Abstract:
:The US Environmental Protection Agency's ToxCast program has generated toxicity data for thousands of chemicals but does not adequately assess potential neurotoxicity. Networks of neurons grown on microelectrode arrays (MEAs) offer an efficient approach to screen compounds for neuroactivity and distinguish between compound effects on firing, bursting, and connectivity patterns. Previously, single concentrations of the ToxCast Phase II library were screened for effects on mean firing rate (MFR) in rat primary cortical networks. Here, we expand this approach by retesting 384 of those compounds (including 222 active in the previous screen) in concentration-response across 43 network activity parameters to evaluate neural network function. Using hierarchical clustering and machine learning methods on the full suite of chemical-parameter response data, we identified 15 network activity parameters crucial in characterizing activity of 237 compounds that were response actives ("hits"). Recognized neurotoxic compounds in this network function assay were often more potent compared to other ToxCast assays. Of these chemical-parameter responses, we identified three k-means clusters of chemical-parameter activity (i.e., multivariate MEA response patterns). Next, we evaluated the MEA clusters for enrichment of chemical features using a subset of ToxPrint chemotypes, revealing chemical structural features that distinguished the MEA clusters. Finally, we assessed distribution of neurotoxicants with known pharmacology within the clusters and found that compounds segregated differentially. Collectively, these results demonstrate that multivariate MEA activity patterns can efficiently screen for diverse chemical activities relevant to neurotoxicity, and that response patterns may have predictive value related to chemical structural features.
journal_name
Arch Toxicoljournal_title
Archives of toxicologyauthors
Kosnik MB,Strickland JD,Marvel SW,Wallis DJ,Wallace K,Richard AM,Reif DM,Shafer TJdoi
10.1007/s00204-019-02636-xsubject
Has Abstractpub_date
2020-02-01 00:00:00pages
469-484issue
2eissn
0340-5761issn
1432-0738pii
10.1007/s00204-019-02636-xjournal_volume
94pub_type
杂志文章abstract::A number of industrial chemicals and therapeutic agents cause liver tumors in rats and mice by activating the nuclear receptor peroxisome proliferator-activated receptor α (PPARα). The molecular and cellular events by which PPARα activators induce rodent hepatocarcinogenesis have been extensively studied elucidating a...
journal_title:Archives of toxicology
pub_type: 杂志文章,评审
doi:10.1007/s00204-017-2094-7
更新日期:2018-01-01 00:00:00
abstract::Organotin compounds such as tributyltin (TBT) and triphenyltin can induce diabetes and insulin resistance. However, the development of diabetes caused by organotins and its underlying mechanisms remain unclear. In the present study, male KM mice were orally administered with TBT (0.5, 5, and 50 μg/kg) once every 3 day...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-017-1961-6
更新日期:2017-10-01 00:00:00
abstract::The effects of diabetes on cytochrome P450 (CYP)-dependent drug metabolizing enzymes are yet to be clarified. The most widely used animals in these studies have been rats, and information on the effects of diabetes on rabbit liver drug metabolizing enzymes have been unavailable until now. In this study, for the first ...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-005-0654-8
更新日期:2005-08-01 00:00:00
abstract::Delta 9-THC at the dose of 1 mg/kg/die was administered subcutaneously in growing rats, from the second to the 30th day of life. A statistically significant myeloid hyperplasia was demonstrated, which persisted up to 4 months after the end of the treatment, together with significant blood granulocytosis. ...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00353318
更新日期:1975-10-20 00:00:00
abstract::Occupational and environmental asbestos exposure is the main determinant of malignant pleural mesothelioma (MPM), however, the mechanisms by which its fibres contribute to cell toxicity and transformation are not completely clear. Aberrant DNA methylation is a common event in cancer but epigenetic modifications involv...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-018-2179-y
更新日期:2018-05-01 00:00:00
abstract::Platinum coordination complexes (PtCx) are potent against several types of cancer but are often nephrotoxic. With a view to developing a PtCx nephrotoxicity model, the toxicity of cisplatin (cDDP), transplatin (tDDP) and carboplatin (CBDCA) was studied in primary cultures of rabbit proximal tubule (RPT) cells and in t...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF01973705
更新日期:1993-01-01 00:00:00
