Exposition prénatale aux perturbateurs endocriniens et risque sur le neurodéveloppement : étude de fratries exposées au diéthylstilbestrol

Many endocrine disruptors are found in our environment. They act on hormonal receptors, on their action and synthesis. They may alter neuronal transmission and neuronal formation. A lot of neurodevelopmental diseases have a growing prevalence, raising many questions about a possible association with endocrine disruptors. One of their action mechanisms may be an effect on DNA methylation of the developing brain.Objectives: To study neurodevelopmental characteristics and the epigenetic signature of patients exposed in utero to diethylstilbestrol. To identify differentially methylated regions in neurodevelopmental related genes, which could lead to a psychiatric vulnerability.Materials and Methods: We recruited 75 siblings from 31 families, in which at least one member was exposed in utero to diethylstilbestrol. A psychiatric evaluation was assessed with standardized questionnaires. We used the Infinium HumanMethylation450 BeadChip and analyzed the methylation variations of 411 947 CpG loci.Results: We found clinical differences in non-specific psychiatric symptoms and in neurological soft signs, such as lateralization, associated with the exposure. We found several biological pathways in which methylation modifications were associated to diethylstilbestrol exposure. These pathways are implicated in neurodevelopmental pathways, general metabolism and oncogenesis mostly.Conclusion : Prenatal diethylstilbestrol exposure seems associated with non-specific psychiatric symptoms, lateralization abnormalities and methylation alterations in genes that participate to pathways known to be involved in psychiatric diseases, notably in neurotransmitters signalization.De nombreux perturbateurs endocriniens sont retrouvés dans notre environnement. Ils interfèrent sur l’action des récepteurs hormonaux. Plusieurs travaux argumentent qu’ils altéreraient la formation des réseaux neuronaux. Un parallèle a été évoqué avec l’augmentation de la prévalence des troubles neurodéveloppementaux. Un mécanisme d’action évoqué est un effet sur la méthylation de l’ADN dans le cerveau en maturation.Objectifs : Étudier les caractéristiques neurodéveloppementales et la signature épigénétique des patients exposés in utero au diéthylstilbestrol. Identifier des régions de méthylation différentielles sur des gènes impliqués dans le neurodéveloppement, pouvant mener à une vulnérabilité psychiatrique.Matériels et méthodes: Nous avons recruté 75 frères et sœurs issus de 31 familles dont au moins un membre fut exposé in utero au diéthylstilbestrol. Une évaluation neuropsychiatrique a été réalisée. Nous avons utilisé une puce de méthylation et avons analysé les variations de méthylation de 411 947 CpG.Résultats: Nous avons observé des différences significatives au niveau de symptômes psychiatriques aspécifiques et de signes neurologiques mineurs, tels que la latéralisation, associées à l’exposition. Plusieurs réseaux biologiques présentant des modifications de méthylation sont associés à l’exposition. Ils concernent les fonctions neurodéveloppementales, le métabolisme et l’oncogenèse.Conclusion : L’exposition au diéthylstilbestrol paraît associée à des profils cliniques aspécifiques, à des troubles de la latéralisation, et à des altérations de méthylation au sein de réseaux biologiques spécifiques

1st International Experts' Meeting on Agitation: Conclusions Regarding the Current and Ideal Management Paradigm of Agitation.

Agitation is a heterogeneous concept without a uniformly accepted definition, however, it is generally considered as a state of cognitive and motor hyperactivity characterized by excessive or inappropriate motor or verbal activity with marked emotional arousal. Not only the definition but also other aspects of agitated patients' care are still unsolved and need consensus and improvement. To help the discussion about agitation among experts and improve the identification, management, and treatment of agitation, the 1st International Experts' Meeting on Agitation was held in October 2016 in Madrid. It was attended by 20 experts from Europe and Latin America with broad experience in the clinical management of agitated patients. The present document summarizes the key conclusions of this meeting and highlights the need for an updated protocol of agitation management and treatment, the promotion of education and training among healthcare professionals to improve the care of these patients and the necessity to generate clinical data of agitated episodes

Perinatal Exposure to Environmental Endocrine Disruptors in the Emergence of Neurodevelopmental Psychiatric Diseases: A Systematic Review

Background: Exposure to endocrine disruptors is on the rise, with new compounds regularly incriminated. In animals and humans, this exposure during critical developmental windows has been associated with various developmental abnormalities, including the emergence of psychiatric disorders. We aimed to review the association between perinatal endocrine disruptor exposure and neurodevelopmental disorders in humans, focusing on cognitive and psychiatric disorders. Methods: We performed a systematic review with key words referring to the fields of neurodevelopment and endocrine disruptors. We reviewed 896 titles, choosing studies on the basis of titles and abstracts. We searched through the methodology sections to find perinatal exposure and neurodevelopmental disorders, following the categories indicated in the Diagnostic and Statistic Manual of Mental Disorders (5th edition). References in some studies brought us to a total of 47 studies included here. Results: Convergent studies report an association between exposure to endocrine disruptors and autism spectrum disorder, attention-deficit hyperactivity disorder, global developmental delay, intellectual disability, communication disorders and unspecified neurodevelopmental disorders. Conclusion: Sufficient data exist to report that exposure to some endocrine disruptors is a risk factor for the emergence of neurodevelopmental disorders. Studying endocrine disruptor exposure in humans is still associated with some limits that are difficult to overcome

