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Article ; Online: Influence of Methylene Blue or Dimethyl Sulfoxide on Larval Zebrafish Development and Behavior.

Hedge, Joan M / Hunter, Deborah L / Sanders, Erik / Jarema, Kimberly A / Olin, Jeanene K / Britton, Katy N / Lowery, Morgan / Knapp, Bridget R / Padilla, Stephanie / Hill, Bridgett N

Zebrafish

2023 Volume 20, Issue 4, Page(s) 132–145

Abstract: The use of larval zebrafish developmental testing and assessment, specifically larval zebrafish locomotor activity, has been recognized as a higher throughput testing strategy to identify developmentally toxic and neurotoxic chemicals. There are, however, ...

Abstract	The use of larval zebrafish developmental testing and assessment, specifically larval zebrafish locomotor activity, has been recognized as a higher throughput testing strategy to identify developmentally toxic and neurotoxic chemicals. There are, however, no standardized protocols for this type of assay, which could result in confounding variables being overlooked. Two chemicals commonly employed during early-life stage zebrafish assays, methylene blue (antifungal agent) and dimethyl sulfoxide (DMSO, a commonly used vehicle) have been reported to affect the morphology and behavior of freshwater fish. In this study, we conducted developmental toxicity (morphology) and neurotoxicity (behavior) assessments of commonly employed concentrations for both chemicals (0.6-10.0 μM methylene blue; 0.3%-1.0% v/v DMSO). A light-dark transition behavioral testing paradigm was applied to morphologically normal, 6 days postfertilization (dpf) zebrafish larvae kept at 26°C. Additionally, an acute DMSO challenge was administered based on early-life stage zebrafish assays typically used in this research area. Results from developmental toxicity screens were similar between both chemicals with no morphological abnormalities detected at any of the concentrations tested. However, neurodevelopmental results were mixed between the two chemicals of interest. Methylene blue resulted in no behavioral changes up to the highest concentration tested, 10.0 μM. By contrast, DMSO altered larval behavior following developmental exposure at concentrations as low as 0.5% (v/v) and exhibited differential concentration-response patterns in the light and dark photoperiods. These results indicate that developmental DMSO exposure can affect larval zebrafish locomotor activity at routinely used concentrations in developmental neurotoxicity assessments, whereas methylene blue does not appear to be developmentally or neurodevelopmentally toxic to larval zebrafish at routinely used concentrations. These results also highlight the importance of understanding the influence of experimental conditions on larval zebrafish locomotor activity that may ultimately confound the interpretation of results.
MeSH term(s)	Animals ; Zebrafish/physiology ; Dimethyl Sulfoxide/toxicity ; Methylene Blue/toxicity ; Behavior, Animal ; Locomotion ; Larva
Chemical Substances	Dimethyl Sulfoxide (YOW8V9698H) ; Methylene Blue (T42P99266K)
Language	English
Publishing date	2023-07-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2156020-1
ISSN	1557-8542 ; 1545-8547
ISSN (online)	1557-8542
ISSN	1545-8547
DOI	10.1089/zeb.2023.0017
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Article ; Online: Inconsistencies in variable reporting and methods in larval zebrafish behavioral assays.

Hill, Bridgett N / Britton, Katy N / Hunter, Deborah L / Olin, Jeanene K / Lowery, Morgan / Hedge, Joan M / Knapp, Bridget R / Jarema, Kimberly A / Rowson, Zachary / Padilla, Stephanie

Neurotoxicology and teratology

2023 Volume 96, Page(s) 107163

Abstract: New approaches in developmental neurotoxicity (DNT) screening are needed due to the tens of thousands of chemicals requiring hazard assessments. Zebrafish (Danio rerio) are an alternative vertebrate model for DNT testing, but without a standardized ... ...