abstract::In case of mycotoxin contaminations, food and feedstuff are usually contaminated by more than one toxin. However toxicological data concerning the effects of mycotoxin combinations are sparse. The intestinal epithelium is the first barrier against food contaminants and this constantly renewing organ is particularly se...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-014-1309-4
更新日期:2015-08-01 00:00:00
abstract::To clarify whether oxidative stress is involved in the development of hepatocellular preneoplastic foci induced by fenofibrate (FF), a peroxisome proliferator-activated receptor alpha agonist, male F344/N rats were fed a diet containing 6,000, 3,000, or 0 ppm of FF for 13 weeks after N-diethylnitrosamine initiation. T...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-007-0278-2
更新日期:2008-09-01 00:00:00
abstract::Aspergillus versicolor and A. flavus are primary colonizers in damp dwellings, and they produce sterigmatocystin (ST) and aflatoxin B1 (AFB(1)), respectively. These hepatotoxic and carcinogenic mycotoxins and their precursors and derivates possess a furofuran ring, which has proven responsible for their toxicity. The ...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-012-0871-x
更新日期:2012-10-01 00:00:00
abstract::Metabolism of isobutene (2-methylpropene) in rats (Sprague Dawley) and mice (B6C3F1) follows kinetics according to Michaelis-Menten. The maximal metabolic elimination rates are 340 mumol/kg/h for rats and 560 mumol/kg/h for mice. The atmospheric concentration at which Vmax/2 is reached is 1200 ppm for rats and 1800 pp...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF02034934
更新日期:1991-01-01 00:00:00
abstract::Hexamoll® DINCH® (diisononyl-cyclohexane-1,2-dicarboxylate) is a new high molecular weight plasticizer and a non-aromatic phthalate substitute. In this follow-up study, we further investigated the extensive oxidative metabolism of Hexamoll® DINCH® after oral dosage of 50 mg to three male volunteers (0.552-0.606 mg/kg ...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-016-1688-9
更新日期:2017-01-01 00:00:00
abstract::The ethylene oxide adduct formed on the N-terminal valine in haemoglobin was investigated as a biological monitor of tobacco smoke intake. The modified method developed for the determination of the hydroxyethylvaline adduct (HOEtVal) involved reaction of globin with pentafluorophenyl isothiocyanate, extraction of the ...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00332482
更新日期:1988-01-01 00:00:00
abstract::Rats were exposed to black tea (2.5% w/v) as their sole drinking liquid for either 1 day or 1 month, while controls were maintained on water. After this treatment period, all animals received a single oral dose IQ (2-amino-3-methylimidazo-[4,5-f]quinoline), and urine was collected for 48 h. Mutagenic activity of the u...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-004-0562-3
更新日期:2004-08-01 00:00:00
abstract::Several structurally different metal chelating agents were screened for their relative efficacy in counteracting acute manganese intoxication in mice. Polyaminocarboxylic acids with nitrogen and oxygen as metal binding sites were more effective than certain sulfhydryl chelating agents and common drugs in preventing mo...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00569233
更新日期:1982-05-01 00:00:00
abstract::A new strategy for the evaluation of mixtures is presented. The mixture used was the organic extract of diesel exhaust particles (DEP). After extraction with dichloromethane (DCM), the crude extract was fractionated according to polarity into five fractions: aliphatic hydrocarbons, polycyclic aromatic hydrocarbons (PA...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s002040050392
更新日期:1997-01-01 00:00:00
abstract::Regarding the cancer risk assessment of acrylamide (AA) it is of basic interest to know, as to what amount of the absorbed AA is metabolized to glycidamide (GA) in humans, compared to what has been observed in laboratory animals. GA is suspected of being the ultimate carcinogenic metabolite of AA. From experiments wit...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-008-0296-8
更新日期:2008-10-01 00:00:00
abstract::The present study was designed to evaluate the possible protective effects of 3,3'-diselenodipropionic acid (DSePA), a potent radioprotector, against oxidative organ damage induced by whole body γ-irradiation and explore its mechanistic effects. The mice were subjected to whole body γ-irradiation at 5 Gy for the detec...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-011-0687-0
更新日期:2011-11-01 00:00:00
abstract::The possibility that the exposure of the embryo to certain chemical substances can lead to behavioral disturbances is known from human epidemiological studies, e.g., in chronic poisoning with mercury and ethanol. Therefore, efforts are made to develop toxicological techniques with which new behavioral teratogens can b...
