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1.
Environ Sci Technol ; 57(48): 19202-19213, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-37931007

RESUMO

We assessed phthalate-hormone associations in 382 pregnant women of the new-generation SEPAGES cohort (2014-2017, France) using improved exposure and outcome assessments. Metabolites from seven phthalate compounds and the replacement di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) were measured in within-subject pools of repeated urine samples collected at the second and third pregnancy trimesters (≈21 samples/trimester). Metabolites from five steroid hormones were measured in maternal hair samples collected at delivery, reflecting cumulative levels over the previous weeks to months. Adjusted linear regression and Bayesian weighted quantile sum (BWQS) mixture models were performed. Each doubling in third-trimester urinary mono-benzyl phthalate (MBzP) concentrations was associated with an average increase of 13.3% (95% CI: 2.65, 24.9) for ∑cortisol, 10.0% (95% CI: 0.26, 20.7) for ∑cortisone, 17.3% (95% CI: 1.67, 35.4) for 11-dehydrocorticosterone, and 16.2% (95% CI: 2.20, 32.1) for testosterone, together with a suggestive 10.5% (95% CI: -1.57, 24.1) increase in progesterone levels. Each doubling in second-trimester urinary di-isononyl phthalate (DiNP) concentrations was inversely associated with testosterone levels (-11.6%; 95% CI: -21.6, -0.31). For most hormones, a nonsignificant trend toward a positive phthalate mixture effect was observed in the third but not in the second trimester. Our study showed that exposure to some phthalate metabolites, especially MBzP, may affect adrenal and reproductive hormone levels during pregnancy.


Assuntos
Poluentes Ambientais , Ácidos Ftálicos , Efeitos Tardios da Exposição Pré-Natal , Humanos , Feminino , Gravidez , Teorema de Bayes , Ácidos Ftálicos/metabolismo , Esteroides , Testosterona , Cabelo/metabolismo , Exposição Ambiental , Exposição Materna
2.
Environ Res ; 228: 115788, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37004856

RESUMO

Health effects of endocrine disrupting chemicals (EDCs) are challenging to detect in the general population. Omics technologies become increasingly common to identify early biological changes before the apparition of clinical symptoms, to explore toxic mechanisms and to increase biological plausibility of epidemiological associations. This scoping review systematically summarises the application of omics in epidemiological studies assessing EDCs-associated biological effects to identify potential gaps and priorities for future research. Ninety-eight human studies (2004-2021) were identified through database searches (PubMed, Scopus) and citation chaining and focused on phthalates (34 studies), phenols (19) and PFASs (17), while PAHs (12) and recently-used pesticides (3) were less studied. The sample sizes ranged from 10 to 12,476 (median = 159), involving non-pregnant adults (38), pregnant women (11), children/adolescents (15) or both latter populations studied together (23). Several studies included occupational workers (10) and/or highly exposed groups (11) focusing on PAHs, PFASs and pesticides, while studies on phenols and phthalates were performed in the general population only. Analysed omics layers included metabolic profiles (30, including 14 targeted analyses), miRNA (13), gene expression (11), DNA methylation (8), microbiome (5) and proteins (3). Twenty-one studies implemented targeted multi-assays focusing on clinical routine blood lipid traits, oxidative stress or hormones. Overall, DNA methylation and gene expression associations with EDCs did not overlap across studies, while some EDC-associated metabolite groups, such as carnitines, nucleotides and amino acids in untargeted metabolomic studies, and oxidative stress markers in targeted studies, were consistent across studies. Studies had common limitations such as small sample sizes, cross-sectional designs and single sampling for exposure biomonitoring. In conclusion, there is a growing body of evidence evaluating the early biological responses to exposure to EDCs. This review points to a need for larger longitudinal studies, wider coverage of exposures and biomarkers, replication studies and standardisation of research methods and reporting.


