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JAMA Network Open Jun 2024Concerns exist about teratogenic and long-term neurodevelopmental outcomes of paternal use of valproate during spermatogenesis.
IMPORTANCE
Concerns exist about teratogenic and long-term neurodevelopmental outcomes of paternal use of valproate during spermatogenesis.
OBJECTIVE
To evaluate the association between paternal use of valproate during spermatogenesis and offspring risk of congenital malformations and neurodevelopmental disorders.
DESIGN, SETTING, AND PARTICIPANTS
This nationwide cohort study included 1 235 353 singletons born in Denmark between January 1, 1997, and December 31, 2017, identified in the Medical Birth Register; 1336 children had fathers who had filled prescriptions for valproate during spermatogenesis. Congenital malformations were identified in the first year of life and neurodevelopmental disorders were identified from 1 year of age until December 31, 2018. Statistical analysis was performed March 2024.
EXPOSURES
Paternal valproate exposure was defined as fathers who filled 1 or more prescriptions for valproate immediately before or during the time of spermatogenesis (ie, 3 months prior to conception).
MAIN OUTCOMES AND MEASURES
Children with major congenital malformations in the first year of life and with neurodevelopmental disorders before death or end of follow-up were identified in Danish health registers. Log-binomial regression was used to estimate adjusted relative risks (ARRs) of congenital malformations, and Cox proportional hazards regression was used to estimate adjusted hazards ratios (AHRs) of neurodevelopmental disorders, adjusted for relevant confounders.
RESULTS
Among 1 235 353 live births (634 415 boys [51.4%] and 600 938 girls [48.6%]), 1336 children (0.1%) had fathers who filled prescriptions for valproate during spermatogenesis. The median follow-up was 10.1 years (IQR, 5.1-14.8 years) for valproate-exposed children and 10.3 years (IQR, 5.2-15.6 years) for valproate-unexposed children. A total of 43 903 children (3.6%) received a diagnosis of major congenital malformations in the first year of life, and 51 633 children (4.2%) received a diagnosis of neurodevelopmental disorders during follow-up. When comparing the risk among valproate-exposed children with that among unexposed children, the ARR of major congenital malformations was 0.89 (95% CI, 0.67-1.18), the AHR of neurodevelopmental disorders was 1.10 (95% CI, 0.88-1.37), and the AHR of autism spectrum disorder was 0.92 (95% CI, 0.65-1.30). In analyses addressing the robustness of the findings (ie, dose-response analyses, sibling analyses, analyses restricted to children of fathers with epilepsy, analyses that used children with paternal lamotrigine exposure as active comparator, and analyses that used children with paternal exposure to valproate only before spermatogenesis as a negative control exposure), there still was no increased risk of any of the included end points.
CONCLUSIONS AND RELEVANCE
In all analyses based on this large Danish cohort study, results suggest that exposure to valproate during spermatogenesis was not associated with offspring risk of congenital malformations or neurodevelopmental disorders, including autism spectrum disorder.
Topics: Humans; Valproic Acid; Male; Denmark; Spermatogenesis; Female; Neurodevelopmental Disorders; Infant; Adult; Cohort Studies; Child, Preschool; Child; Paternal Exposure; Anticonvulsants; Registries; Infant, Newborn; Abnormalities, Drug-Induced; Risk Factors; Congenital Abnormalities; Prenatal Exposure Delayed Effects
PubMed: 38833248
DOI: 10.1001/jamanetworkopen.2024.14709 -
IBRO Neuroscience Reports Jun 2024The precise cause of autism spectrum disorder (ASD) is not fully understood. Despite the involvement of glutamatergic dysregulation in autism, the specific contribution...
Effect of intrahippocampal microinjection of VU0155041, a positive allosteric modulator of mGluR4, on long term potentiation in a valproic acid-induced autistic male rat model.