Abstract	New approaches in developmental neurotoxicity (DNT) screening are needed due to the tens of thousands of chemicals requiring hazard assessments. Zebrafish (Danio rerio) are an alternative vertebrate model for DNT testing, but without a standardized protocol for larval behavioral assays, comparison of results among laboratories is challenging. To evaluate the congruence of protocols across laboratories, we conducted a literature review of DNT studies focusing on larval zebrafish behavior assays and cataloged experimental design consistencies. Our review focused on 51 unique method variables in publications where chemical exposure occurred in early development and subsequent larval locomotor evaluation focused on assays that included a light/dark photoperiod transition. We initially identified 94 publications, but only 31 exclusively met our inclusion criteria which focused on parameters that are important to an assay employed by our laboratory. No publication reported 100% of the targeted variables; only 51 to 86% of those variables were reported in the reviewed publications, with some aspects of the experimental design consistent among laboratories. However, no protocol was exactly the same for any two publications. Many of these variables had more than one parameter/design reported, highlighting the inconsistencies among methods. Overall, there is not only a strong need for the development of a standardized testing protocol for larval zebrafish locomotor assays, but there is also a need for a standardized protocol for reporting experimental variables in the literature. Here we include an extensive guideline checklist for conducting larval zebrafish developmental behavior assays.
MeSH term(s)	Animals ; Zebrafish ; Larva ; Motor Activity ; Behavior, Animal ; Research Design
Language	English
Publishing date	2023-02-08
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	639165-5
ISSN	1872-9738 ; 0892-0362
ISSN (online)	1872-9738
ISSN	0892-0362
DOI	10.1016/j.ntt.2023.107163
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Zs.A 1626: Show issues

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Article ; Online: Neurotoxicological and thyroid evaluations of rats developmentally exposed to tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) and tris(2-chloro-2-ethyl)phosphate (TCEP).

Moser, Virginia C / Phillips, Pamela M / Hedge, Joan M / McDaniel, Katherine L

Neurotoxicology and teratology

2015 Volume 52, Issue Pt B, Page(s) 236–247

Abstract: Tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) and tris(2-chloro-2-ethyl)phosphate (TCEP) are organophosphorous flame retardants with widespread usage and human exposures through food, inhalation, and dust ingestion. They have been detected in human ... ...

Abstract	Tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) and tris(2-chloro-2-ethyl)phosphate (TCEP) are organophosphorous flame retardants with widespread usage and human exposures through food, inhalation, and dust ingestion. They have been detected in human tissues including urine and breast milk. Reports of disrupted neural growth in vitro, abnormal development in larval zebrafish, and altered thyroid hormones in several species have raised concern for neurodevelopmental toxicity. This is especially the case for TDCIPP, which is more potent and has more activity in those assays than does TCEP. We evaluated the potential for developmental neurotoxicity of TDCIPP and TCEP in a mammalian model. Pregnant Long-Evans rats were administered TDCIPP (15, 50, or 150 mg/kg/day) or TCEP (12, 40, 90 mg/kg/day) via oral gavage from gestational day 10 to weaning. Corn oil was the vehicle control in both studies. Body weight and righting reflex development were monitored in all pups. A subset of offspring at culling and weaning, and dams at weaning, were sacrificed for serum and organ collection for measurement of brain, liver, and thyroid weights, serum thyroid levels, and serum and brain acetylcholinesterase activities. Brain weights were also measured in a group of adult TDCIPP-treated offspring. One male and one female from each litter were allocated for behavioral testing at several ages: standard locomotor activity (preweaning, postweaning, adults), locomotor activity including a lighting change mid-way (postweaning, adults), elevated zero maze (postweaning, adults), functional observational battery (FOB; postweaning, adults), and Morris water maze (place learning, reference and working memory; adults). Neither chemical produced changes in maternal body weight or serum thyroid hormones, but relative liver weight was increased at the high doses of both TDCIPP and TCEP. In offspring, there were no effects on viability, litter size, or birth weight. With TDCIPP, absolute liver weights were lower at weaning and weight gain was lower in the high-dose offspring until about two months of age. Thyroid hormones and brain weights were not altered and acetylcholinesterase (both brain and serum) was not inhibited by either chemical. TDCIPP-treated offspring showed slight differences in floating in the water maze, hindlimb grip strength, and altered activity habituation, whereas TCEP-treated rats showed differences in quadrant time (probe) and middle-zone preference in the water maze. Regarding these few changes, the effects were minimal, mostly not related to dose, and did not appear treatment-related or biologically significant. Overall, these data do not support the potential for thyrotoxicity or developmental neurotoxicity produced by TDCIPP or TCEP.
MeSH term(s)	Acetylcholinesterase/metabolism ; Animals ; Body Weight/drug effects ; Female ; Flame Retardants/toxicity ; Male ; Maternal Exposure/adverse effects ; Maze Learning/drug effects ; Motor Activity/drug effects ; Organ Size/drug effects ; Organophosphorus Compounds/toxicity ; Phosphines/toxicity ; Pregnancy ; Prenatal Exposure Delayed Effects/chemically induced ; Rats ; Rats, Long-Evans ; Reflex/drug effects ; Thyroxine/metabolism ; Triiodothyronine/metabolism
Chemical Substances	Flame Retardants ; Organophosphorus Compounds ; Phosphines ; Triiodothyronine (06LU7C9H1V) ; tris(2-carboxyethyl)phosphine (22OAC2MO2S) ; tris(1,3-dichloro-2-propyl)phosphate (B1PRV4G0T0) ; Acetylcholinesterase (EC 3.1.1.7) ; Thyroxine (Q51BO43MG4)
Language	English
Publishing date	2015-11
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	639165-5
ISSN	1872-9738 ; 0892-0362
ISSN (online)	1872-9738
ISSN	0892-0362
DOI	10.1016/j.ntt.2015.08.004
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Article: Lack of alterations in thyroid hormones following exposure to polybrominated diphenyl ether 47 during a period of rapid brain development in mice.

