scholarly journals Application of grouping and read-across for the evaluation of parabens of different chain lengths with a particular focus on endocrine properties

2021 ◽  
Vol 95 (3) ◽  
pp. 853-881
Author(s):  
Susann Fayyaz ◽  
Reinhard Kreiling ◽  
Ursula G. Sauer
Keyword(s):  
Body Weight ◽  
In Vivo Studies ◽  
Repeated Dose ◽  
Hydroxybenzoic Acid ◽  
The European Union ◽  
Methyl Paraben ◽  
Propyl Paraben ◽  
Repeated Dose Toxicity ◽  
Endocrine Disrupting

AbstractThis article presents the outcomes of higher-tier repeated-dose toxicity studies and developmental and reproductive toxicity (DART) studies using Wistar rats requested for methyl paraben and propyl paraben under the European Union chemicals legislation. All studies revealed no-observed adverse effects (NOAELs) at 1000 mg/kg body weight/day. These findings (absence of effects) were then used to interpolate the hazard profile for ethyl paraben, further considering available data for butyl paraben. The underlying read-across hypothesis (all shorter-chained linear n-alkyl parabens are a ‘category’ based on very high structural similarity and are transformed to a common compound) was confirmed by similarity calculations and comparative in vivo toxicokinetics screening studies for methyl paraben, ethyl paraben, propyl paraben and butyl paraben. All four parabens were rapidly taken up systemically following oral gavage administration to rats, metabolised to p-hydroxybenzoic acid, and rapidly eliminated (parabens within one hour; p-hydroxybenzoic acid within 4–8 h). Accordingly, for ethyl paraben, the NOAELs for repeated-dose toxicity and DART were interpolated to be 1000 mg/kg body weight/day. Finally, all evidence was evaluated to address concerns expressed in the literature that parabens might be endocrine disruptors. This evaluation showed that the higher-tier studies do not provide any indication for any endocrine disrupting property. This is the first time that a comprehensive dataset from higher-tier in vivo studies following internationally agreed test protocols has become available for shorter-chained linear n-alkyl parabens. Consistently, the dataset shows that these parabens are devoid of repeated-dose toxicity and do not possess any DART or endocrine disrupting properties.

scholarly journals Effective Control of Postprandial Glucose Level through Inhibition of Intestinal Alpha Glucosidase byCymbopogon martinii(Roxb.)

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Varsha Ghadyale ◽  
Shrihari Takalikar ◽  
Vivek Haldavnekar ◽  
Akalpita Arvindekar
Keyword(s):  
Body Weight ◽  
Silica Gel ◽  
Glucose Level ◽  
Postprandial Glucose ◽  
Hot Water ◽  
In Vivo Studies ◽  
Effective Control ◽  
Alpha Glucosidase ◽  
Postprandial Glucose Level

Inhibition of intestinal alpha glucosidase plays a major role in preventing rise in postprandial glucose level in diabetics.Cymbopogon martinii(CM) (family Poaceae) is used in traditional Indian medicine in treatment of diabetes mellitus. The alpha glucosidase inhibitory action of the plant is studied. The active component was separated using hot water extraction of the whole plant powder, differential solvent extraction, and silica gel column chromatography. The 30 : 70 toluene : ethyl acetate fraction showed optimum activity. The silica gel chromatography fraction demonstrated 98, 98, and 68% inhibition for starch, maltose, and sucrose, respectively, at 5 mg/kg body weight of rats. Intestinal absorption studies using noneverted intestinal sacs, as well as in vivo studies in streptozotocin-induced diabetic rats using oral glucose tolerance with maltose and sucrose load, revealed better inhibition of alpha glucosidase as compared to acarbose. Kinetic studies using Lineweaver Burk plot showed mixed to noncompetitive type of inhibition by CM. In vivo studies with maltose load of 2 mg and 3 mg/gm body weight showed a noncompetitive pattern of inhibition at 5 mg/kg body weight of CM as against 60 mg/kg body weight of acarbose. Thus CM is more effective alpha glucosidase inhibitor and at lower concentration than acarbose.

