the association between maternal mobile phone use and adverse outcomes in infants, children, and mothers. Method In March 202, we conducted a search on the MEDLINE, Embase, and Scopus databases. Data extraction and an assessment of the quality of the studies were performed by two authors. The quality of the studies was assessed using the checklist of the Newcastle-Ottawa scale. Results Studies assessing behavioral problems in infants aged 6 to 18 months reported null findings. However, an increased risk of emotional and behavioral disorders was observed in children aged between 7 and 11 years whose mothers had been exposed to cell phones. The findings regarding the association between maternal cell phone exposure and adverse outcomes in children aged 3 to 5 are controversial. A study found a significant association between the call time (p=0.002) or the history of mobile phone use (in months) and speech disorders in the children (p=0.003). However, another study found that maternal cell phone use during pregnancy was not significantly associated with child psychomotor and mental developments. Inconclusive results were observed about the adverse outcomes in fetuses, such as fetal growth restriction or t scores for birth weight in cell phone users as opposed to non-users. On the contrary, the children ofmothers who were cell phone users had a lower risk of scoring low on motor skills. Similar results were observed regarding the adverse outcomes of cell phone use in infants, such as fetal growth restriction or low birth weight, and the risk of preeclampsia was lower among subjects with medium and high cell phone exposure, as opposed to those with low exposure. Conclusion Studies on behavioral problems have reported different postnatal results, such as null findings among infants and a positive association in children.

Resumo Objetivo Determinar a associação entre o uso de telefone celular pela mãe e os resultados adversos em recém-nascidos crianças e mães. Método Em março de 2020 realizou-se uma pesquisa nas bases de dados MEDLINE, Embase e Scopus. A extração de dados e avaliação da qualidade dos estudos foram realizadas por dois autores. A qualidade dos estudos foi avaliada por meio da lista de verificação da escala Newcastle-Ottawa. Resultados Estudos que avaliavam problemas comportamentais em recém-nascidos de 6 a 18 meses relataram resultados nulos. No entanto um risco aumentado de transtornos emocionais e comportamentais foi observado em crianças de 7 a 11 anos de idade cujas mães foram expostas a telefones celulares. Os resultados relacionados à associação entre a exposição materna a celulares e resultados adversos em crianças de 3 a 5 anos são controversos. Um estudo encontrou associação significativa entre o tempo de ligação (p=0.002) ou o histórico de uso de celular (emmeses) e distúrbios de fala nas crianças (p=0.003). No entanto outro estudo descobriu que o uso de telefone celular pela mãe durante a gravidez não estava significativamente associado ao desenvolvimento psicomotor e mental da criança. Resultados inconclusivos foram observados com relação aos resultados adversos de fetos como restrição de crescimento intrauterino ou valores de t para peso ao nascer em usuárias de telefone celular em oposição a não usuárias. Pelo contrário os filhos de mães usuárias de telefone celular apresentaram menor risco de pontuação baixa em habilidades motoras. Resultados semelhantes foram observados com relação a resultados adversos em recém-nascidos como restrição de crescimento intrauterino ou valores de peso ao nascere o risco de pré-eclâmpsia foimenor em indivíduos comexposição média e alta a celulares em oposição àqueles com baixa exposição. Conclusão Estudos sobre problemas comportamentais relataram resultados diferentes no pós-natal como achados nulos em recém-nascidos e associação positiva emcrianças.

Intrauterine alcohol exposure disturbs trabecular morphology in the Sprague Dawley rat humerus epiphysis up to 3- weeks postnatally / La exposición al alcohol intrauterino altera la morfología trabecular en la epífisis del húmero de la rata Sprague Dawley hasta 3 semanas después del nacimiento