Gee, Jillian R / Hedge, Joan M / Moser, Virginia C

Drug and chemical toxicology

2008 Volume 31, Issue 2, Page(s) 245–254

Abstract: Thyroid alterations have been shown to occur following exposure to polybrominated diphenyl ether (PBDE) mixtures, possibly indicating that disruptions in thyroid hormone levels may underlie behavior deficits observed in animals following postnatal PBDE ... ...

Abstract	Thyroid alterations have been shown to occur following exposure to polybrominated diphenyl ether (PBDE) mixtures, possibly indicating that disruptions in thyroid hormone levels may underlie behavior deficits observed in animals following postnatal PBDE exposure. This study determined whether acute postnatal exposure to PBDE-47 would alter thyroid hormones. Mice were dosed with PBDE-47 on postnatal day 10, and serum collected either 1, 5, or 10 days after the dose. No effect was observed on thyroxine and triiodothyronine levels at any age examined. This suggests that the neurological abnormalities reported in mice exposed to PBDE-47 are not due to acute changes in circulating thyroid hormones at these observed periods.
MeSH term(s)	Animals ; Behavior, Animal/drug effects ; Body Weight/drug effects ; Brain/drug effects ; Brain/growth & development ; Halogenated Diphenyl Ethers ; Hydrocarbons, Brominated/toxicity ; Male ; Mice ; Mice, Inbred C57BL ; Phenyl Ethers/toxicity ; Thyroxine/blood ; Thyroxine/drug effects ; Time Factors ; Triiodothyronine/blood ; Triiodothyronine/drug effects
Chemical Substances	Halogenated Diphenyl Ethers ; Hydrocarbons, Brominated ; Phenyl Ethers ; Triiodothyronine (06LU7C9H1V) ; 2,2',4,4'-tetrabromodiphenyl ether (0N97R5X10X) ; Thyroxine (Q51BO43MG4)
Language	English
Publishing date	2008-02-21
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	548368-2
ISSN	1525-6014 ; 0148-0545
ISSN (online)	1525-6014
ISSN	0148-0545
DOI	10.1080/01480540701873194
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Zs.A 1380: Show issues

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Article ; Online: Developmental triclosan exposure decreases maternal and neonatal thyroxine in rats.

