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PROVIDER: PRJNA1286163 | ENA |
REPOSITORIES: ENA
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Project description:Nafion byproduct 2 (NBP2; CAS: 749836-20-2; Product #: 6164-3-3J; Lot: 512400; SynQuest Laboratories Alachua, FL, USA) is a polyfluoroalkyl ether sulfonic acid that was recently detected in surface water, drinking water, and human serum samples from monitoring studies in North Carolina, USA. We orally exposed pregnant Sprague-Dawley rats to NBP2 from gestation day (GD) 14–18 (0.1–30 mg/kg/d), GD17-21, and GD8 to postnatal day (PND) 2 (0.3–30 mg/kg/d) to characterize maternal, fetal, and postnatal effects. GD14-18 exposures were also conducted with perfluorooctane sulfonate (PFOS) for comparison to NBP2, as well as data previously published for hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX). NBP2 produced stillbirth (30 mg/kg), reduced pup survival shortly after birth (10 mg/kg), and reduced pup body weight (10 mg/kg). Histopathological evaluation identified reduced glycogen stores in newborn pup livers and hepatocyte hypertrophy in maternal livers at ≥ 10 mg/kg. Exposure to NBP2 from GD14-18 reduced maternal serum total T3 and cholesterol concentrations (30 mg/kg). Maternal, fetal, and neonatal liver gene expression was investigated using RT-qPCR pathway arrays, while maternal and fetal livers were also analyzed using TempO-Seq transcriptomic profiling. Overall, there was limited alteration of genes in maternal or F1 livers from NBP2 exposure with significant changes mostly occurring in the top dose group (30 mg/kg) associated with lipid and carbohydrate metabolism. Metabolomic profiling indicated elevated maternal bile acids for NBP2, but not HFPO-DA or PFOS, while all three reduced 3-indolepropionic acid. Maternal and fetal serum and liver NBP2 concentrations were similar to PFOS, but ∼10–30-fold greater than HFPO-DA concentrations at a given maternal oral dose. NBP2 is a developmental toxicant in the rat, producing neonatal mortality, reduced pup body weight, reduced pup liver glycogen, reduced maternal thyroid hormones, and altered maternal and offspring lipid and carbohydrate metabolism similar to other studied PFAS, with oral toxicity for pup loss that is slightly less potent than PFOS but more potent than HFPO-DA.
2022-01-10 | GSE192589 | GEO
Project description:Per- and polyfluoroalkyl substances (PFAS) are persistent pollutants known for their bio-accumulative properties and prevalence in water supplies and household products. Although legacy PFAS, such as perfluorooctanoic acid, are phased out in the U.S. due to public health concerns, a PFAS variant hexafluoropropylene oxide-dimer acid (HFPO-DA) is an emerging replacement. HFPO-DA is a potential neurotoxicant that has been shown to cause dopaminergic neurodegeneration. We investigated the bioaccumulative potential of HFPO-DA and its effects on lifespan, locomotor activity, and brain gene expression in female and male Drosophila melanogaster (fruit flies). Flies were collected less than 4 hours post-eclosion and exposed to 0, 10, 10^2, 10^3, or 10^4 mg/kg/day HFPO-DA. To measure the effect of HFPO-DA on lifespan, surviving flies from each exposure were recorded every 24 hours. Flies were subjected to a negative geotaxis assay at 3, 7, and 14 days of exposure to measure the effects of acute, sub-chronic, and chronic exposures on locomotor ability. To capture HFPO-DA-induced sexually dimorphic gene expression responses in the brain, we sequenced brain-specific mRNA from flies exposed for 3, 7, or 14 days. The Bioconcentration Factor was 0.031 for females, and 0.026 for males. Dose and median lifespan were negatively correlated in both female (R^2 adj = 0.77, p<0.0001) and male flies (R^2 adj = 0.77, p<0.0001). Log-rank Mantel-Cox tests and one-way ANOVAs revealed that median lifespan was reduced in females starting at 10 mg/kg/day and in males starting at 10^2 mg/kg/day (p< 0.01). Acute exposure at 10 mg/kg/day significantly decreased locomotor ability in females (p<0.0001) while acute exposures at 1 mg/kg/day decreased locomotor activity in males (p <0.0001). Among 7500 genes analyzed, pairwise gene expression comparison between controls and treatments identified 2496 differentially expressed genes. While HFPO-DA does not readily bioaccumulate in fruit fly bodies, high-dose exposures have sex-specific effects on lifespan, locomotor ability, and brain gene expression. LOAEL for median lifespan is 10 mg/kg/day in females, and 10^2 mg/kg/day in males. Both locomotor ability and brain gene expression exhibited non-conventional dose-response as seen in other endocrine disrupting chemical exposures.
