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.

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.

Neonatal exposure to citalopram increases pyramidal and granular cell density in dorsal hippocampus of male but not female adult rats: a quantitative Nissl study / La exposición neonatal al citalopram aumenta la densidad de las células piramidales y granulares en el hipocampo dorsal de ratas adultas macho pero no en hembras: un estudio cuantitativo con tinción de Nissl

Antidepressants use during pregnancy was associated with an increased risk of autism spectrum disorders. Animal models based on early life alterations in serotonin availability replicate some of the anatomical and behavioral abnormalities observed in autistic individuals. In recent years there has been a growing interest in the possible role of the hippocampus in autism. The aim of study is to examine the effects of neonatal antidepressant (CTM) exposure during a sensitive period of brain development on pyramidal and granule cells density of hippocampal formation. We examined the pyramidal and granular cells density of dorsal hippocampus using Nissl stained sections obtained from neonatal citalopram (CTM) exposed rats (5 mg/kg, twice daily, s.c.), from postnatal day 8 to 21 (PN8-21), saline and non-exposed rats. The density of pyramidal cells was significantly increased by 10.2 % in CA1, 10.6 % in CA3 and 13.2 % in CA4 in CTM treated compared with non-treated or saline treated animals (p<0.0001). The density of granule cells in the dentate gyrus was significantly increased by 12.0 % in CTM treated compared with non-treated or saline treated animals (p<0.0001). These findings were obtained only from male rats, suggesting a sexual dimorphism in neural development after SSRI exposure. These data suggest that the neonatal exposure to CTM may induce long-lasting changes in the hippcampal formation in adults, and such effects appear to preferentially target males.

El uso de antidepresivos durante el embarazo se asoció con un mayor riesgo de trastornos del espectro autista. Los modelos animales basados en alteraciones tempranas de la vida en la disponibilidad de serotonina replican algunas de las anomalías anatómicas y de comportamiento observadas en individuos autistas. En los últimos años ha habido un interés creciente en el posible papel del hipocampo en el autismo. El objetivo del estudio fue examinar los efectos de la exposición al antidepresivo neonatal (CTM) durante un período sensible del desarrollo cerebral en la densidad de las células piramidales y granulares de la formación del hipocampo. Examinamos la densidad de las células piramidales y granulares del hipocampo dorsal utilizando secciones teñidas con Nissl obtenidas de ratas expuestas al citalopram neonatal (CTM) (5 mg / kg, dos veces al día, sc), desde el día postnatal 8 a 21 (PN8-21), solución salina y ratas no expuestas. La densidad de células piramidales se incrementó significativamente en un 10,2 % en CA1, 10,6 % en CA3 y 13,2 % en CA4 en CTM tratados en comparación con animales no tratados o tratados con solución salina (p <0,0001). La densidad de células granulares en el giro dentado aumentó significativamente en un 12,0 % en los animales tratados con CTM en comparación con los animales no tratados o tratados con solución salina (p <0,0001). Estos hallazgos se obtuvieron solo en ratas macho, lo que sugiere un dimorfismo sexual en el desarrollo neural después de la exposición a ISRS. Estos datos sugieren que la exposición neonatal a la CTM puede inducir cambios de larga duración en la formación del hipocampo en adultos, y estos efectos parecen dirigirse preferentemente a los machos.

La evidencia acerca de la controversia de las vacunas que contienen timerosal y su asociación con el autismo / Addressing the controversy regarding the association between thimerosal-containing vaccines and autism

La vacunación es una de las medidas de mayor impacto en la salud pública para la reducción de la morbimortalidad infantil. El timerosal es un compuesto orgánico del mercurio utilizado como preservante de los frascos multidosis. Eventualmente, en el Perú, surgen olas de controversia acerca de la seguridad de estas vacunas, asociándolas especialmente con el autismo. Como resultado de estas controversias, se han propuesto, incluso, leyes que prohíben este tipo de vacunas, lo que tendría un importante impacto en los costos y en los aspectos logísticos de la estrategia nacional de vacunación. En este artículo se revisa la literatura sobre las principales controversias acerca de las vacunas que contienen timerosal y su supuesta asociación con el autismo. Se realiza una aproximación histórica sobre estas controversias, se hace una actualización de la evidencia científica disponible al momento, y se revisa la posición de los organismos internacionales más importantes con respecto a este tema. Se concluye que la evidencia científica no apoya la noción que exista una asociación entre el uso del timerosal en las vacunas con los trastornos del espectro autista en niños.