Paul, Katie B / Hedge, Joan M / Devito, Michael J / Crofton, Kevin M

Environmental toxicology and chemistry

2010 Volume 29, Issue 12, Page(s) 2840–2844

Abstract: Disruption of maternal thyroid hormones during fetal developmental may result in irreversible neurological consequences in offspring. The present study tested the hypothesis that perinatal triclosan exposure of dams decreases thyroxine in dams and ... ...

Abstract	Disruption of maternal thyroid hormones during fetal developmental may result in irreversible neurological consequences in offspring. The present study tested the hypothesis that perinatal triclosan exposure of dams decreases thyroxine in dams and offspring prior to weaning. Pregnant Long-Evans rats received triclosan by oral gavage (0-300 mg/kg/d) in corn oil from gestational day (GD)6 through postnatal day (PND)21. Serum was obtained from pups on PND4, 14, and 21, and from dams on PND22. Serum thyroxine (T4) was reduced 31% in dams on PND22. In pups, a unique pattern of hypothyroxinemia was observed; serum T4 decreased 27% in PND4 pups with no significant reduction observed on PND14 or PND21. Comparable reductions of approximately 30% in serum T4 at 300 mg/kg/d for dams and PND4 neonates and a lack of effect at PND14 and PND21 suggest that toxicokinetic or toxicodynamic factors may have contributed to a reduced exposure or a reduced toxicological response during the lactation period.
MeSH term(s)	Animals ; Female ; Humans ; Models, Animal ; Pregnancy ; Prenatal Exposure Delayed Effects ; Rats ; Rats, Long-Evans ; Thyroxine/blood ; Triclosan/pharmacology
Chemical Substances	Triclosan (4NM5039Y5X) ; Thyroxine (Q51BO43MG4)
Language	English
Publishing date	2010-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	46234-2
ISSN	1552-8618 ; 0730-7268
ISSN (online)	1552-8618
ISSN	0730-7268
DOI	10.1002/etc.339
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Zs.A 2312: Show issues

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Article ; Online: Development of a thyroperoxidase inhibition assay for high-throughput screening.

Paul, Katie B / Hedge, Joan M / Rotroff, Daniel M / Hornung, Michael W / Crofton, Kevin M / Simmons, Steven O

Chemical research in toxicology

2014 Volume 27, Issue 3, Page(s) 387–399

Abstract: High-throughput screening (HTPS) assays to detect inhibitors of thyroperoxidase (TPO), the enzymatic catalyst for thyroid hormone (TH) synthesis, are not currently available. Herein, we describe the development of a HTPS TPO inhibition assay. Rat thyroid ...

Abstract	High-throughput screening (HTPS) assays to detect inhibitors of thyroperoxidase (TPO), the enzymatic catalyst for thyroid hormone (TH) synthesis, are not currently available. Herein, we describe the development of a HTPS TPO inhibition assay. Rat thyroid microsomes and a fluorescent peroxidase substrate, Amplex UltraRed (AUR), were employed in an end-point assay for comparison to the existing kinetic guaiacol (GUA) oxidation assay. Following optimization of assay metrics, including Z', dynamic range, and activity, using methimazole (MMI), the assay was tested with a 21-chemical training set. The potency of MMI-induced TPO inhibition was greater with AUR compared to GUA. The dynamic range and Z' score with MMI were as follows: 127-fold and 0.62 for the GUA assay, 18-fold and 0.86 for the 96-well AUR assay, and 11.5-fold and 0.93 for the 384-well AUR assay. The 384-well AUR assay drastically reduced animal use, requiring one-tenth of the rat thyroid microsomal protein needed for the GUA 96-well format assay. Fourteen chemicals inhibited TPO, with a relative potency ranking of MMI > ethylene thiourea > 6-propylthiouracil > 2,2',4,4'-tetrahydroxy-benzophenone > 2-mercaptobenzothiazole > 3-amino-1,2,4-triazole > genistein > 4-propoxyphenol > sulfamethazine > daidzein > 4-nonylphenol > triclosan > iopanoic acid > resorcinol. These data demonstrate the capacity of this assay to detect diverse TPO inhibitors. Seven chemicals acted as negatives: 2-hydroxy-4-methoxybenzophenone, dibutylphthalate, diethylhexylphthalate, diethylphthalate, 3,5-dimethylpyrazole-1-methanol, methyl 2-methyl-benzoate, and sodium perchlorate. This assay could be used to screen large numbers of chemicals as an integral component of a tiered TH-disruptor screening approach.
MeSH term(s)	Animals ; Enzyme Assays ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/metabolism ; Guaiacol/chemistry ; Guaiacol/metabolism ; High-Throughput Screening Assays ; Male ; Methimazole/chemistry ; Methimazole/metabolism ; Microsomes/enzymology ; Oxazines/chemistry ; Oxazines/metabolism ; Oxidation-Reduction ; Peroxidase/antagonists & inhibitors ; Peroxidase/metabolism ; Protein Binding ; Rats ; Rats, Long-Evans ; Substrate Specificity ; Thyroid Gland/metabolism
Chemical Substances	Enzyme Inhibitors ; Oxazines ; amplex red reagent (119171-73-2) ; Methimazole (554Z48XN5E) ; Guaiacol (6JKA7MAH9C) ; Peroxidase (EC 1.11.1.7)
Language	English
Publishing date	2014-03-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/tx400310w
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Zs.A 2320: Show issues