Assuntos
Disruptores Endócrinos , Fluorocarbonos , Praguicidas , Criança , Adulto , Humanos , Gravidez , Feminino , Adolescente , Disruptores Endócrinos/toxicidade , Estudos Transversais , Fenóis/toxicidade
3.
Epidemiology ; 33(5): 616-623, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35700189

RESUMO

BACKGROUND: Some synthetic phenols alter pathways involved in fetal development. Despite their high within-subject temporal variability, earlier studies relied on spot urine samples to assess pregnancy exposure. In this study, we examined associations between prenatal phenol exposure and fetal growth. METHODS: We measured concentrations of two bisphenols, four parabens, benzophenone-3, and triclosan in 478 pregnant women in two weekly pools of 21 samples each, collected at 18 and 34 gestational weeks. We used adjusted linear regressions to study associations between phenol concentrations and growth outcomes assessed twice during pregnancy and at birth. RESULTS: Benzophenone-3 was positively associated with all ultrasound growth parameters in at least one time point, in males but not females. In females, butylparaben was negatively associated with third-trimester abdominal circumference and weight at birth. We observed isolated associations for triclosan (negative) and for methylparaben and bisphenol S (positive) and late pregnancy fetal growth. CONCLUSIONS: Our results suggest associations between prenatal exposure to phenols and fetal growth. Benzophenone-3 was the exposure most consistently (positively) associated across all growth parameters.


Assuntos
Triclosan , Peso ao Nascer , Feminino , Desenvolvimento Fetal , Humanos , Recém-Nascido , Masculino , Exposição Materna/efeitos adversos , Fenol , Fenóis/toxicidade , Fenóis/urina , Gravidez , Triclosan/efeitos adversos
4.
Hum Mol Genet ; 25(18): 3887-3907, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27466189

RESUMO

Cyclin-dependent kinase-like 5 (CDKL5) is a Ser/Thr protein kinase predominantly expressed in the brain. Mutations of the CDKL5 gene lead to CDKL5 disorder, a neurodevelopmental pathology that shares several features with Rett Syndrome and is characterized by severe intellectual disability. The phosphorylation targets of CDKL5 are largely unknown, which hampers the discovery of therapeutic strategies for improving the neurological phenotype due to CDKL5 mutations. Here, we show that the histone deacetylase 4 (HDAC4) is a direct phosphorylation target of CDKL5 and that CDKL5-dependent phosphorylation promotes HDAC4 cytoplasmic retention. Nuclear HDAC4 binds to chromatin as well as to MEF2A transcription factor, leading to histone deacetylation and altered neuronal gene expression. By using a Cdkl5 knockout (Cdkl5 -/Y) mouse model, we found that hypophosphorylated HDAC4 translocates to the nucleus of neural precursor cells, thereby reducing histone 3 acetylation. This effect was reverted by re-expression of CDKL5 or by inhibition of HDAC4 activity through the HDAC4 inhibitor LMK235. In Cdkl5 -/Y mice treated with LMK235, defective survival and maturation of neuronal precursor cells and hippocampus-dependent memory were fully normalized. These results demonstrate a critical role of HDAC4 in the neurodevelopmental alterations due to CDKL5 mutations and suggest the possibility of HDAC4-targeted pharmacological interventions.


Assuntos
Histona Desacetilases/biossíntese , Deficiência Intelectual/genética , Proteínas Serina-Treonina Quinases/genética , Síndrome de Rett/genética , Espasmos Infantis/genética , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Síndromes Epilépticas , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Hipocampo/patologia , Histona Desacetilases/efeitos dos fármacos , Histona Desacetilases/genética , Humanos , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/fisiopatologia , Fatores de Transcrição MEF2/genética , Camundongos , Camundongos Knockout , Mutação , Células-Tronco Neurais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fosforilação , Síndrome de Rett/tratamento farmacológico , Síndrome de Rett/patologia , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/patologia
5.
Environ Int ; 186: 108584, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38513557

