Developmental EDC exposures alter hippocampal lipids and metabolites linked to long-term behavioral impairments in rats.

Metabolism is critical for neurodevelopment, yet the mechanisms by which endocrine-disrupting chemicals (EDCs) contribute to neurodevelopmental disorders remain poorly defined. Using a rat model, we investigated hippocampal metabolomic responses at postnatal day 6 following maternal exposure to six structurally diverse EDCs (bisphenol F, permethrin, butyl benzyl phthalate, triphenyl phosphate, perfluorooctane sulfonic acid, and DINCH) from pre-mating through lactation. Targeted steroid, thyroid, and neurosteroid hormones, neurotransmitters, and untargeted lipidomics were profiled to map disrupted pathways. The analysis revealed sex-specific, chemical-specific, and shared metabolic signatures of developmental neurotoxicity. Key affected endpoints across chemicals included corticosterone, pregnenolone sulfate, and N-acylethanolamine lipids, confirming hormonal disruption while uncovering novel non-EATS (estrogen, androgen, thyroid, and steroidogenesis) pathways and mechanisms of action. These findings provide new insights into EDC-mediated disruption of hippocampal development and identify potential molecular biomarkers that may support future mechanistic research and chemical risk assessment.

Changes in urinary excretion of phthalates, phthalate substitutes, bisphenols and other polychlorinated and phenolic substances in young Danish men; 2009-2017.

Unraveling DINCH - Induced hepatotoxicity mechanisms via network toxicology and molecular docking with experimental validation.

Temporal development of behavioral impairments in rats following locus coeruleus lesion induced by 6-hydroxydopamine: Involvement of β3-adrenergic receptors

Integrated enzymatic, transcriptomic, and metabolite identification insights into the degradation of diverse endocrine-disrupting compounds by Pleurotus ostreatus GEMB-PO1.

A range of chemicals with various levels of activity as actual or potential endocrine disrupters have been evaluated for activity in the peripubertal male rat assay. The chemicals studied included anti-androgens (vinclozolin), cyproterone acetate, flutamide, 2, 2-bis(4-chlorophenyl)-1,1-dichloroethylene (DDE), metabolic modulators (anastrazole, finasteride, ketoconazole) and oestrogens (butyl benzyl phthalate (BBP), methoxychlor, bisphenol A (BPA), diethylstilboestrol (DES)), the suspected anti-androgen dibutyl phthalate (DBP) and the non-oestrogen fenitrothion. Dosing extended over postnatal days (pnd) 22-35, 36-50, 36-55 and 22-35, with recovery to pnd 55 or 22-55. The endpoints studied were changes in the weights of testes, epididymides, seminal vesicles and prostate. Changes in body weight and the weights of the liver and kidney were also monitored. In some experiments changes in the day of prepuce separation (PPS) were also determined. Only BBP and BPA were inactive in all the assays conducted. Changes in the weight of reproductive tissues provided a sensitive indicator of activity for the remaining chemicals with the exception of DDE, for which higher dose levels could have been used. However, none of the curtailed periods of exposure were able to detect all of the agents. Diethyl stilboestrol, and to a lesser extent DBP and DDE, delayed PPS when exposure occurred over the period pnd 22-55. A complex dependence of the day of PPS on the period of exposure and the body weight of the test animals was observed, and caution is recommended when assessing this endpoint in the presence of reductions in body weight. It is concluded that reproductive tissue weight changes in the peripubertal male have shown sensitivity to a range of biochemical modulators, oestrogens and anti-androgens, and that as such the assay warrants further evaluation. Measurement of delays in PPS may be of value in cases of large delays, but delays of 1-2 days will be difficult to interpret with confidence. The present results are discussed within the context of the sexually mature male rat assay described by O'Connor and the castrated male rat assay described by Hershberger, both of which are the subject of current international study. It is concluded that a decision on the usefulness of the peripubertal male rat assay must await the generation of further data on each of these three assays. There is an urgent need for international agreement on a list of reference endocrine disrupters and their active dose levels, with which to validate individual endocrine disruption assays and batteries of assays.

Protective effect of propranolol and nadolol on social defeat-induced behavioral impairments in rats

Temporal lobe epilepsy is a widespread chronic disorder that manifests as spontaneous seizures and is often characterized by refractoriness to drug treatment. Temporal lobe epilepsy can be caused by a primary brain injury; therefore, the prevention of epileptogenesis after a primary event is considered one of the best treatment options. However, a preventive treatment for epilepsy still does not exist. Neuroinflammation is directly involved in epileptogenesis and neurodegeneration, leading to the epileptic condition and cognitive decline. In the present study, we aimed to clarify the effect of treatment with a recombinant form of the Interleukin-1 receptor antagonist (anakinra) on epileptogenesis and behavioral impairments in rats using the lithium–pilocarpine model. We found that anakinra administration during the latent phase of the model significantly suppressed the duration and frequency of spontaneous recurrent seizures in the chronic phase. Moreover, anakinra administration prevented some behavioral impairments, including motor hyperactivity and disturbances in social interactions, during both the latent and chronic periods. Histological analysis revealed that anakinra administration decreased neuronal loss in the CA1 and CA3 areas of the hippocampus but did not prevent astro- and microgliosis. The treatment increased the expression level of the solute carrier family 1 member 2 gene (Slc1a2, encoding excitatory amino acid transporter 2 (EAAT2)) in the hippocampus, potentially leading to a neuroprotective effect. However, the increased gene expression of proinflammatory cytokine genes (Interleukin-1β (Il1b) and tumor necrosis factor α (Tnfa)) and astroglial marker genes (glial fibrillary acidic protein (Gfap) and inositol 1,4,5-trisphosphate receptor type 2 (Itpr2)) in experimental rats was not affected by anakinra treatment. Thus, our data demonstrate that the administration of anakinra during epileptogenesis has some beneficial disease-modifying effects.