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Article: Short-term in vivo exposure to the water contaminant triclosan: Evidence for disruption of thyroxine.

Crofton, Kevin M / Paul, Katie B / Devito, Michael J / Hedge, Joan M

Environmental toxicology and pharmacology

2007 Volume 24, Issue 2, Page(s) 194–197

Abstract: Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) is a chlorinated phenolic antibacterial compound found as an active ingredient in many personal care and household products. The structural similarity of triclosan to thyroid hormones and recent studies ... ...

Abstract	Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) is a chlorinated phenolic antibacterial compound found as an active ingredient in many personal care and household products. The structural similarity of triclosan to thyroid hormones and recent studies demonstrating activation of the human pregnane X receptor (PXR) and inhibition of diiodothyronine (T(2)) sulfotransferases, have raised concerns about adverse effects on thyroid homeostasis. The current research tested the hypothesis that triclosan alters circulating concentrations of thyroxine. The hypothesis was tested using a 4-day oral triclosan exposure (0-1000mg/kg/day) in weanling female Long-Evans rats, followed by measurement of circulating levels of serum total thyroxine (T(4)). Dose-dependent decreases in total T(4) were observed. The benchmark dose (BMD) and lower bound on the BMD (BMDL) for the effects on T(4) were 69.7 and 35.6mg/kg/day, respectively. These data demonstrate that triclosan disrupts thyroid hormone homeostasis in rats.
Language	English
Publishing date	2007-09
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1318302-3
ISSN	1382-6689
ISSN	1382-6689
DOI	10.1016/j.etap.2007.04.008
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Zs.A 4490: Show issues

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Article ; Online: Cross-species analysis of thyroperoxidase inhibition by xenobiotics demonstrates conservation of response between pig and rat.

Paul, Katie B / Hedge, Joan M / Macherla, Chitralekha / Filer, Dayne L / Burgess, Emily / Simmons, Steven O / Crofton, Kevin M / Hornung, Michael W

Toxicology

2013 Volume 312, Page(s) 97–107

Abstract: Thyroperoxidase (TPO), the enzyme that catalyzes the synthesis of thyroid hormone, is a known target for thyroid-disrupting chemicals. In vivo toxicological evidence supporting TPO-inhibition as one molecular-initiating event that leads to thyroid ... ...