Vaccination is one of the most important public health interventions in the reduction childhood morbidity and mortality. Thimerosal is an organic mercury compound used as preservante in multi-dose vials. Often in Peru, there are waves of controversy about the safety of this type of vaccines, mainly arguing that there is an association between them and autism. As a result of these controversies, there have been some voices asking for laws banning thimerosal-containing vaccines, which would have a large impact in costs and the logistic aspects of the public vaccination programs. The aim of this article is to review the literature for the main controversies about thimerosal in vaccines and its supposed association to autism. We made an historical review about these controversies given the available scientific evidence and the statements from important international organizations. We concluded that the current available evidence do not support an association between thimerosal and childhood neurodevelopmental disorders, such as autism.

A comprehensive review of mercury provoked autism.

Emerging evidence supports the theory that some autism spectrum disorders (ASDs) may result from a combination of genetic/biochemical susceptibility, specifically a reduced ability to excrete mercury (Hg), and exposure to Hg at critical developmental periods. Elemental/inorganic Hg is released into the air/water where it becomes methylated and accumulates in animal tissues. The US population is primarily exposed to methyl-Hg by fish consumption. In addition, many pharmaceuticals have been, and some continue to be, a ubiquitous source of danger because they contain mercurials. Mercurials may be found in drugs for the eye, ear, nose, throat, and skin; in bleaching creams; as preservatives in cosmetics, tooth pastes, lens solutions, vaccines, allergy test and immunotherapy solutions; in antiseptics, disinfectants, and contraceptives; in fungicides and herbicides; in dental fillings and thermometers; and many other products. Hg has been found to cause immune, sensory, neurological, motor, and behavioural dysfunctions similar to traits defining/associated with ASDs, and that these similarities extend to neuroanatomy, neurotransmitters, and biochemistry. Furthermore, a review of molecular mechanisms indicates that Hg exposure can induce death, disorganization and/or damage to selected neurons in the brain similar to that seen in recent ASD brain pathology studies, and this alteration may likely produce the symptoms by which ASDs are diagnosed. Finally, a review of treatments suggests that ASD patients who undergo protocols to reduce Hg and/or its effects show significant clinical improvements in some cases. In conclusion, the overwhelming preponderance of the evidence favours acceptance that Hg exposure is capable of causing some ASDs.

Seguridad de las vacunas que contienen timerosal: Declaración del Comité Consultivo de Inmunizaciones (CCI) de la Sociedad Chilena de Infectología / Safety of thimerosal containing vaccines. Statement of the Consultive Committee of Immunizations on behalf of the Chilean Infectious Diseases Society

El timerosal es un derivado del mercurio utilizado desde 1930 como preservante de vacunas. En las últimas décadas ha sido cuestionada su seguridad, especialmente por la posibilidad de toxicidad neurológica. La revisión de varios estudios realizados en niños que recibieron vacunas que contienen timerosal y la posición de organismos de expertos internacionales en relación al uso de este compuesto en vacunas, permite al Comité Consultivo de Inmunizaciones concluir que no existe evidencia de eventos adversos en lactantes o niños por exposición al timerosal contenido en vacunas rutinarias y, por lo tanto, no habría razón para modificar las actuales prácticas de inmunización en Chile.

Thimerosal is a mercury derivative included in vaccines since 1930 with the aim to prevent microbial contamination. During the last decades, the use of thimerosal has been questioned, specifically because of a potential association with neurotoxicity. After a thorough review of published studies on pediatric use of thimerosal-containing vaccines, and of position papers from international expert groups, the Consultive Committee of Immunizations of the Chilean Society of Infectious Diseases concludes that there is no solid evidence of adverse events associated with the use of thimerosal containing vaccines in infants and children. Therefore, a change in current vaccine practices refererred to thimerosal-containing vaccines is not justified in Chile.

Measles, mumps, rubella (MMR) vaccine.

MMR is a live attenuated vaccine. Indian children show almost 90% seroconversion against measles and rubella and 90% against mumps. Several adverse effects have been reported. Epidemiological studies do not support a causative link between MMR and autism, IBD or GBS. There is an association between the Urabe strain of mumps vaccine and viral meningitis. Vaccine associated thrombocytopenia has been reported. Severe hypersensitivity reactions occur, mainly due to the gelatin component. Outbreaks of measles occur in areas of high measles vaccine coverage, when susceptible individuals accumulate. A second dose is given mainly to vaccinate those who missed the first dose or had primary vaccine failure, rather than to boost waning antibody levels. The possibility or eradication of mumps with a second dose of mumps vaccine is being considered.