SUMMARY: Gestational alcohol exposure inhibits neurological as well as bone growth and development both in fetal and postnatal life. Stunted stature, osteoporosis and fractures in adult life are some of the adverse effects. While the impact of intrauterine alcohol on the brain has been extensively investigated, studies on the effects on bone are relatively few. Therefore, our study aimed to examine the impact of prenatal alcohol exposure on bone microarchitecture in 3-week-old rats using Micro-focus X-Ray Computed Tomography (Micro CT). Time mated pregnant Sprague Dawley dams (13) were randomly placed into 3 groups: ethanol (n=5), saline control (n=5) and untreated control (n=3). The former 2 groups received treatment with 0.015ml/g of 25.2 % ethanol and 0.9 % saline, respectively, for the first 19 days of gestation. The untreated group received no treatment. The pups remained with their dams until termination at 21 days of age. From each dam, 2 pups were collected resulting in: ethanol (n=10), saline controls (n= 10) and untreated controls (n = 6). The humeri of the pups were dissected and scanned using a 3D-μCT scanner (Nikon XTH 225L) at 15μm resolution. Trabecular and cortical parameters were analysed using Volume Graphics Studio® software following reconstruction. Results showed a decrease in trabecular size, spaces, thickness, and volume. There was a decrease in cortical bone area in the ethanol group compared to the controls. These findings may suggest that osteoporosis and fractures seen as gestational alcohol effects may be due to compromised trabecular structure.

RESUMEN: La exposición al alcohol durante la gestación inhibe el crecimiento y desarrollo neurológico y óseo tanto en la vida fetal como posnatal. Algunos de los efectos adversos incluyen la estatura atrofiada, osteoporosis y fracturas en la vida adulta. Si bien se ha estudiado el impacto del alcohol intrauterino en el cerebro, los estudios sobre los efectos en los huesos son escasos. Por lo tanto, nuestro estudio tuvo como objetivo examinar el impacto de la exposición prenatal al alcohol en la microarquitectura ósea en ratas de 3 semanas de edad utilizando Tomografía Computarizada de Rayos X Micro-focus (Micro CT). Las hembras de Sprague Dawley preñadas con apareamiento temporal (13) se colocaron aleatoriamente en 3 grupos: etanol (n = 5), control de solución salina (n = 5) y control sin tratar (n = 3). Los primeros 2 grupos recibieron tratamiento con 0,015 ml /g de etanol al 25,2 % y solución salina al 0,9 %, respectivamente, durante los primeros 19 días de gestación. El grupo no tratado no recibió tratamiento. Las crías permanecieron con sus madres hasta la terminación a los 21 días de edad. De cada madre, se recolectaron 2 crías que dieron como resultado: etanol (n = 10), controles salinos (n = 10) y controles no tratados (n = 6). Se diseccionaron y escanearon los húmero de las crías usando un escáner 3D-μCT (Nikon XTH 225L) a una resolución de 15 μm. Los parámetros trabeculares y corticales se analizaron utilizando el software Volume Graphics Studio® después de la reconstrucción. Los resultados mostraron una disminución en el tamaño trabecular, los espacios, el grosor y el volumen. Hubo una disminución en el área del hueso cortical en el grupo de etanol en comparación con los controles. Estos hallazgos pueden sugerir que la osteoporosis y las fracturas por causa de los efectos del alcohol gestacional se pueden deber a una estructura trabecular comprometida.

Intrauterine and postnatal exposure to tobacco and wood smoke on hypothalamic development and cognition: an integrative review of the literature / Exposición intrauterina y postnatal al humo de tabaco y de leña en el desarrollo hipotalámico y la cognición: una revisión integrativa de la literatura

SUMMARY: Exposure to air pollution and its pollutants has been associated with important effects on human health since the first years of life, thus it has been seen that exposure to tobacco smoke and wood smoke is directly related to cardiovascular and pulmonary diseases, respiratory and cancers. However, exposure to air pollution during fetal development and its effects on brain structure and function during early childhood and adolescence have been little studied. In this review we have analyzed the literature on prenatal exposure to tobacco and wood smoke and its relationship with hypothalamic development and cognition in the first years of life.The molecular, morphological and physiological aspects of the relationship between pre- and postnatal exposure to tobacco and wood smoke with neural developmental, cognitive and behavioral problems during early childhood and adolescence have not yet been fully clarified. The information available in the scientific literature based on antecedents obtained from epidemiological studies has been negatively affected by confounding variables and great methodological challenges that make it impossible to affirm an exact causal relationship with certainty.