Abstract	Thyroperoxidase (TPO), the enzyme that catalyzes the synthesis of thyroid hormone, is a known target for thyroid-disrupting chemicals. In vivo toxicological evidence supporting TPO-inhibition as one molecular-initiating event that leads to thyroid disruption is derived largely from rat models; however, a significant fraction of research on the inhibition of TPO by xenobiotics has been conducted using porcine TPO. The current work tested the hypothesis that porcine and rat thyroid microsomes exposed to TPO-inhibiting chemicals would demonstrate different responses in a guaiacol oxidation assay. A primary objective of this work is to establish the degree of concordance between rat and porcine TPO inhibition data. Microsomes were isolated from both rat and pig thyroid glands, and the guaiacol oxidation assay was performed for a training set of 12 chemicals, including previously reported TPO inhibitors, thyroid-disrupting chemicals thought to perturb other targets, and several previously untested chemicals, to determine the relative TPO inhibition responses across species. Concentration-response curves were derived for methimazole (MMI), dibutylphthalate (DBP), diethylhexylphthalate (DEHP), diethylphthalate (DEP), 3,5-dimethylpyrazole-1-methanol (DPM), iopanoic acid (IOA), 2-mercaptobenzothiazole (MBT), sodium perchlorate (PERC), p-nonylphenol (PNP), 4-propoxyphenol (4POP), 6-propylthiouracil (PTU), and triclosan (TCS). MMI, PTU, MBT, DPM, 4POP, and at extremely high concentrations, PERC, inhibited TPO activity. Results demonstrated a strong qualitative concordance of response between the two species. All chemicals that inhibited TPO in porcine microsomes also inhibited TPO in rat microsomes. Hill model-derived IC50 values revealed approximate 1.5- to 50-fold differences in relative potency to MMI between species for positive chemicals. DPM, MBT, 4POP, and PTU exhibited greater relative potency to MMI using rat TPO versus porcine TPO, but rank order potency for inhibition was similar for the other test chemicals, with: PTU>MBT>DPM>4POP>PERC for rat TPO and MBT>PTU>DPM>4POP>PERC for porcine TPO. These data support the extrapolation of porcine TPO data to potential thyroid-disrupting activity in rodent models to evaluate TPO-inhibiting chemicals.
MeSH term(s)	Animals ; Dose-Response Relationship, Drug ; Guaiacol/metabolism ; Iodide Peroxidase/antagonists & inhibitors ; Male ; Microsomes/drug effects ; Rats ; Rats, Long-Evans ; Species Specificity ; Swine ; Thyroid Gland/drug effects ; Xenobiotics/pharmacology
Chemical Substances	Xenobiotics ; Guaiacol (6JKA7MAH9C) ; Iodide Peroxidase (EC 1.11.1.8)
Language	English
Publishing date	2013-10-04
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	184557-3
ISSN	1879-3185 ; 0300-483X
ISSN (online)	1879-3185
ISSN	0300-483X
DOI	10.1016/j.tox.2013.08.006
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Zs.A 888: Show issues

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Article ; Online: Tiered High-Throughput Screening Approach to Identify Thyroperoxidase Inhibitors Within the ToxCast Phase I and II Chemical Libraries.

Paul Friedman, Katie / Watt, Eric D / Hornung, Michael W / Hedge, Joan M / Judson, Richard S / Crofton, Kevin M / Houck, Keith A / Simmons, Steven O

Toxicological sciences : an official journal of the Society of Toxicology

2016 Volume 151, Issue 1, Page(s) 160–180

Abstract: High-throughput screening for potential thyroid-disrupting chemicals requires a system of assays to capture multiple molecular-initiating events (MIEs) that converge on perturbed thyroid hormone (TH) homeostasis. Screening for MIEs specific to TH- ... ...

Abstract	High-throughput screening for potential thyroid-disrupting chemicals requires a system of assays to capture multiple molecular-initiating events (MIEs) that converge on perturbed thyroid hormone (TH) homeostasis. Screening for MIEs specific to TH-disrupting pathways is limited in the U.S. Environmental Protection Agency ToxCast screening assay portfolio. To fill 1 critical screening gap, the Amplex UltraRed-thyroperoxidase (AUR-TPO) assay was developed to identify chemicals that inhibit TPO, as decreased TPO activity reduces TH synthesis. The ToxCast phase I and II chemical libraries, comprised of 1074 unique chemicals, were initially screened using a single, high concentration to identify potential TPO inhibitors. Chemicals positive in the single-concentration screen were retested in concentration-response. Due to high false-positive rates typically observed with loss-of-signal assays such as AUR-TPO, we also employed 2 additional assays in parallel to identify possible sources of nonspecific assay signal loss, enabling stratification of roughly 300 putative TPO inhibitors based upon selective AUR-TPO activity. A cell-free luciferase inhibition assay was used to identify nonspecific enzyme inhibition among the putative TPO inhibitors, and a cytotoxicity assay using a human cell line was used to estimate the cellular tolerance limit. Additionally, the TPO inhibition activities of 150 chemicals were compared between the AUR-TPO and an orthogonal peroxidase oxidation assay using guaiacol as a substrate to confirm the activity profiles of putative TPO inhibitors. This effort represents the most extensive TPO inhibition screening campaign to date and illustrates a tiered screening approach that focuses resources, maximizes assay throughput, and reduces animal use.
Language	English
Publishing date	2016-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfw034
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Zs.A 1709: Show issues