Biomarkers of phthalates and alternative plasticizers in the Flemish Environment and Health Study (FLEHS IV): Time trends and exposure assessment.

Benzyl butyl phthalate (BBP) triggers the migration and invasion of hemangioma cells via upregulation of Zeb1

1969-P: Moderate Dosage of Benzyl Butyl Phthalate Synergizes the High-Fat Diet Induced Diabesity in Male Mice

BackgroundAlzheimer's disease (AD) is the leading cause of dementia worldwide, yet effective therapies for this neurodegenerative disorder remain scarce. Epimedium, a herb with a history of thousands of years in traditional Chinese medicine, exhibits diverse biological activities and holds potential therapeutic effects against Alzheimer's disease. However, studies on its modern pharmacological mechanisms remain relatively limited.MethodsTCMSP and PubChem were used to retrieve Epimedium constituents, and SwissTargetPrediction was used to predict potential targets. GeneCards, OMIM, and GEO databases were used to identify targets associated with AD. The AD model was established by intragastric administration of AlCl3 combined with intraperitoneal injection of D-galactose, with the normal saline group serving as controls. Cognitive function was assessed by the Morris water maze, and histopathological changes were observed by H&E staining. ELISA detected IL-1β and TNF-α levels, and qRT-PCR detected KAT2B, NF-κB, IL-1β, and TNF-α expression.ResultsWe identified 172 key targets, with KAT2B and ACACB determined as core genes through transcriptomic screening. In vivo studies showed that Epimedium significantly ameliorated cognitive deficits and alleviated histopathological damage in hippocampal neurons. Furthermore, Epimedium suppressed neuroinflammation by reducing IL-1β and TNF-α levels and modulated the mRNA expression of key targets (KAT2B, NF-κB) in the hippocampus.ConclusionEpimedium improves pathological alterations in the hippocampal tissue and alleviates cognitive and behavioral impairments in rats by modulating neuroinflammation through KAT2B, thereby providing a scientific basis for its potential application and development as a therapeutic agent.

Ultrasound gel as an unrecognized source of exposure to phthalates and phenols among pregnant women undergoing routine scan.

Exposure to endocrine-disrupting chemicals (EDCs) increases the risk of obesity and related cardiometabolic disorders. Bisphenol F (BPF), an EDC that affects the thyroid, reproductive health, and immune cell function, is a common substitute for bisphenol A (BPA) and is used in manufacturing polycarbonates and consumer products. EDC exposure effects likely vary in the population, indicating gene x EDC interactions; however, genetic risk factors interacting with EDCs are unknown. In vivo toxicity studies performed in isogenic or genetically undefined outbred models may obscure or overemphasize exposure outcomes and do not address significant variability in population-level effects. These limitations can be avoided by studying the N/NIH Heterogeneous Stock (HS) rats, an outbred population derived from eight founder inbred strains readily amenable to genetic study. We hypothesize that BPF-induced metabolic disease has underlying genetic risk, which can be identified using HS rats and their founding inbred strains. We previously demonstrated that post-wean BPF exposure increases body growth and adiposity in male HS rats. We evaluated the metabolic impact of post-weaning BPF exposure in BUF/Mna rats, one of the HS-founding inbred strains that has genetic risks for thymic hyperplasia and focal segmental glomerulosclerosis. Weanling littermate pairs of male and female BUF rats were randomly exposed to either vehicle (0.1% EtOH) or 1.125 mg BPF/L in 0.1% EtOH for 10 weeks in drinking water. Metabolic measures, tissues, urine, and feces were taken. Males exposed to BPF did not differ from vehicle control. In females, BPF exposure did not change body composition or body weight gain; however, examination of two metabolic cage time points found that BPF females had decreased energy efficiency (weight gained/calorie absorbed) compared to vehicle control. There was an energy balance disruption in BPF females with increased 24 hr distance traveled and decreased resting metabolic rate compared to vehicle females. Also, BPF females had increased thymus and kidney mass compared to vehicle females. Our preliminary data indicate that post-wean BPF exposure affects immune, metabolic, and renal phenotypes in BUF rats in a sex-specific manner. These results suggest that BPF exacerbates inherent organ dysfunction in a genetically susceptible HS-founding inbred strain. This work supports BPF exposure as a metabolic disease risk factor and indicates that the HS rat will be a useful model for dissecting gene x BPF interactions on metabolic health. NIH T32 GM008629, NIH P30 ES005605, NIH R24 OD024617. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Benzyl butyl phthalate induces epigenetic stress to enhance adipogenesis in mesenchymal stem cells