RESUMO

BACKGROUND: Most previous studies investigating the associations between prenatal exposure to phthalates and fetal growth relied on measurements of phthalate metabolites at a single time point. They also focused on weight at birth without assessing growth over pregnancy, preventing the identification of potential periods of fetal vulnerability. We examined the associations between pregnancy urinary phthalate metabolites and fetal growth outcomes measured twice during pregnancy and at birth. METHODS: For 484 pregnant women, we assessed 13 phthalate and two 1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH) metabolite concentrations from two within-subject weekly pools of up to 21 urine samples (median of 18 and 34 gestational weeks, respectively). Fetal biparietal diameter, femur length, head and abdominal circumferences were measured during two routine pregnancy follow-up ultrasonographies (median 22 and 32 gestational weeks, respectively) and estimated fetal weight (EFW) was calculated. Newborn weight, length, and head circumference were measured at birth. Associations between phthalate/DINCH metabolite and growth parameters were investigated using adjusted linear regression and Bayesian kernel machine regression models. RESULTS: Detection rates were above 99 % for all phthalate/DINCH metabolites. While no association was observed with birth measurements, mono-iso-butyl phthalate (MiBP) and mono-n-butyl phthalate (MnBP) were positively associated with most fetal growth parameters measured at the second trimester. Specifically, MiBP was positively associated with biparietal diameter, head and abdominal circumferences, while MnBP was positively associated with EFW, head and abdominal circumferences, with stronger associations among males. Pregnancy MnBP was positively associated with biparietal diameter and femur length at third trimester. Mixture of phthalate/DINCH metabolites was positively associated with EFW at second trimester. CONCLUSIONS: In this pregnancy cohort using repeated urine samples to assess exposure, MiBP and MnBP were associated with increased fetal growth parameters. Further investigation on the effects of phthalates on child health would be relevant for expanding current knowledge on their long-term effects.


Assuntos
Desenvolvimento Fetal , Exposição Materna , Ácidos Ftálicos , Humanos , Ácidos Ftálicos/urina , Feminino , Gravidez , Desenvolvimento Fetal/efeitos dos fármacos , Adulto , Estudos de Coortes , Poluentes Ambientais/urina , Masculino , Recém-Nascido , Adulto Jovem , Peso ao Nascer/efeitos dos fármacos
6.
Environ Int ; 189: 108763, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38824843

RESUMO

BACKGROUND: Endocrine disrupting compounds (EDCs) such as phthalates and phenols can affect placental functioning and fetal health, potentially via epigenetic modifications. We investigated the associations between pregnancy exposure to synthetic phenols and phthalates estimated from repeated urine sampling and genome wide placental DNA methylation. METHODS: The study is based on 387 women with placental DNA methylation assessed with Infinium MethylationEPIC arrays and with 7 phenols, 13 phthalates, and two non-phthalate plasticizer metabolites measured in pools of urine samples collected twice during pregnancy. We conducted an exploratory analysis on individual CpGs (EWAS) and differentially methylated regions (DMRs) as well as a candidate analysis focusing on 20 previously identified CpGs. Sex-stratified analyses were also performed. RESULTS: In the exploratory analysis, when both sexes were studied together no association was observed in the EWAS. In the sex-stratified analysis, 114 individual CpGs (68 in males, 46 in females) were differentially methylated, encompassing 74 genes (36 for males and 38 for females). We additionally identified 28 DMRs in the entire cohort, 40 for females and 42 for males. Associations were mostly positive (for DMRs: 93% positive associations in the entire cohort, 60% in the sex-stratified analysis), with the exception of several associations for bisphenols and DINCH metabolites that were negative. Biomarkers associated with most DMRs were parabens, DEHP, and DiNP metabolite concentrations. Some DMRs encompassed imprinted genes including APC (associated with parabens and DiNP metabolites), GNAS (bisphenols), ZIM2;PEG3;MIMT1 (parabens, monoethyl phthalate), and SGCE;PEG10 (parabens, DINCH metabolites). Terms related to adiposity, lipid and glucose metabolism, and cardiovascular function were among the enriched phenotypes associated with differentially methylated CpGs. The candidate analysis identified one CpG mapping to imprinted LGALS8 gene, negatively associated with ethylparaben. CONCLUSIONS: By combining improved exposure assessment and extensive placental epigenome coverage, we identified several novel genes associated with the exposure, possibly in a sex-specific manner.