journal_title:Archives of toxicology
pub_type: 杂志文章,评审
doi:10.1007/BF00310480
更新日期:1981-09-01 00:00:00
abstract::Prudhoe Bay crude oil (PBCO) and its aliphatic, aromatic and heterocyclic fractions were tested on the developing chick embryo for (i) embryotoxicity (ii) their ability to induce hepatic and renal cytochrome P450 levels as well as hepatic, renal and pulmonary aryl hydrocarbon hydroxylase activities. On the basis of it...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00302389
更新日期:1987-08-01 00:00:00
abstract::Sulfur mustard (SM) is a bifunctional alkylating agent. Its primary toxic consequence is severe skin damage with blisters, occurring after skin contact. These vesicant properties of SM have been linked to cell death of proliferating keratinocytes in the basal layer of the skin. Catalytic activation of the nuclear enzy...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-007-0265-7
更新日期:2008-07-01 00:00:00
abstract::The neurotoxicity of "ecstasy" (3,4-methylenedioxymethamphetamine, MDMA) is thought to involve hepatic metabolism, though its real contribution is not completely understood. Most in vitro neurotoxicity studies concern isolated exposures of MDMA or its metabolites, at high concentrations, not considering their mixture,...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-013-1120-7
更新日期:2014-02-01 00:00:00
abstract::Cisplatin and its derivatives are widely used chemotherapeutic drugs for cancer treatment. However, they have debilitating side effects in normal tissues and induce ototoxicity, neurotoxicity, and nephrotoxicity. In kidneys, cisplatin preferentially accumulates in renal tubular cells causing tubular cell injury and de...
journal_title:Archives of toxicology
pub_type: 杂志文章,评审
doi:10.1007/s00204-015-1633-3
更新日期:2015-12-01 00:00:00
abstract::Renal papillary necrosis (RPN) was induced in Fischer 344 (F344) rats (n = 4) using 2-bromoethanamine hydrobromide (BEA) dosed at 150 mg/kg, and in multimammate desert mice (Mastomys natalensis) at 150 and 250 mg/kg (n = 4 per group). Control rats and Mastomys were dosed with 0.9% saline (n = 4 per group). Urine was c...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF02733668
更新日期:1995-01-01 00:00:00
abstract::The toxicity of 60 micrograms/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) given IP in corn oil/5% acetone was examined in male Sprague-Dawley rats adapted to 25 degrees C or 4 degrees C ambient temperature. Cold exposure significantly reduced mean time to death and tended to increase mortality. Body weight at the ti...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00290540
更新日期:1986-12-01 00:00:00
abstract::Effects of the oxime HI-6, unrelated to reactivation of acetylcholinesterase (AChE), on field potentials in the dentate gyrus of the rat hippocampus following AChE inhibition, were investigated both in vitro and in vivo. In hippocampal slices, AChE inhibition decreased the perforant path evoked population spike amplit...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s002040050146
更新日期:1994-01-01 00:00:00
abstract::Environmental carcinogens-induced lung cancer and potential mechanisms have attracted widespread attention. Currently, microRNAs (miRNAs) have been recognized as key players in development of cancer, among which guide strand of miRNA has been well documented rather than its passenger strand (miRNA*). Our previous stud...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-015-1551-4
更新日期:2016-05-01 00:00:00
abstract::Capillary gas chromatography coupled to mass spectrometry was employed to quantify ethylmorphine in biological fluids and tissues in a death attributed to oral ethylmorphine ingestion. The femoral blood concentration of the drug was 488 ng/ml. Hair analysis revealed the individual's drug abuse pattern, particularly th...
journal_title:Archives of toxicology
pub_type: 信件
doi:10.1007/s002040050057
更新日期:1994-01-01 00:00:00
abstract::To investigate the effect of long term hashish use on T-lymphocytes we have measured the incorporation of 14C-thymidine by peripheral blood lymphocytes, unstimulated and stimulated by phytohemagglutinin, as well as the proportion and number of E-rosettes in 12 healthy male chronic users of the drug before and after a ...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF01891963
更新日期:1978-04-27 00:00:00
abstract::Polyclonal antibodies raised toward a debrisoquine 4-hydroxylating cytochrome P-450 species purified from rat liver (P-450UT-A) were used to determine which monooxygenase reactions are linked to debrisoquine hydroxylation in human liver. Anti P-450UT-A did not inhibit the oxidation of dimethylnitrosamine, morphine, di...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00296955
更新日期:1987-01-01 00:00:00
abstract::Cadmium (Cd), an occupational and environmental pollutant, induces nephrotoxicity by primarily damaging renal proximal tubular cells. In this study, we hypothesized that pyroptosis, a caspase-1-dependent inflammatory programmed cell death mechanism, mediates Cd-induced nephrotoxicity. Human proximal tubular epithelial...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-019-02415-8
更新日期:2019-04-01 00:00:00