The precise cause of autism spectrum disorder (ASD) is not fully understood. Despite the involvement of glutamatergic dysregulation in autism, the specific contribution of mGlu4 receptors to synaptic plasticity remains unclear. Using the positive allosteric modulator VU0155041, we aimed to restore long-term potentiation (LTP) in the perforant path-dentate gyrus (PP-DG) pathway in VPA-induced autistic rat model. High-frequency stimulation was applied to the PP-DG synapse to induce LTP, while the VU0155041 was administered into the DG. Unexpectedly, VU0155041 failed to alleviate the observed LTP reduction in VPA-exposed rats, further resulting in a significant decrease in population spike LTP. This unexpected outcome prompts discussion on the complex nature of mGlu4 receptor modulation, highlighting potential interference with physiological processes underlying synaptic plasticity.
PubMed: 38832089
DOI: 10.1016/j.ibneur.2024.05.005 -
Andrology Jun 2024Real-world big data studies on drug-reduced male semen quality are few and far between, with most studies based on animal trials, small scale retrospective studies, or a...
BACKGROUND
Real-world big data studies on drug-reduced male semen quality are few and far between, with most studies based on animal trials, small scale retrospective studies, or a limited number of pre-market clinical trials.
METHODS
This study aimed to identify culprit drugs that reduced male semen quality based on the United States Food and Drug Administration adverse event reporting system. The Medical Dictionary for Regulatory Activities preferred terms and standardized Medical Dictionary for Regulatory Activities queries were used to define reduced male semen quality. Adverse events related to drug-reduced male semen quality were then analyzed by disproportionality analysis using the United States Food and Drug Administration adverse event reporting system data between 2004 and 2023.
RESULTS
At the preferred term level, 59 drugs with risk signals were detected to be associated with drug-reduced male semen quality, with the three most frequently reported second-level Anatomical Therapeutic Chemical groups being antineoplastic agents (n = 16, 27.12%), psychoanaleptics (n = 9, 15.25%), and psycholeptics (n = 6, 10.17%). At the standardized Medical Dictionary for Regulatory Activities queries level, the five drugs with the greatest number of cases were finasteride (845 cases, IC = 7.72), dutasteride (163 cases, IC = 7.22), tamsulosin (148 cases, IC= 5.99), testosterone (101 cases, IC= 4.08), and valproic acid (54 cases, IC= 2.44). Additionally, clinical information about drug-reduced male semen quality is absent from the Summary of Product Characteristics of 41 drugs in our study.
CONCLUSIONS
Using the United States Food and Drug Administration adverse event reporting system database, we offer a list of drugs with risk signals for reducing male semen quality. In the future, there is still a need for more studies on drugs whose effects on male semen quality are not fully understood.
PubMed: 38831673
DOI: 10.1111/andr.13668 -
Therapeutic Advances in... 2024This case report examines the possible correlation between the clozapine/norclozapine ratio and the occurrence of constipation and paralytic ileus. We present the case...
This case report examines the possible correlation between the clozapine/norclozapine ratio and the occurrence of constipation and paralytic ileus. We present the case of a 42-year-old patient diagnosed with schizoaffective disorder undergoing clozapine therapy. Despite intensive treatment with clozapine, haloperidol, valproic acid and biweekly electroconvulsive therapy sessions for over a year, florid psychotic symptoms and fluctuating mood swings persisted. Therefore, valproic acid was replaced by carbamazepine, a potent inducer of several CYP450-enzymes. To maintain clozapine plasma levels, fluvoxamine, a CYP1A2-inhibitor, was introduced at a dose of 25 mg before this switch. After addition of carbamazepine, there was a significant decline in clozapine levels, necessitating an increase in fluvoxamine dosage to 50 mg. Five weeks later the patient was admitted to a general hospital with a diagnosis of paralytic ileus. Treatment with enemas proved effective. Drug concentration analysis revealed a 2.5-fold increase in norclozapine levels in the weeks preceding hospital admission, resulting in an inverted clozapine/norclozapine ratio. Treatment with clozapine, carbamazepine and fluvoxamine was continued as the patient demonstrated clinical improvement on carbamazepine. Concurrently, an intensive laxative regimen was initiated. Two weeks later, the patient was readmitted to the general hospital due to suspected paralytic ileus and faecal vomiting, once again displaying an inverted clozapine/norclozapine ratio. We discuss potential mechanisms contributing to the occurrence of the paralytic ileus in this patient, including the antagonism of muscarinic M3 receptors by both clozapine and norclozapine, as well as the agonism of delta-opioid receptors by norclozapine. This case highlights the potential significance of both the clozapine/norclozapine ratio and absolute norclozapine levels as risk factors for constipation and paralytic ileus in patients on clozapine therapy.