RESUMEN: La exposición a la contaminación del aire se ha asociado con importantes efectos en la salud humana desde los primeros años de vida. Estudios han demostrado con certeza que la exposición al humo de tabaco y humo de leña está directamente relacionada con enfermedades cardiovasculares, pulmonares, respiratorias y cánceres. Sin embargo, la exposición a la contaminación del aire durante el desarrollo fetal y sus efectos a posteriori sobre la estructura y función del cerebro durante la primera infancia y la adolescencia son aún desconocidos. En esta revisión analizamos la literatura sobre la exposición prenatal al tabaco y al humo de leña y su relación con el desarrollo hipotalámico y la cognición en los primeros años de vida. Los aspectos moleculares, morfológicos y fisiológicos de la asociación entre la exposición pre y postnatal al humo de tabaco o al humo de leña con problemas del desarrollo neurológico normal, cognitivos y de comportamiento durante la primera infancia y la adolescencia aún no se han aclarado completamente. La información disponible en la literatura científica basada en antecedentes obtenidos de estudios epidemiológicos ha sido afectada negativamente por variables de confusión y grandes desafíos metodológicos que hacen imposible afirmar una relación directa y causal exacta con certeza.

Effects of prenatal tobacco smoke on cerebellum histomorphological changes at critical developmental stages in CD-1 mice / Efectos del humo de tabaco en los cambios histomorfológicos del cerebelo en las etapas críticas del desarrollo prenatal en ratones CD-1

SUMMARY: In this study the consequences of prenatal exposure to tobacco smokes on the histo-morphological changes of cerebellum was assessed by comparing the smoker mice to the nonsmoker mice. A total of 30 pregnant cd-1 mice were divided into three groups of 10 mice each and with two replicates per group (5 mice each). Following acclimation for five days, the mice were placed in a special modified smoking machine for 2 hours per day over a two- and three-week period for group two and group three, respectively. Group one was considered as a control group. Mice in the control group were exposed simultaneously to fresh air from the room, while those in the treatment groups were exposed to tobacco smoke from six commercial filter cigarettes, containing 0.8 mg of nicotine, 10 mg of tar, and 10 mg of carbon monoxide, for three 1-hour exposure periods every day for three weeks. The mice in the control group were exposed to room air for three 1-hour periods every day for the same period of three weeks. The results from this study showed a correlation between maternal smoking and histological changes in Neuron purkinjense (Purkinje cells) of the cerebellum. They also showed that prenatal smoking period may have caused more damage in the histology and structure of Neuron purkinjense in some juvenile mice. An increased incidence of morphology damage of the cerebellum's Neuron purkinjense' structures was also observed in fetuses with prolonged exposure to tobacco smoking. Exposure of in utero maternal smoking may interfere with brain biological development parameters, giving rise to structural abnormalities of the cerebellum. This study concluded that tobacco smoke exposure to pregnant mice may affect neurodevelopment which may induce behavioural changes as a result of reduced cerebellar size and function.

RESUMEN: Se evaluaron los efectos producidos por la exposición prenatal al humo de tabaco en ratones expuestos y no expuestos y los cambios histomorfológicos observados en el cerebelo en ambos grupos. Un total de 30 ratones cd-1 preñados se dividieron en tres grupos de 10 ratones cada uno y con dos réplicas por grupo (5 ratones cada uno). Después de la aclimatación durante cinco días, los ratones se colocaron en una máquina de fumar modificada, especial durante 2 horas al día, durante un período de dos y tres semanas para el grupo dos y el grupo tres, respectivamente. El grupo uno se consideró como grupo control. Los ratones del grupo de control fueron expuestos simultáneamente al aire limpio de la habitación, mientras que los grupos de tratamiento fueron expuestos al humo de tabaco de seis cigarrillos comerciales, que contenían 0,8 mg de nicotina, 10 mg de alquitrán y 10 mg de monóxido de carbono. durante tres períodos de 1 hora diariamente, durante tres semanas. Los ratones del grupo de control se expusieron al aire ambiente durante tres períodos de 1 hora todos los días durante el mismo período de tres semanas. Los resultados de este estudio mostraron una correlación entre el tabaquismo materno y los cambios histológicos en las neuronas purkinjenses (células de Purkinje). Se observó además que el período de tabaquismo prenatal puede haber causado mayor daño en la histología y estructura de las neuronas purkinjenses en algunos ratones jóvenes. También se observó una mayor incidencia de daño morfológico de las estructuras de las neuronas purkinjenses del cerebelo en fetos con exposición prolongada al tabaquismo. La exposición al tabaquismo materno en el útero puede interferir con los parámetros de desarrollo biológico del cerebro, dando lugar a anomalías estructurales del cerebelo. Este estudio concluyó que la exposición al humo del tabaco en ratones preñados puede afectar el desarrollo neurológico, lo que puede inducir cambios de comportamiento como resultado de la reducción del tamaño y la función del cerebelo.