Voiding behavior in awake unrestrained untethered spontaneously hypertensive and Wistar control rats

2021 ◽  
Author(s):  
Christopher L Langdale ◽  
Danielle J Degoski ◽  
Philip H Milliken ◽  
Warren M. Grill
Keyword(s):  
Body Weight ◽  
Water Consumption ◽  
Genetic Model ◽  
Spontaneously Hypertensive Rat ◽  
Infusion Pump ◽  
Bladder Capacity ◽  
In Vivo Studies ◽  
Spontaneously Hypertensive ◽  
Voided Volume

The spontaneously hypertensive rat (SHR), a genetic model of high blood pressure, has also been studied as a potential model of overactive bladder (OAB). In vivo studies confirmed the presence of surrogate markers of OAB, including detrusor overactivity (DO), increased urinary frequency, decreased bladder capacity and voided volume, and afferent hypersensitivity to bladder irritation. However, these observations were during awake cystometry (CMG) using implanted bladder catheters tethered to an infusion pump and artificially filled. We conducted studies in awake unrestrained untethered age-matched female SHR and Wistar rats to quantify naïve consumption and voiding behavior and the effect of capsaicin desensitization on consumption and voiding behavior. Food and water consumption, body weight, voiding frequency (VF), and voided volume (VV) were recorded. Rats were placed in metabolism cages for 24 h, up to twice a week, from 17 to 37 weeks of age. In SHRs, body weight, food, and water consumption were decreased compared to Wistars. However, after normalizing for body weight, only water consumption was reduced. Wistars exhibited a diurnal pattern of voiding behavior. Compared to Wistars, SHRs showed smaller VV and lacked a diurnal voiding pattern such that VV was similar during both light cycles. No difference in VF was observed after normalizing for water consumption. We observed no change in SHR voiding behavior following capsaicin desensitization, which was in contrast to a prior awake in vivo cystometry study describing increased VV and micturition interval in SHRs, and suggests that C-fiber activity may not contribute to bladder hypersensitivity in SHRs.

scholarly journals Azaspiracids Increase Mitochondrial Dehydrogenases Activity in Hepatocytes: Involvement of Potassium and Chloride Ions

Marine Drugs ◽  
2019 ◽  
Vol 17 (5) ◽  
pp. 276 ◽  
Author(s):  
Marco Pelin ◽  
Jane Kilcoyne ◽  
Chiara Florio ◽  
Philipp Hess ◽  
Aurelia Tubaro ◽  
...  
Keyword(s):  
Chloride Channels ◽  
Gastrointestinal Symptoms ◽  
In Vitro Study ◽  
Chloride Ions ◽  
In Vivo Studies ◽  
The European Union ◽  
Channel Inhibition ◽  
Dehydrogenases Activity

Background: Azaspiracids (AZAs) are marine toxins that are produced by Azadinium and Amphidoma dinoflagellates that can contaminate edible shellfish inducing a foodborne poisoning in humans, which is characterized by gastrointestinal symptoms. Among these, AZA1, -2, and -3 are regulated in the European Union, being the most important in terms of occurrence and toxicity. In vivo studies in mice showed that, in addition to gastrointestinal effects, AZA1 induces liver alterations that are visible as a swollen organ, with the presence of hepatocellular fat droplets and vacuoles. Hence, an in vitro study was carried out to investigate the effects of AZA1, -2, and -3 on liver cells, using human non-tumor IHH hepatocytes. Results: The exposure of IHH cells to AZA1, -2, or -3 (5 × 10−12–1 × 10−7 M) for 24 h did not affect the cell viability and proliferation (Sulforhodamine B assay and 3H-Thymidine incorporation assay), but they induced a significant concentration-dependent increase of mitochondrial dehydrogenases activity (MTT reduction assay). This effect depends on the activity of mitochondrial electron transport chain complex I and II, being counteracted by rotenone and tenoyl trifluoroacetone, respectively. Furthermore, AZAs-increased mitochondrial dehydrogenase activity was almost totally suppressed in the K+-, Cl−-, and Na+-free media and sensitive to the specific inhibitors of KATP and hERG potassium channels, Na+/K+, ATPase, and cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels. Conclusions: These results suggest that AZA mitochondrial effects in hepatocytes derive from an imbalance of intracellular levels of K+ and, in particular, Cl− ions, as demonstrated by the selective reduction of toxin effects by CFTR chloride channel inhibition.

Development of a Full Flexion 3D Musculoskeletal Model of the Knee Considering Intersegmental Contact During High Knee Flexion Movements

2020 ◽  
Vol 36 (6) ◽  
pp. 444-456
Author(s):  
David C. Kingston ◽  
Stacey M. Acker
Keyword(s):  
Body Weight ◽  
Knee Flexion ◽  
Knee Extensor ◽  
Musculoskeletal Model ◽  
Contact Forces ◽  
Model Verification ◽  
In Vivo Studies ◽  
Muscle Groups ◽  
The Right