PubMed: 38827014
DOI: 10.1177/20451253241255487 -
Brain Research May 2024The contribution of the thalamus to the development and behavioural changes in autism spectrum disorders (ASD), a neurodevelopmental syndrome, remains unclear. The aim...
The contribution of the thalamus to the development and behavioural changes in autism spectrum disorders (ASD), a neurodevelopmental syndrome, remains unclear. The aim of this study was to determine the changes in thalamic volume and cell number in the valproic acid (VPA)-induced ASD model using stereological methods and to clarify the relationship between thalamus and ASD-like behaviour. Ten pregnant rats were administered a single dose (600 mg/kg) of VPA intraperitoneally on G12.5 (VPA group), while five pregnant rats were injected with 5 ml saline (control group). Behavioural tests were performed to determine appropriate subjects and ASD-like behaviours. At P55, the brains of the subjects were removed. The sagittal sections were stained with cresyl violet and toluidine blue. The thalamic and hemispheric volumes with their ratios, the total number of thalamic cells, neurons and non-neuronal cells were calculated using stereological methods. Data were compared using a t-test and a Pearson correlation analysis was performed to examine the relationship between behaviour and stereological outcomes. VPA-treated rats had lower sociability and sociability indexes. There was no difference in social novelty preference and anxiety. The VPA group had larger hemispheric volume, lower thalamic volume, and fewer neurons. The highest percentage decrease was in non-neuronal cells. There was a moderate positive correlation between the number of non-neuronal cells and sociability, thalamic volume and the number of neurons as well as the time spent in the light box. The correlation between behaviour and stereological data suggests that the thalamus is associated with ASD-like behaviour.
PubMed: 38823508
DOI: 10.1016/j.brainres.2024.149047 -
Pakistan Journal of Pharmaceutical... Mar 2024This study assessed the inhibitory effect of sodium valproate (VPA) on apoptosis of cardiomyocytes in lethally scalded rats. The model of a 50% total body surface area...
This study assessed the inhibitory effect of sodium valproate (VPA) on apoptosis of cardiomyocytes in lethally scalded rats. The model of a 50% total body surface area (TBSA) third-degree full-thickness scald was produced, 48 male SD rats were randomly divided into three groups (n = 16), the sham group and the scald group were given an intraperitoneal injection of 0.25ml of saline, the scald +VPA group was given an intraperitoneal injection of VPA (300 mg/kg) after scalded, Each group was subdivided into two subgroups (n=8) according to the two observation time points of 3h and 6h after scald. Apoptotic cardiomyocytes were observed, and myocardial tissue levels of nitric oxide (NO), cysteine protease-3 (caspase-3) activity, hypoxia-inducible factor-1α (HIF-1α), inducible nitric oxide synthase (iNOS), BCL2/adenovirus E1B interacting protein 3 (BNIP3) and caspase-3 protein were measured. Compared with sham scald group, severe scald elevated CK-MB, cardiomyocyte apoptosis rate, caspase-3 activity and protein levels, NO content, and HIF-1α signalling pathway proteins; whereas VPA decreased CK-MB, cardiomyocyte apoptosis rate and inhibited HIF-1α signalling pathway protein expression. In conclusion, these results suggested that VPA inhibited early cardiomyocyte apoptosis and attenuated myocardial injury in lethally scalded rats, which may be related to the regulation of the HIF-1α signalling pathway.
Topics: Animals; Male; Rats; Apoptosis; Burns; Caspase 3; Disease Models, Animal; Hypoxia-Inducible Factor 1, alpha Subunit; Membrane Proteins; Mitochondrial Proteins; Myocytes, Cardiac; Nitric Oxide; Nitric Oxide Synthase Type II; Rats, Sprague-Dawley; Valproic Acid
PubMed: 38822545
DOI: No ID Found -
The British Journal of Dermatology May 2024Recessive dystrophic epidermolysis bullosa (RDEB) is a blistering disease caused by mutations in the gene encoding type VII collagen (C7). RDEB is associated with...