Assuntos
Metilação de DNA , Disruptores Endócrinos , Epigênese Genética , Exposição Materna , Fenóis , Ácidos Ftálicos , Placenta , Humanos , Metilação de DNA/efeitos dos fármacos , Feminino , Gravidez , Placenta/metabolismo , Placenta/efeitos dos fármacos , Adulto , Masculino , Ilhas de CpG , Poluentes Ambientais
7.
Environ Pollut ; 335: 122197, 2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-37481027

RESUMO

A previous study reported positive associations of maternal urinary concentrations of triclosan, a synthetic phenol with widespread exposure in the general population, with placental DNA methylation of male fetuses. Given the high number of comparisons performed in -omic research, further studies were needed to validate and extend on these findings. Using a cohort of male and female fetuses with repeated maternal urine samples to assess exposure, we studied the associations between triclosan and placental DNA methylation. We assessed triclosan concentrations in two pools of 21 urine samples collected among 395 women from the SEPAGES cohort. We used Infinium Methylation EPIC arrays to measure DNA methylation in placental biopsies collected at delivery. We performed a candidate study restricted to a set of candidate CpGs (n = 500) identified in a previous work as well as an exploratory epigenome-wide association study to investigate the associations between triclosan and differentially methylated probes and regions. Analyses were conducted on the whole population and stratified by child's sex. Mediation analysis was performed to test whether heterogeneity of placental tissue may mediate the observed associations. In the candidate approach, we confirmed 18 triclosan-associated genes when both sexes were considered. After stratification for child's sex, triclosan was associated with 72 genes in females and three in males. Most of the associations were positive and several CpGs mapped to imprinted genes: FBRSL1, KCNQ1, RHOBTB3, and SMOC1. A mediation effect by placental tissue heterogeneity was identified for most of the observed associations. In the exploratory analysis, we identified a few isolated associations in the sex-stratified analysis. In line with a previous study on male placentas, our approach revealed several positive associations between triclosan exposure and placental DNA methylation. Several identified loci mapped to imprinted genes.


Assuntos
Efeitos Tardios da Exposição Pré-Natal , Triclosan , Criança , Humanos , Feminino , Gravidez , Masculino , Placenta/metabolismo , Metilação de DNA , Triclosan/toxicidade , Triclosan/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo
8.
Environ Int ; 160: 107054, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35032864

RESUMO

BACKGROUND: Exposure to phthalates during pregnancy may alter DNA methylation in the placenta, a crucial organ for the growth and development of the fetus. OBJECTIVES: We studied associations between urinary concentrations of phthalate biomarkers during pregnancy and placental DNA methylation. METHODS: We measured concentrations of 11 phthalate metabolites in maternal spot urine samples collected between 22 and 29 gestational weeks in 202 pregnant women. We analyzed DNA methylation levels in placental tissue (fetal side) collected at delivery. We first investigated changes in global DNA methylation of repetitive elements Alu and LINE-1. We then performed an adjusted epigenome-wide association study using IlluminaHM450 BeadChips and identified differentially methylated regions (DMRs) associated with phthalate exposure. RESULTS: Monobenzyl phthalate concentration was inversely associated with placental methylation of Alu repeats. Moreover, all phthalate biomarkers except for monocarboxy-iso-octyl phthalate and mono(2-ethyl-5-hydroxyhexyl) phthalate were associated with at least one DMR. All but three DMRs showed increased DNA methylation with increased phthalate exposure. The largest identified DMR (22 CpGs) was positively associated with monocarboxy-iso-nonyl phthalate and encompassed heat shock proteins (HSPA1A, HSPA1L). The remaining DMRs encompassed transcription factors and nucleotide exchange factors, among other genes. CONCLUSIONS: This is the first description of genome-wide modifications of placental DNA methylation in association with pregnancy exposure to phthalates. Our results suggest epigenetic mechanisms by which exposure to these compounds could affect fetal development. Of interest, four identified DMRs had been previously associated with maternal smoking, which may suggest particular sensitivity of these genomic regions to the effect of environmental contaminants.