A musculoskeletal model of the right lower limb was developed to estimate 3D tibial contact forces in high knee flexion postures. This model determined the effect of intersegmental contact between thigh–calf and heel–gluteal structures on tibial contact forces. This model includes direct tracking and 3D orientation of intersegmental contact force, femoral translations from in vivo studies, wrapping of knee extensor musculature, and a novel optimization constraint for multielement muscle groups. Model verification consisted of calculating the error between estimated tibial compressive forces and direct measurements from the Grand Knee Challenge during movements to ∼120° of knee flexion as no high knee flexion data are available. Tibial compression estimates strongly fit implant data during walking (R2 = .83) and squatting (R2 = .93) with a root mean squared difference of .47 and .16 body weight, respectively. Incorporating intersegmental contact significantly reduced model estimates of peak tibial anterior–posterior shear and increased peak medial–lateral shear during the static phase of high knee flexion movements by an average of .33 and .07 body weight, respectively. This model supports prior work in that intersegmental contact is a critical parameter when estimating tibial contact forces in high knee flexion movements across a range of culturally and occupationally relevant postures.

In vivo anti-arthritic effect and repeated dose toxicity of standardized methanolic extracts of Buddleja cordata Kunth (Scrophulariaceae) wild plant leaves and cell culture

2019 ◽  
Vol 240 ◽  
pp. 111875 ◽  
Author(s):  
Gabriel Alfonso Gutiérrez-Rebolledo ◽  
María Elena Estrada-Zúñiga ◽  
Leticia Garduño-Siciliano ◽  
Gretel Esthefania García-Gutiérrez ◽  
Claudia Albany Reséndiz Mora ◽  
...  
Keyword(s):  
Cell Culture ◽  
Wild Plant ◽  
Repeated Dose ◽  
Plant Leaves ◽  
Methanolic Extracts ◽  
Repeated Dose Toxicity ◽  
Buddleja Cordata

scholarly journals Membrane filtration in water recycling: removal of natural hormones

2003 ◽  
Vol 3 (3) ◽  
pp. 155-160 ◽  
Author(s):  
L.D. Nghiem ◽  
A.I. Schäfer ◽  
T.D. Waite
Keyword(s):  
Membrane Filtration ◽  
Endocrine Disrupting Chemicals ◽  
In Vivo Studies ◽  
Water Recycling ◽  
Endocrine Disrupting ◽  
Adsorptive Behavior ◽  
Stirred Cell ◽  
Natural Hormones

Recent detections of endocrine-disrupting chemicals (EDCs) in effluent are of great concern to sections of the community associated with the issue of water recycling. In vitro and in vivo studies by many researchers have confirmed the impacts of EDCs on trout at the common concentration encountered in sewage effluent. Amongst many types of EDCs the impacts of steroid estrogens such as estrone, estradiol (natural hormones) and ethinylestradiol (a synthetic hormone) are prominent as they have far higher endocrine-disrupting potency than other synthetic EDCs. Given the continuous developments in membrane technology, tertiary treatment using membrane processes has been identified as a promising technology to provide a safeguard to water recycling practice and to protect the environment. This paper investigates retention and adsorptive behavior of the natural hormones estrone and estradiol by two commercial low-pressure nanofiltration membranes TFC-SR2 and TFC-S, using dead end stirred cell systems. The removal phenomena of estradiol are similar to that of estrone. pH has been found to significantly influence the adsorption of estrone and estradiol by the membranes, presumably due to hydrogen bonding. This adsorption is critical in the risk of possible release of such hormones to the product waters. Total adsorbed amounts were calculated for standard membrane elements and are indeed important.

scholarly journals Twenty-Eight-Day Repeated-Dose Toxicity Studies for Detection of Weak Endocrine Disrupting Effects of Nonylphenol and Atrazine in Female Rats.

2000 ◽  
Vol 13 (1) ◽  
pp. 13-20 ◽  
Author(s):  
Sunao Aso ◽  
Makiko Anai ◽  
Shyuji Noda ◽  
Nobuya Imatanaka ◽  
Kanji Yamasaki ◽  
...  
Keyword(s):  
Female Rats ◽  
Repeated Dose ◽  
Toxicity Studies ◽  
Repeated Dose Toxicity ◽  
Endocrine Disrupting

scholarly journals Response to and recovery from treatment in human liver-mimetic clinostat spheroids: a model for assessing repeated-dose drug toxicity

2020 ◽  
Vol 9 (4) ◽  
pp. 379-389
Author(s):  
Stephen J Fey ◽  
Barbara Korzeniowska ◽  
Krzysztof Wrzesinski
Keyword(s):  
In Vitro Models ◽  
Repeated Dose ◽  
Treatment Results ◽  
Return To Equilibrium ◽  
Repeated Dose Toxicity ◽  
Repeated Use ◽  
Phase Out