BACKGROUND
Recessive dystrophic epidermolysis bullosa (RDEB) is a blistering disease caused by mutations in the gene encoding type VII collagen (C7). RDEB is associated with fibrosis, which is responsible for severe complications. The phenotypic variability observed in RDEB siblings suggests that epigenetic modifications contribute to disease severity. Identifying epigenetic changes may help to uncover molecular mechanisms underlying RDEB pathogenesis and new therapeutic targets.
OBJECTIVES
To investigate histone acetylation in RDEB skin and to explore histone deacetylase inhibitors (HDACis) as therapeutic molecules capable of counteracting fibrosis and disease progression in RDEB mice.
METHODS
Acetylated histone levels were detected in human skin by immunofluorescence and in RDEB fibroblasts by ELISA. The effects of Givinostat and valproic acid (VPA) on RDEB fibroblast fibrotic behaviour were assessed by collagen-gel contraction assay, Western blot and immunocytofluorescence for α-smooth muscle actin, ELISA for released transforming growth factor-β1 (TGF-β1). RNA-seq was performed in HDACi- and vehicle-treated RDEB fibroblasts. VPA was systemically administered to RDEB mice, and effects on overt phenotype were monitored. Fibrosis was investigated in the skin using histological and immunofluorescence analyses. Eye and tongue defects were examined microscopically. Mass spectrometry proteomics was performed on skin protein extracts from VPA-treated RDEB and control mice.
RESULTS
Histone acetylation decreases in RDEB skin and primary fibroblasts. RDEB fibroblasts treated with HDACis lowered fibrotic traits including contractility, TGF-β1 release, and proliferation. VPA administration to RDEB mice mitigated severe manifestations affecting eyes and paws. These effects were associated with fibrosis inhibition. Proteomic analysis of mouse skin revealed that VPA almost normalised protein sets involved in protein synthesis and immune response, processes linked to the increased susceptibility to cancer and bacterial infections observed in RDEB patients.
CONCLUSIONS
Dysregulated histone acetylation contributes to RDEB pathogenesis by facilitating the progression of fibrosis. Repurposing of HDACi could be considered for disease-modifying treatments of RDEB.
PubMed: 38820176
DOI: 10.1093/bjd/ljae225 -
Biochemical Pharmacology Jul 2024Xenobiotic metabolic reactions in the hepatocyte endoplasmic reticulum (ER) including UDP-glucuronosyltransferase and carboxylesterase play central roles in the...
Xenobiotic metabolic reactions in the hepatocyte endoplasmic reticulum (ER) including UDP-glucuronosyltransferase and carboxylesterase play central roles in the detoxification of medical agents with small- and medium-sized molecules. Although the catalytic sites of these enzymes exist inside of ER, the molecular mechanism for membrane permeation in the ER remains enigmatic. Here, we investigated that organic anion transporter 2 (OAT2) regulates the detoxification reactions of xenobiotic agents including anti-cancer capecitabine and antiviral zidovudine, via the permeation process across the ER membrane in the liver. Pharmacokinetic studies in patients with colorectal cancer revealed that the half-lives of capecitabine in rs2270860 (1324C > T) variants was 1.4 times higher than that in the C/C variants. Moreover, the hydrolysis of capecitabine to 5'-deoxy-5-fluorocytidine in primary cultured human hepatocytes was reduced by OAT2 inhibitor ketoprofen, whereas capecitabine hydrolysis directly assessed in human liver microsomes were not affected. The immunostaining of OAT2 was merged with ER marker calnexin in human liver periportal zone. These results suggested that OAT2 is involved in distribution of capecitabine into ER. Furthermore, we clarified that OAT2 plays an essential role in drug-drug interactions between zidovudine and valproic acid, leading to the alteration in zidovudine exposure to the body. Our findings contribute to mechanistically understanding medical agent detoxification, shedding light on the ER membrane permeation process as xenobiotic metabolic machinery to improve chemical changes in hydrophilic compounds.