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Article: Cross-species analysis of thyroperoxidase inhibition by xenobiotics demonstrates conservation of response between pig and rat

Paul, Katie B / Hedge, Joan M / Macherla, Chitralekha / Filer, Dayne L / Burgess, Emily / Simmons, Steven O / Crofton, Kevin M / Hornung, Michael W

Toxicology. 2013 Oct. 4, v. 312

2013

Abstract	Thyroperoxidase (TPO), the enzyme that catalyzes the synthesis of thyroid hormone, is a known target for thyroid-disrupting chemicals. In vivo toxicological evidence supporting TPO-inhibition as one molecular-initiating event that leads to thyroid disruption is derived largely from rat models; however, a significant fraction of research on the inhibition of TPO by xenobiotics has been conducted using porcine TPO. The current work tested the hypothesis that porcine and rat thyroid microsomes exposed to TPO-inhibiting chemicals would demonstrate different responses in a guaiacol oxidation assay. A primary objective of this work is to establish the degree of concordance between rat and porcine TPO inhibition data. Microsomes were isolated from both rat and pig thyroid glands, and the guaiacol oxidation assay was performed for a training set of 12 chemicals, including previously reported TPO inhibitors, thyroid-disrupting chemicals thought to perturb other targets, and several previously untested chemicals, to determine the relative TPO inhibition responses across species. Concentration–response curves were derived for methimazole (MMI), dibutylphthalate (DBP), diethylhexylphthalate (DEHP), diethylphthalate (DEP), 3,5-dimethylpyrazole-1-methanol (DPM), iopanoic acid (IOA), 2-mercaptobenzothiazole (MBT), sodium perchlorate (PERC), p-nonylphenol (PNP), 4-propoxyphenol (4POP), 6-propylthiouracil (PTU), and triclosan (TCS). MMI, PTU, MBT, DPM, 4POP, and at extremely high concentrations, PERC, inhibited TPO activity. Results demonstrated a strong qualitative concordance of response between the two species. All chemicals that inhibited TPO in porcine microsomes also inhibited TPO in rat microsomes. Hill model-derived IC₅₀ values revealed approximate 1.5- to 50-fold differences in relative potency to MMI between species for positive chemicals. DPM, MBT, 4POP, and PTU exhibited greater relative potency to MMI using rat TPO versus porcine TPO, but rank order potency for inhibition was similar for the other test chemicals, with: PTU>MBT>DPM>4POP>PERC for rat TPO and MBT>PTU>DPM>4POP>PERC for porcine TPO. These data support the extrapolation of porcine TPO data to potential thyroid-disrupting activity in rodent models to evaluate TPO-inhibiting chemicals.
Keywords	animal models ; guaiacol ; inhibitory concentration 50 ; iodide peroxidase ; microsomes ; oxidation ; rats ; swine ; thyroid hormones ; xenobiotics
Language	English
Dates of publication	2013-1004
Size	p. 97-107.
Publishing place	Elsevier Ireland Ltd
Document type	Article
ZDB-ID	184557-3
ISSN	1879-3185 ; 0300-483X
ISSN (online)	1879-3185
ISSN	0300-483X
DOI	10.1016/j.tox.2013.08.006
Database	NAL-Catalogue (AGRICOLA)

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