Assuntos
Metilação de DNA , Ácidos Ftálicos , Epigenoma , Feminino , Humanos , Masculino , Exposição Materna/efeitos adversos , Ácidos Ftálicos/metabolismo , Ácidos Ftálicos/toxicidade , Placenta/metabolismo , Gravidez
9.
Environ Pollut ; 290: 118024, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34523531

RESUMO

In utero exposure to environmental chemicals, such as synthetic phenols, may alter DNA methylation in different tissues, including placenta - a critical organ for fetal development. We studied associations between prenatal urinary biomarker concentrations of synthetic phenols and placental DNA methylation. Our study involved 202 mother-son pairs from the French EDEN cohort. Nine phenols were measured in spot urine samples collected between 22 and 29 gestational weeks. We performed DNA methylation analysis of the fetal side of placental tissues using the IlluminaHM450 BeadChips. We evaluated methylation changes of individual CpGs in an adjusted epigenome-wide association study (EWAS) and identified differentially methylated regions (DMRs). We performed mediation analysis to test whether placental tissue heterogeneity mediated the association between urinary phenol concentrations and DNA methylation. We identified 46 significant DMRs (≥5 CpGs) associated with triclosan (37 DMRs), 2,4-dichlorophenol (3), benzophenone-3 (3), methyl- (2) and propylparaben (1). All but 2 DMRs were positively associated with phenol concentrations. Out of the 46 identified DMRs, 7 (6 for triclosan) encompassed imprinted genes (APC, FOXG1, GNAS, GNASAS, MIR886, PEG10, SGCE), which represented a significant enrichment. Other identified DMRs encompassed genes encoding proteins responsible for cell signaling, transmembrane transport, cell adhesion, inflammatory, apoptotic and immunological response, genes encoding transcription factors, histones, tumor suppressors, genes involved in tumorigenesis and several cancer risk biomarkers. Mediation analysis suggested that placental cell heterogeneity may partly explain these associations. This is the first study describing the genome-wide modifications of placental DNA methylation associated with pregnancy exposure to synthetic phenols or their precursors. Our results suggest that cell heterogeneity might mediate the effects of triclosan exposure on placental DNA methylation. Additionally, the enrichment of imprinted genes within the DMRs suggests mechanisms by which certain exposures, mainly to triclosan, could affect fetal development.


Assuntos
Metilação de DNA , Epigenoma , Feminino , Histonas/metabolismo , Humanos , Lactente , Masculino , Fenóis/metabolismo , Placenta/metabolismo , Gravidez
10.
Sci Total Environ ; 763: 144115, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33422710

RESUMO

BACKGROUND: Studies looking at associations between environmental chemicals and child behaviour usually consider only one exposure or family of exposures. OBJECTIVE: This study explores associations between prenatal exposure to a wide range of environmental chemicals and child behaviour. METHODS: We studied 708 mother-child pairs from five European cohorts recruited in 2003-2009. We assessed 47 exposure biomarkers from eight chemical exposure families in maternal blood or urine collected during pregnancy. We used the Strengths and Difficulties Questionnaire (SDQ) to evaluate child behaviour between three and seven years of age. We assessed associations of SDQ scores with exposures using an adjusted least absolute shrinkage and selection operator (LASSO) considering all exposures simultaneously and an adjusted exposome-wide association study (ExWAS) considering each exposure independently. RESULTS: LASSO selected only copper (Cu) as associated with externalizing behaviour. In the ExWAS, bisphenol A [BPA, incidence rate ratio (IRR): 1.06, 95% confidence interval (95%CI): 1.01;1.12] and mono-n-butyl phthalate (MnBP, IRR: 1.06, 95%CI: 1.00;1.13) were associated with greater risk of externalizing behaviour problems. Cu (IRR: 0.90, 95%CI: 0.82;0.98), perfluoroundecanoate (PFUnDA, IRR: 0.92, 95%CI: 0.84;0.99) and organochlorine compounds (OCs) were associated with lower risk of externalizing behaviour problems, however the associations with OCs were mainly seen among women with insufficient weight gain during pregnancy. Internalizing score worsen in association with exposure to diethyl thiophosphate (DETP, IRR: 1.11, 95%CI: 1.00;1.24) but the effect was driven by the smallest cohort. Internalizing score improved with increased concentration of perfluorooctane sulfonate (PFOS, IRR: 0.92, 95%CI: 0.85;1.00), however the association was driven by the two smallest cohorts with the lowest PFOS concentrations. DISCUSSION: This study added evidence on deleterious effects of prenatal exposure to BPA and MnBP on child behaviour. Other associations should be interpreted cautiously since they were not consistent with previous studies or they have not been studied extensively.