Topics: Humans; Endoplasmic Reticulum; Drug Interactions; Hepatocytes; Male; Organic Anion Transporters, Sodium-Independent; Zidovudine; Female; Microsomes, Liver
PubMed: 38815630
DOI: 10.1016/j.bcp.2024.116322 -
Cellular and Molecular Biology... May 2024Periodontal ligament stem cells (PDLSCs) show plasticity towards the adipogenic lineage; however, little has been done on the participation of epigenetic mechanisms....
Periodontal ligament stem cells (PDLSCs) show plasticity towards the adipogenic lineage; however, little has been done on the participation of epigenetic mechanisms. Histone acetylation is a dynamic process, though balanced by histone acetyltransferases (HATs) and histone deacetylases (HDACs) activities. This process can be halted by HDACs inhibitors, such as trichostatin A (TSA) and valproic acid (VPA). This study aimed to determine the role of HDACs class I in adipogenic differentiation of PDL cells. PDLSCs were treated with TSA at concentrations of 100, 200, and 250 nM, or VPA at 1, 4 and 8 mM. Cell viability was assessed using MTT assays. Gene expression of pluripotency markers (NANOG, OCT4, SOX2), HAT genes (p300, GCN5), and HDACs genes (HDAC1-3) was analyzed by RT-qPCR. Adipogenic differentiation was evaluated via oil red O staining, and acetylation of histone H3 lysine 9 (H3K9ac) was examined by Western blot. VPA treatment resulted in a 60% reduction in cell proliferation, compared to a 50% when using TSA. Cell viability was not affected by either inhibitor. Furthermore, both TSA and VPA induced adipogenic differentiation, through an increase in the deposition of lipid droplets and in GCN5 and p300 expression were observed. Western blot analysis showed that TSA increased H3K9ac levels on adipogenic differentiation of PDLSCs. These findings highlight the potential of HDAC inhibitors as a tool for modulating H3K9 acetylation status and thus influencing adipogenic differentiation of PDLCs.
Topics: Humans; Periodontal Ligament; Histone Deacetylase Inhibitors; Adipogenesis; Valproic Acid; Cell Differentiation; Cell Survival; Acetylation; Histone Deacetylases; Hydroxamic Acids; Cells, Cultured; Histones; Cell Proliferation; Stem Cells
PubMed: 38814236
DOI: 10.14715/cmb/2024.70.5.7 -
Frontiers in Behavioral Neuroscience 2024Autism spectrum disorder (ASD) is a group of diseases often characterized by poor sociability and challenges in social communication. The anterior cingulate cortex (ACC)...
INTRODUCTION
Autism spectrum disorder (ASD) is a group of diseases often characterized by poor sociability and challenges in social communication. The anterior cingulate cortex (ACC) is a core brain region for social function. Whether it contributes to the defects of social communication in ASD and whether it could be physiologically modulated to improve social communication have been poorly investigated. This study is aimed at addressing these questions.
METHODS
Fragile X mental retardation 1 (FMR1) mutant and valproic acid (VPA)-induced ASD mice were used. Male-female social interaction was adopted to elicit ultrasonic vocalization (USV). Immunohistochemistry was used to evaluate USV-activated neurons. Optogenetic and precise target transcranial magnetic stimulation (TMS) were utilized to modulate anterior cingulate cortex (ACC) neuronal activity.
RESULTS
In wild-type (WT) mice, USV elicited rapid expression of c-Fos in the excitatory neurons of the left but not the right ACC. Optogenetic inhibition of the left ACC neurons in WT mice effectively suppressed social-induced USV. In - and VPA-induced ASD mice, significantly fewer c-Fos/CaMKII-positive neurons were observed in the left ACC following USV compared to the control. Optogenetic activation of the left ACC neurons in or VPA-pretreated mice significantly increased social activity elicited by USV. Furthermore, precisely stimulating neuronal activity in the left ACC, but not the right ACC, by repeated TMS effectively rescued the USV emission in these ASD mice.
DISCUSSION
The excitatory neurons in the left ACC are responsive to socially elicited USV. Their silence mediates the deficiency of social communication in and VPA-induced ASD mice. Precisely modulating the left ACC neuronal activity by repeated TMS can promote the social communication in and VPA-pretreated mice.
PubMed: 38813469
DOI: 10.3389/fnbeh.2024.1387447