Air pollution and children's health-a review of adverse effects associated with prenatal exposure from fine to ultrafine particulate matter

BACKGROUND@#Particulate matter (PM), a major component of ambient air pollution, accounts for a substantial burden of diseases and fatality worldwide. Maternal exposure to PM during pregnancy is particularly harmful to children's health since this is a phase of rapid human growth and development.@*METHOD@#In this review, we synthesize the scientific evidence on adverse health outcomes in children following prenatal exposure to the smallest toxic components, fine (PM@*RESULTS@#Maternal exposure to fine and ultrafine PM directly and indirectly yields numerous adverse birth outcomes and impacts on children's respiratory systems, immune status, brain development, and cardiometabolic health. The biological mechanisms underlying adverse effects include direct placental translocation of ultrafine particles, placental and systemic maternal oxidative stress and inflammation elicited by both fine and ultrafine PM, epigenetic changes, and potential endocrine effects that influence long-term health.@*CONCLUSION@#Policies to reduce maternal exposure and health consequences in children should be a high priority. PM

Association between tobacco and/or alcohol consumption during pregnancy and infant development: BRISA Cohort

Fetuses exposed to alcohol and/or tobacco are at risk for perinatal adversities. However, little is currently known about the association of the separate or concomitant use of alcohol and tobacco with infant motor and cognitive development. Thus, the objective of the present study was to investigate the association between maternal consumption of alcohol and/or tobacco during pregnancy and the motor and cognitive development of children starting from the second year of life. The study included 1006 children of a cohort started during the prenatal period (22-25 weeks of pregnancy), evaluated at birth and reevaluated during the second year of life in 2011/2013. The children were divided into four groups according to the alcohol and/or tobacco consumption reported by their mothers at childbirth: no consumption (NC), separate alcohol consumption (AC), separate tobacco consumption (TC), and concomitant use of both (ACTC). The Bayley Scale of Infant and Toddler Development Third Edition screening tool was used for the assessment of motor and cognitive development. Adjusted Poisson regression models were used to determine the association between groups and delayed development. The results indicated that only the ACTC group showed a higher risk of motor delay, specifically regarding fine motor skills, compared to the NC group (RR=2.81; 95%CI: 1.65; 4.77). Separate alcohol or tobacco consumption was not associated with delayed gross motor or cognitive development. However, the concomitant use of the two substances increased the risk of delayed acquisition of fine motor skills.

Hokkaido birth cohort study on environment and children's health: cohort profile 2021

BACKGROUND@#The Hokkaido Study on Environment and Children's Health is an ongoing study consisting of two birth cohorts of different population sizes: the Sapporo cohort and the Hokkaido cohort. Our primary objectives are to (1) examine the effects that low-level environmental chemical exposures have on birth outcomes, including birth defects and growth retardation; (2) follow the development of allergies, infectious diseases, and neurobehavioral developmental disorders, as well as perform a longitudinal observation of child development; (3) identify high-risk groups based on genetic susceptibility to environmental chemicals; and (4) identify the additive effects of various chemicals, including tobacco.@*METHODS@#The purpose of this report is to provide an update on the progress of the Hokkaido Study, summarize recent results, and suggest future directions. In particular, this report provides the latest details from questionnaire surveys, face-to-face examinations, and a collection of biological specimens from children and measurements of their chemical exposures.@*RESULTS@#The latest findings indicate different risk factors of parental characteristics on birth outcomes and the mediating effect between socioeconomic status and children that are small for the gestational age. Maternal serum folate was not associated with birth defects. Prenatal chemical exposure and smoking were associated with birth size and growth, as well as cord blood biomarkers, such as adiponectin, leptin, thyroid, and reproductive hormones. We also found significant associations between the chemical levels and neuro development, asthma, and allergies.@*CONCLUSIONS@#Chemical exposure to children can occur both before and after birth. Longer follow-up for children is crucial in birth cohort studies to reinforce the Developmental Origins of Health and Disease hypothesis. In contrast, considering shifts in the exposure levels due to regulation is also essential, which may also change the association to health outcomes. This study found that individual susceptibility to adverse health effects depends on the genotype. Epigenome modification of DNA methylation was also discovered, indicating the necessity of examining molecular biology perspectives. International collaborations can add a new dimension to the current knowledge and provide novel discoveries in the future.