Abstract Medicines are usually prescribed for repeated use over shorter or longer times. Unfortunately, repeated-dose animal toxicity studies do not correlate well with observations in man. As emphasized by the ‘3Rs’ and the desire to phase-out animal research, in vitro models are needed. One potential approach uses clinostat-cultured 3D HepG2–C3A liver-mimetic spheroids. They take 18 days to recover in vivo physiological functionality and reach a metabolic equilibrium, which is thereafter stable for a year. Acute and chronic repeated-dose studies of six drugs (amiodarone, diclofenac, metformin, phenformin, paracetamol and valproic acid) suggest that spheroids are more predictive of human in vivo toxicity than either 2D-cultured HepG2 cells or primary human hepatocytes. Repeated non-lethal treatment results in a clear response and return to equilibrium. Mitochondrial toxic compounds can be identified using a galactose-based medium. Some drugs induced a protective (or stress) response that intensifies after the second treatment. This 3D spheroid model is inexpensive, highly reproducible and well-suited for the determination of repeated-dose toxicity of compounds (naturally or chemically synthesized).

scholarly journals Effects of Endocrine-Disrupting Chemicals on Endometrial Receptivity and Embryo Implantation: A Systematic Review of 34 Mouse Model Studies

2021 ◽  
Vol 18 (13) ◽  
pp. 6840
Author(s):  
Donatella Caserta ◽  
Flavia Costanzi ◽  
Maria Paola De Marco ◽  
Luisa Di Benedetto ◽  
Eleonora Matteucci ◽  
...  
Keyword(s):  
Systematic Review ◽  
Mouse Model ◽  
Prolonged Exposure ◽  
Embryo Implantation ◽  
Endocrine Disrupting Chemicals ◽  
Progesterone Receptors ◽  
Endometrial Receptivity ◽  
In Vivo Studies ◽  
Endocrine Disrupting

Several available studies have already analyzed the systemic effects of endocrine-disrupting chemicals (EDCs) on fertile woman and neonatal outcomes, but little is still known in humans about the precise mechanisms of interference of these compounds with the endometrial receptivity. There is consistent evidence that continuous and prolonged exposure to EDCs is a risk factor for reduced fertility and fecundity in women. Preliminary studies on mammalian models provide robust evidence about this issue and could help gynecologists worldwide to prevent long term injury caused by EDCs on human fertility. In this systematic review, we aimed to systematically summarize all available data about EDC effects on blastocyst endometrial implantation. We performed a systematic review using PubMed®/MEDLINE® to summarize all in vivo studies, carried out on mice models, analyzing the molecular consequences of the prolonged exposure of EDC on the implantation process. 34 studies carried out on mouse models were included. Primary effects of EDC were a reduction of the number of implantation sites and pregnancy rates, particularly after BPA and phthalate exposure. Furthermore, the endometrial expression of estrogen (ER) and progesterone receptors (PR), as well as their activation pathways, is compromised after EDC exposure. Finally, the expression of the primary endometrial markers of receptivity (such as MUC1, HOXA10, Inn and E-cadherin) after EDC contact was analyzed. In conclusion EDC deeply affect blastocyst implantation in mouse model. Several players of the implantation mechanism are strongly influenced by the exposure to different categories of EDC.

scholarly journals Preparation of Ex Vivo Rodent Phantoms for Developing, Testing, and Training MR Imaging of the Kidney and Other Organs

2021 ◽  
pp. 75-85
Author(s):  
Jason M. Millward ◽  
João S. Periquito ◽  
Paula Ramos Delgado ◽  
Christian Prinz ◽  
Thoralf Niendorf ◽  
...  
Keyword(s):  
Mr Imaging ◽  
Ex Vivo ◽  
In Vivo Studies ◽  
The European Union ◽  
Target Organs ◽  
Preclinical Mri ◽  
Renal Mri ◽  
And Training

AbstractHere we describe a simple and inexpensive protocol for preparing ex vivo rodent phantoms for use in MR imaging studies. The experimental animals are perfused and fixed with formaldehyde, and then wrapped with gauze and sealed with liquid latex. This yields a phantom that preserves all organs in situ, and which avoids the need to keep fixed animals and organs in containers that have dimensions very different from living animals. This is especially important for loading in MR detectors, and specifically the RF coils, they are usually used with. The phantom can be safely stored and conveniently reused, and can provide MR scientists with a realistic phantom with which to establish protocols in preparation for preclinical in vivo studies—for renal, brain, and body imaging. The phantom also serves as an ideal teaching tool, for trainees learning how to perform preclinical MRI investigations of the kidney and other target organs, while avoiding the need for handling living animals, and reducing the total number of animals required.This protocol chapter is part of the PARENCHIMA initiative “MRI Biomarkers for CKD” (CA16103), a community-driven Action of the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers.

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