Abnormalities in one-carbon metabolism in young patients with psychosis

International audienceIntroduction: Folates, the main actors in one-carbon (C1) metabolism, are involved in synthesising monoamines and maintaining genomic stability. Previous studies support the association between C1 metabolism and schizophrenia. The main purpose of this study was to assess the prevalence of plasma folate, and/or vitamin B12 deficiencies and hyperhomocysteinemia in young patients with psychotic disorders. Methods: We included young inpatients (15–30 years old) with psychosis between 2014 and 2017 from Sainte-Anne Hospital in Paris. Plasma folate, vitamin B12 deficiency and homocysteinemia dosages were done at admission. Clinical data were extracted retrospectively, and patients diagnosed with a first-episode psychosis (FEP), schizophrenia, schizoaffective disorder, or persistent delusional disorder were retained for the analysis. Results: Among the 334 inpatients, 188 (56%) had C1 dosages available (135 males; 53 females). From the 188 patients, 32% had a C1 abnormality. This abnormality reached 38% of FEP patients. The most frequent abnormality was folate deficiency: 21% of all patients and 27% of FEP. Lower levels of folates were found in males compared to females (p = 0.02) and were correlated with more severe disorder, as assessed by Clinical Global Impression – Severity (CGI-S; p = 0.009). Antipsychotic dosage was positively associated with B12 levels (p = 0.013) and negatively with homocysteinemia (p = 0.034). Conclusion: One-carbon metabolism anomalies in young patients with psychotic disorders are highly prevalent, reaching almost half of the patients with FEP. Potential protective effects from females and antipsychotics have emerged. These results spotlight the need for new therapeutic prospects, such as folate supplementation, to achieve personalised medical approaches to the early stages of psychotic disorders. Copyrigh

Methylomic changes in individuals with psychosis, prenatally exposed to endocrine disrupting compounds: Lessons from diethylstilbestrol.

In the Western world, between 1940 and 1970, more than 2 million people were exposed in utero to diethylstilbestrol (DES). In exposed individuals, and in their descendants, adverse outcomes have been linked to such exposure, including cancers, genital malformations, and less consistently, psychiatric disorders. We aimed to explore whether prenatal DES exposure would be associated with DNA methylation changes, and whether these epigenetic modifications would be associated with increased risk of psychosis.From 247 individuals born from mothers exposed to DES, we selected 69 siblings from 30 families. In each family, at least one sibling was exposed in utero to DES. We performed a methylome-wide association study using HumanMethylation450 DNA Analysis BeadChip® in peripheral blood. We analyzed methylation changes at individual CpGs or regions in exposed (n = 37) versus unexposed individuals (n = 32). We also compared exposed individuals with (n = 7) and without psychosis (n = 30).There were more individuals with schizophrenia in the DES-exposed group. We found no significant differences between exposed and unexposed individuals with respect to differentially methylated CpGs or regions. The largest difference was in a region near the promoter of an ADAMTS proteoglycanase gene (ADAMTS9). Compared to exposed individuals without psychosis, exposed individuals with psychosis had differential methylation in the region encompassing the gene encoding the zinc finger protein 57 (ZFP57).In utero exposure to DES was not associated with methylation changes at specific CpG or regions. In exposed individuals, however, psychosis was associated with specific methylomic modifications that could impact neurodevelopment and neuroplasticity

Influence of polygenic risk scores for schizophrenia and resilience on the cognition of individuals at-risk for psychosis

International audienceCognitive impairment is a core feature of schizophrenia which precedes the onset of full psychotic symptoms, even in the ultrahigh-risk stage (UHR). Polygenic risk scores (PRS) can be computed for many psychiatric disorders and phenotyping traits, including scores for resilience. We explored the correlations between several PRS and neurocognition in UHR individuals. We included 107 UHR individuals; 29.9% of them converted to psychosis (UHR-C) while 57.0% did not (UHR-NC) during the 1-year follow-up. Cognitive performances were assessed with the Wechsler Adult Intelligence Scale estimating the Intelligence Quotient (IQ), the Trail Making Test, the verbal fluency, the Stroop test, and the Wisconsin card sorting test. Linear regression models were used to test their association with the PRS for schizophrenia, bipolar disorder, major depression, ADHD, cross-disorders, cognitive performance, intelligence, education attainment, and resilience to schizophrenia. UHR-C had a lower IQ than UHR-NC. The PRS for schizophrenia negatively correlated with IQ, while the PRS for cognitive performance and for resilience positively correlated with IQ. PRS for schizophrenia showed a significant correlation with working memory and processing speed indices. PRS for schizophrenia showed a higher effect on IQ in UHR-NC, and UHR-NC with high PRS for schizophrenia had a similar IQ as UHR-C. Conversely, UHR-C with a high PRS for resilience performed as well as UHR-NC. Our findings suggest that cognitive deficits may predate the onset of psychosis. The genetic architecture of schizophrenia seems to impacts the cognition in UHR-NC. Cognition is also mediated by PRS for resilience

Hazard Ratios for Psychiatric Phenotypes in Siblings with and Those without Diethylstilbestrol Exposure.

<p>Hazard Ratios for Psychiatric Phenotypes in Siblings with and Those without Diethylstilbestrol Exposure.</p

DMRs associated with psychosis in exposed individuals.

<p>Top findings (fwer < 0,8, length > 1 base, HLA-DQ and HLA-DRB excluded).</p

DMRs associated with prenatal exposure to DES.

<p>Top findings (fwer < 0,8, length > 1 base, HLA-DQ and HLA-DRB excluded).</p