Maternal metal concentration during gestation and pediatric morbidity in children: an exploratory analysis

BACKGROUND@#The majority of studies linking exposure to metals with certain health outcomes focus on known toxic metals. Alternatively, this study assesses the extent to which exposure to a wider range of metals during gestation is associated with childhood morbidity.@*METHODS@#We analyzed the concentrations of 25 metals found in urine samples of 111 pregnant women of Arab-Bedouin origin collected prior to birth. In addition, we collected medical records on their offspring for six years following birth, including every interaction with HMOs, local hospitals, and pharmacies.@*RESULTS@#The main types of morbidities diagnosed and treated during this period were preterm births, malformations, asthma-like morbidity, cardiovascular and behavioral problems, and obesity. Multivariable analysis showed that offspring born before term were more likely to have been exposed to elevated maternal concentrations of zinc, thallium, aluminum, manganese, and uranium, all with adjusted relative risk above 1.40 for an increase by each quintile. Likewise, children with asthma had been exposed to higher levels of magnesium, strontium, and barium at gestation, while behavioral outcomes were associated with elevated biometals, i.e., sodium, magnesium, calcium, selenium, and zinc, as well as higher levels of lithium, cobalt, nickel, strontium, cadmium, vanadium, arsenic, and molybdenum. A heatmap of adjusted relative risk estimates indicates the considerable implications that exposure to metals may have for preterm birth and developmental outcomes.@*CONCLUSIONS@#The current study shows that perinatal exposure to metals is adversely associated with pediatric morbidity. Further such analyses on additional samples are warranted.

Effects of maternal exposure to arsenic on social behavior and related gene expression in F2 male mice

BACKGROUND@#Arsenic is a developmental neurotoxicant. It means that its neurotoxic effect could occur in offspring by maternal arsenic exposure. Our previous study showed that developmental arsenic exposure impaired social behavior and serotonergic system in C3H adult male mice. These effects might affect the next generation with no direct exposure to arsenic. This study aimed to detect the social behavior and related gene expression changes in F2 male mice born to gestationally arsenite-exposed F1 mice.@*METHODS@#Pregnant C3H/HeN mice (F0) were given free access to tap water (control mice) or tap water containing 85 ppm sodium arsenite from days 8 to 18 of gestation. Arsenite was not given to F1 or F2 mice. The F2 mice were generated by mating among control F1 males and females, and arsenite-F1 males and females at the age of 10 weeks. At 41 weeks and 74 weeks of age respectively, F2 males were used for the assessment of social behavior by a three-chamber social behavior apparatus. Histological features of the prefrontal cortex were studied by ordinary light microscope. Social behavior-related gene expressions were determined in the prefrontal cortex by real time RT-PCR method.@*RESULTS@#The arsenite-F2 male mice showed significantly poor sociability and social novelty preference in both 41-week-old group and 74-week-old group. There was no significant histological difference between the control mice and the arsenite-F2 mice. Regarding gene expression, serotonin receptor 5B (5-HT 5B) mRNA expression was significantly decreased (p < 0.05) in the arsenite-F2 male mice compared to the control F2 male mice in both groups. Brain-derived neurotrophic factor (BDNF) and dopamine receptor D1a (Drd1a) gene expressions were significantly decreased (p < 0.05) only in the arsenite-F2 male mice of the 74-week-old group. Heme oxygenase-1 (HO-1) gene expression was significantly increased (p < 0.001) in the arsenite-F2 male mice of both groups, but plasma 8-hydroxy-2'-deoxyguanosine (8-OHdG) and cyclooxygenase-2 (COX-2) gene expression were not significantly different. Interleukin-1β (IL-1β) mRNA expression was significantly increased only in 41-week-old arsenite-F2 mice.@*CONCLUSIONS@#These findings suggest that maternal arsenic exposure affects social behavior in F2 male mice via serotonergic system in the prefrontal cortex. In this study, COX-2 were not increased although oxidative stress marker (HO-1) was increased significantly in arsnite-F2 male mice.