Assuntos
Poluentes Ambientais , Efeitos Tardios da Exposição Pré-Natal , Criança , Comportamento Infantil , Estudos de Coortes , Exposição Ambiental , Expossoma , Feminino , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/epidemiologia
11.
Learn Mem ; 16(7): 439-51, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19553382

RESUMO

The role of adult brain neurogenesis (generating new neurons) in learning and memory appears to be quite firmly established in spite of some criticism and lack of understanding of what the new neurons serve the brain for. Also, the few experiments showing that blocking adult neurogenesis causes learning deficits used irradiation and various drugs known for their side effects and the results obtained vary greatly. We used a novel approach, cyclin D2 knockout mice (D2 KO mice), specifically lacking adult brain neurogenesis to verify its importance in learning and memory. D2 KO mice and their wild-type siblings were tested in several behavioral paradigms, including those in which the role of adult neurogenesis has been postulated. D2 KO mice showed no impairment in sensorimotor tests, with only sensory impairment in an olfaction-dependent task. However, D2 KO mice showed proper procedural learning as well as learning in context (including remote memory), cue, and trace fear conditioning, Morris water maze, novel object recognition test, and in a multifunctional behavioral system-IntelliCages. D2 KO mice also demonstrated correct reversal learning. Our results suggest that adult brain neurogenesis is not obligatory in learning, including the kinds of learning where the role of adult neurogenesis has previously been strongly suggested.


Assuntos
Ciclinas/deficiência , Hipocampo/citologia , Memória/fisiologia , Neurogênese/genética , Neurônios/fisiologia , Análise de Variância , Animais , Ansiedade/genética , Bromodesoxiuridina/metabolismo , Condicionamento Clássico/fisiologia , Condicionamento Operante/fisiologia , Ciclina D2 , Proteínas do Domínio Duplacortina , Comportamento Exploratório/fisiologia , Medo/fisiologia , Locomoção/genética , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Neuropeptídeos/metabolismo , Transtornos do Olfato/genética , Desempenho Psicomotor/fisiologia
12.
Dis Model Mech ; 8(10): 1323-37, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26398945

RESUMO

Ototoxicity is known to cause permanent loss of vestibule function through degeneration of sensory hair cells (HCs). However, functional recovery has been reported during washout after chronic ototoxicity, although the mechanisms underlying this reversible dysfunction are unknown. Here, we study this question in rats chronically exposed to the ototoxic compound 3,3'-iminodipropionitrile (IDPN). Pronounced alterations in vestibular function appeared before significant loss of HCs or stereociliary coalescence became evident by ultrastructural analyses. This early dysfunction was fully reversible if the exposure was terminated promptly. In cristae and utricles, the distinct junctions formed between type I HCs (HCI) and calyx endings were completely dismantled at these early stages of reversible dysfunction, and completely rebuilt during washout. Immunohistochemical observations revealed loss and recovery of the junction proteins CASPR1 and tenascin-C and RT-PCR indicated that their loss was not due to decreased gene expression. KCNQ4 was mislocalized during intoxication and recovered control-like localization after washout. At early stages of the intoxication, the calyces could be classified as showing intact or lost junctions, indicating that calyceal junction dismantlement is triggered on a calyx-by-calyx basis. Chronic toxicity also altered the presence of ribeye, PSD-95 and GluA2 puncta in the calyces. These synaptic alterations varied between the two types of calyx endings (formed by calyx-only or dimorphic afferents) and some persisted at the end of the washout period. The present data reveal new forms of plasticity of the calyx endings in adult mammals, including a robust capacity for rebuilding the calyceal junction. These findings contribute to a better understanding of the phenomena involved in progressive vestibular dysfunction and its potential recovery during and after ototoxic exposure.