2022-06-17 | GSE206119 | GEO
Project description:Domoic acid (DA), a potent glutamate agonist, is produced by marine algae and can bioconcentrate in finfish and shellfish. Current regulatory limits constrain environmental exposures to this toxin to 20 ppm in shellfish tissue (~0.075-0.1 mg/kg), but changing environmental conditions are leading to more frequent and longer lasting DA algal blooms. Further, recent studies suggest that chronic DA exposure, at levels below this limit, is associated with deficits in memory in adults. To understand how low-level, chronic exposure to this toxin impacts the limbic system of the brain, the present study used magnetic resonance imaging (MRI) and histopathology to assess changes in the hippocampus, thalamus, fornix, fimbria, and internal capsule in a nonhuman primate model. Twenty-eight adult, female Macaca fascicularis were orally exposed to 0.075 and 0.15 mg/kg/day for up to two years. A subset of these females (n=12) underwent a single, sedated MRI scan in vivo, to assess volumetric and tractography changes in the hippocampus, thalamus, and connecting white matter tracts, and all animals were necropsied to evaluate the cellularity and morphology of the neurons, astrocytes, and microglia in these regions. MRI and histopathology evaluations did not suggest signs of overt neuropathology, but revealed that some animals, especially in the 0.15 mg/kg/day DA exposure group, expressed focal microglia reactions within both white and gray matter structures of the limbic system. These results suggest that chronic exposure to levels of DA near the human regulatory limit does not lead to acute neuropathic effects but may induce microglial responses and promote neuroinflammatory pathways in a nonhuman primate model of contemporary human exposure to DA.
2022-10-04 | GSE163026 | GEO
Project description:Dopaminergic (DA) neurons marked by the dopamine transporter (DAT) have multiple physiological functions and are involved in the regulation of mental and neurological diseases, prompting in-depth studies into their development and functions. This research explores the spatiotemporal proteomic and transcriptomic changes in DAT+ DA neurons within key brain regions involved in DA signaling—the nucleus accumbens (NAc), substantia nigra (SNc), and ventral tegmental area (VTA). Utilizing cutting-edge multi-omics techniques, such as ultrasensitive trace sample proteomics and SMART_x0002_seq2 for transcriptomics, we examine the DA neuronal system at critical postnatal milestones: postnatal day 7 (P7), postnatal day 30 (P30), and postnatal day 60 (P60). The study reveals unique molecular profiles within DA neuron populations, showcasing their varied functional roles and developmental progression. Immunofluorescence mapping illustrates these molecular distributions, validating the quantitative data and highlighting the dynamic molecular structure of DA neurons. Our findings notably highlight a marked increase over time in Aldh1a1 expression, an essential enzyme for retinoic acid production, suggesting its evolving role in neuronal development and specific functions. This comprehensive analysis offers a profound molecular perspective on DAT+ DA neuron development, enhancing our understanding of their functional diversity and potential relevance in DA-related diseases.
2025-04-16 | GSE285556 | GEO
Project description:Purpose: to identify specific miRNAs as biomarkers associated with immunosuppressive treatment response in MG patients. Methods: Blood miRNome profiles of 15 responder and 15 non-responder MG patients by miRNA-seq using Illumina NextSeq 500 sequencing. Raw data were de-multiplexed and FASTQ files for each sample were generated using the bcl2fastq software. FASTQ data were checked using the FastQC tool. After mapping the data and counting to relevant entries in miRBase 20 (http://www.mirbase.org/), the numbers of known microRNAs was calculated.For statistical analysis, along with TPM normalization, the trimmed mean of M-values (TMM) normalization method was used. Validation was perfomed using TaqMan Advanced real-time PCR on microRNA array cards. Results: An average of 9.98 million reads was obtained per sample. We identified 41 statistically significant differentially expressed miRNAs (logFoldChange from +1.371 to -1.439, p < 0.05), including 18 miRNAs up-regulated and 23 miRNAs down-regulated in non-responder versus responder MG patients. 23 miRNAs were selected for validation. Among them, three miRNAs were significantly decreased in non-responder versus responder patients, whereas two showed an opposite trend. Conclusions: We identified a blood miRNA signature associated with drug responsiveness in MG patients, that could represent a valuable tool for therapeutic follow-up in MG.
2020-05-23 | GSE131703 | GEO