The mechanism of enriched environment repairing the learning and memory impairment in offspring of prenatal stress by regulating the expression of activity-regulated cytoskeletal-associated and insulin-like growth factor-2 in hippocampus

BACKGROUND@#Prenatal stress can cause neurobiological and behavioral defects in offspring; environmental factors play a crucial role in regulating the development of brain and behavioral; this study was designed to test and verify whether an enriched environment can repair learning and memory impairment in offspring rats induced by prenatal stress and to explore its mechanism involving the expression of insulin-like growth factor-2 (IGF-2) and activity-regulated cytoskeletal-associated protein (Arc) in the hippocampus of the offspring.@*METHODS@#Rats were selected to establish a chronic unpredictable mild stress (CUMS) model during pregnancy. Offspring were weaned on 21st day and housed under either standard or an enriched environment. The learning and memory ability were tested using Morris water maze and Y-maze. The expression of IGF-2 and Arc mRNA and protein were respectively measured by using RT-PCR and Western blotting.@*RESULTS@#There was an elevation in the plasma corticosterone level of rat model of maternal chronic stress during pregnancy. Maternal stress's offspring exposed to an enriched environment could decrease their plasma corticosterone level and improve their weight. The offspring of maternal stress during pregnancy exhibited abnormalities in Morris water maze and Y-maze, which were improved in an enriched environment. The expression of IGF-2, Arc mRNA, and protein in offspring of maternal stress during pregnancy was boosted and some relationships existed between these parameters after being exposed enriched environment.@*CONCLUSIONS@#The learning and memory impairment in offspring of prenatal stress can be rectified by the enriched environment, the mechanism of which is related to the decreasing plasma corticosterone and increasing hippocampal IGF-2 and Arc of offspring rats following maternal chronic stress during pregnancy.

Inflammatory state and autism-like behavioral phenotype of offspring induced by maternal exposure to low-dose chemical mixtures during pregnancy in mice / 浙江大学学报·医学版

To investigate the effects of maternal exposure to 13 chemicals mixture (CM) during pregnancy on pregnancy outcome and health status of maternal/offspring mice. C57BL/6 pregnant mice were given drinking water containing carbaryl dimethoate glyphosate methomyl methyl parathion triadimefon aspartame sodium benzoate calcium disodium ethylene diamine tetra-acetate ethylparaben butylparaben bisphenol A and acacia gum The effects of CM exposure on pregnancy outcome, health status of dams/offspring, levels of circulating inflammatory cytokines in dams/offspring and emotional related behaviors of offspring were evaluated. CM exposure during pregnancy had no significant effect on pregnancy outcome, liver function, body weight of the dams in late pregnancy and uterine/ovarian weight after delivery, however, it led to an increase in maternal serum IFN-γ level （<0.05）. CM exposure during pregnancy had no significant effect on the liver function of offspring, but increased the serum IFN-γ, prefrontal cortex IFN-γ, and TNF-α and hippocampus IFN-γ levels in the offspring（all <0.01）. In addition, the offspring of CM group showed significant abnormal emotion-related (autism-like) behaviors in adulthood, especially in male offspring. Low dose CM exposure during pregnancy may induce inflammation status in dams/offspring, and lead to autism-like behaviors in offspring, indicating the potential effects of low dose CM exposure on human maternal and infant health.

Valerian treatment during the postpartum period alters breast milk composition and impairs long-term memory in female rat offspring

Maternal anxiety symptoms in the perinatal period might have long-term health effects on both the mother and the developing child. Valerian is a phytotherapeutic agent that is widely used for the treatment of anxiety. This study investigated the effects of valerian treatment in postpartum rats on maternal care, toxicity, and milk composition. Postnatal development, memory, and anxiety behavior in the offspring were also assessed. Postpartum Wistar rats received the valerian (500, 1000, or 2000 mg·kg-1·day-1) by oral gavage. Clinical and biochemical toxicity was evaluated with commercial kits. Maternal behavior was observed daily. Milk composition was analyzed by colorimetric methods. Physical and neuromotor tests were used to analyze postnatal development. Anxiolytic activity was assessed by the elevated plus maze, and memory was evaluated by the step-down inhibitory avoidance task. Maternal toxicity and care behavior were not altered by the treatment, while only the highest dose promoted a significant increase of lactose, and the doses 1000 and 2000 mg·kg-1·day-1 promoted a reduction of protein contents in milk. Postnatal development was similar in all offspring. Adult offspring did not display altered anxiety behavior, while long-term memory was impaired in the female adult offspring by maternal treatment with 1000 mg·kg-1·day-1. These results suggested that high doses of valerian had significant effects on important maternal milk components and can cause long-term alterations of offspring memory; thus, treatment with high doses of valerian is not safe for breastfeeding Wistar rat mothers.