Assuntos
Células Ciliadas Vestibulares/patologia , Sinapses/metabolismo , Animais , Doença Crônica , Epitélio/metabolismo , Epitélio/patologia , Epitélio/ultraestrutura , Células Ciliadas Vestibulares/ultraestrutura , Canais de Potássio KCNQ/metabolismo , Masculino , Nitrilas , Ratos Long-Evans , Estereocílios/patologia , Tenascina/metabolismo
13.
J Psychiatr Res ; 56: 106-11, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24931850

RESUMO

The neurogenesis hypothesis of major depression has two main facets. One states that the illness results from decreased neurogenesis while the other claims that the very functioning of antidepressants depends on increased neurogenesis. In order to verify the latter, we have used cyclin D2 knockout mice (cD2 KO mice), known to have virtually no adult brain neurogenesis, and we demonstrate that these mice successfully respond to chronic fluoxetine. After unpredictable chronic mild stress, mutant mice showed depression-like behavior in forced swim test, which was eliminated with chronic fluoxetine treatment, despite its lack of impact on adult hippocampal neurogenesis in cD2 KO mice. Our results suggest that new neurons are not indispensable for the action of antidepressants such as fluoxetine. Using forced swim test and tail suspension test, we also did not observe depression-like behavior in control cD2 KO mice, which argues against the link between decreased adult brain neurogenesis and major depression.


Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Neurogênese/fisiologia , Animais , Bromodesoxiuridina , Doença Crônica , Ciclina D2/genética , Ciclina D2/metabolismo , Depressão/fisiopatologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Imuno-Histoquímica , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Testes Neuropsicológicos , Natação , Incerteza
14.
Behav Brain Res ; 227(1): 159-66, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22101301

RESUMO

The exact function of the adult brain neurogenesis remains elusive, although it has been suggested to play a role in learning and memory processes. In our studies, we employed cyclin D2 gene knockout (cD2 KO) mice showing impaired neurogenesis as well as decreased hippocampal size. However, irrespectively of the genetic background of cD2 KO mice, this phenotype resulted in neither deficits in the hippocampal-dependent learning ability nor the memory formation. In the present study, cD2 KO mice and control littermates were subjected to hippocampal-dependent behavioral tests with little or no learning component. The knockout mice showed significant impairment in such species-typical behaviors as nest construction, digging, and marble burying. They were building none or poorer nests, digging less robustly, and burying fewer marbles than control mice. Such impairments were previously described, e.g., in animals with hippocampal lesions. Moreover, cD2 KO animals were also more active in the open field and automated motility chamber as well as showed increased explorative behavior in IntelliCage. Both increased motility and explorative behaviors were previously observed in hippocampally lesioned animals. Finally, cD2 KO mice showed normal sucrose preference, however starting from the second exposure to the sweetened solution, while control animals displayed a strong preference immediately. Presented results suggest that either morphological abnormalities of the hippocampal formation or adult brain neurogenesis impairment (or both) alter hippocampal-dependent behaviors of mutant mice without influencing learning abilities. These results may also suggest that adult brain neurogenesis is involved in species-typical behaviors.


Assuntos
Encéfalo/fisiologia , Ciclina D2/deficiência , Hipocampo/fisiologia , Deficiências da Aprendizagem/genética , Neurogênese/genética , Análise de Variância , Animais , Bromodesoxiuridina/metabolismo , Contagem de Células , Condicionamento Psicológico , Sinais (Psicologia) , Ingestão de Líquidos/genética , Comportamento Exploratório/fisiologia , Medo/fisiologia , Preferências Alimentares/fisiologia , Asseio Animal/fisiologia , Deficiências da Aprendizagem/fisiopatologia , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/genética , Comportamento de Nidação/fisiologia , Tamanho do Órgão/genética , Tempo de Reação/genética
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