In Vivo and in Vitro Structure-Dosimetry-Activity Relationships of Substituted Phenols in Developmental Toxicity Assays

1991 ◽  
Vol 16 (2) ◽  
pp. 225-229
Author(s):  
R. J. KAVLOCK ◽  
L. A. OGLESBY ◽  
L. L. HALL ◽  
H. L. FISHER ◽  
F. COPELAND ◽  
...  
Keyword(s):  
Developmental Toxicity ◽  
Substituted Phenols

In vivo and in vitro structure-dosimetry-activity relationships of substituted phenols in developmental toxicity assays

1991 ◽  
Vol 5 (3) ◽  
pp. 255-258 ◽  
Author(s):  
Robert J. Kavlock ◽  
Linda A. Oglesby ◽  
Larry L. Hall ◽  
Henry L. Fisher ◽  
Frank Copeland ◽  
...  
Keyword(s):  
Developmental Toxicity ◽  
Substituted Phenols

scholarly journals Predicting the in vivo developmental toxicity of benzo[a]pyrene (BaP) in rats by an in vitro–in silico approach

2021 ◽  
Author(s):  
Danlei Wang ◽  
Maartje H. Rietdijk ◽  
Lenny Kamelia ◽  
Peter J. Boogaard ◽  
Ivonne M. C. M. Rietjens
Keyword(s):  
Dose Response ◽  
In Silico ◽  
Response Curve ◽  
Developmental Toxicity ◽  
Toxicity Testing ◽  
Maximal Effect ◽  
Blood Concentrations ◽  
Reverse Dosimetry

AbstractDevelopmental toxicity testing is an animal-intensive endpoints in toxicity testing and calls for animal-free alternatives. Previous studies showed the applicability of an in vitro–in silico approach for predicting developmental toxicity of a range of compounds, based on data from the mouse embryonic stem cell test (EST) combined with physiologically based kinetic (PBK) modelling facilitated reverse dosimetry. In the current study, the use of this approach for predicting developmental toxicity of polycyclic aromatic hydrocarbons (PAHs) was evaluated, using benzo[a]pyrene (BaP) as a model compound. A rat PBK model of BaP was developed to simulate the kinetics of its main metabolite 3-hydroxybenzo[a]pyrene (3-OHBaP), shown previously to be responsible for the developmental toxicity of BaP. Comparison to in vivo kinetic data showed that the model adequately predicted BaP and 3-OHBaP blood concentrations in the rat. Using this PBK model and reverse dosimetry, a concentration–response curve for 3-OHBaP obtained in the EST was translated into an in vivo dose–response curve for developmental toxicity of BaP in rats upon single or repeated dose exposure. The predicted half maximal effect doses (ED50) amounted to 67 and 45 mg/kg bw being comparable to the ED50 derived from the in vivo dose–response data reported for BaP in the literature, of 29 mg/kg bw. The present study provides a proof of principle of applying this in vitro–in silico approach for evaluating developmental toxicity of BaP and may provide a promising strategy for predicting the developmental toxicity of related PAHs, without the need for extensive animal testing.

Safety assessment of the Clostridium butyricum MIYAIRI 588® probiotic strain including evaluation of antimicrobial sensitivity and presence of Clostridium toxin genes in vitro and teratogenicity in vivo

2016 ◽  
Vol 35 (8) ◽  
pp. 818-832 ◽  
Author(s):  
K Isa ◽  
K Oka ◽  
N Beauchamp ◽  
M Sato ◽  
K Wada ◽  
...  
Keyword(s):  
Developmental Toxicity ◽  
Health Benefit ◽  
Probiotic Strain ◽  
Clostridium Butyricum ◽  
Toxin Genes ◽  
Antimicrobial Sensitivity ◽  
Developmental Effects ◽  
Safety Studies

Probiotics are live microorganisms ingested for the purpose of conferring a health benefit on the host. Development of new probiotics includes the need for safety evaluations that should consider factors such as pathogenicity, infectivity, virulence factors, toxicity, and metabolic activity. Clostridium butyricum MIYAIRI 588® (CBM 588®), an anaerobic spore-forming bacterium, has been developed as a probiotic for use by humans and food animals. Safety studies of this probiotic strain have been conducted and include assessment of antimicrobial sensitivity, documentation of the lack of Clostridium toxin genes, and evaluation of CBM 588® on reproductive and developmental toxicity in a rodent model. With the exception of aminoglycosides, to which anaerobes are intrinsically resistant, CBM 588® showed sensitivity to all antibiotic classes important in human and animal therapeutics. In addition, analysis of the CBM 588® genome established the absence of genes for encoding for α, β, or ε toxins and botulin neurotoxins types A, B, E, or F. There were no deleterious reproductive and developmental effects observed in mice associated with the administration of CBM 588®. These data provide further support for the safety of CBM 588® for use as a probiotic in animals and humans.

scholarly journals 3D kidney organoids for bench-to-bedside translation

2020 ◽  
Author(s):  
Navin Gupta✉ ◽  
Emre Dilmen ◽  
Ryuji Morizane
Keyword(s):  
Collecting Duct ◽  
Developmental Toxicity ◽  
Human Kidney ◽  
Great Promise ◽  
Duct Systems ◽  
Recent Developments ◽  
Induced Pluripotent ◽  
Kidney Organoids

Abstract The kidneys are essential organs that filter the blood, removing urinary waste while maintaining fluid and electrolyte homeostasis. Current conventional research models such as static cell cultures and animal models are insufficient to grasp the complex human in vivo situation or lack translational value. To accelerate kidney research, novel research tools are required. Recent developments have allowed the directed differentiation of induced pluripotent stem cells to generate kidney organoids. Kidney organoids resemble the human kidney in vitro and can be applied in regenerative medicine and as developmental, toxicity, and disease models. Although current studies have shown great promise, challenges remain including the immaturity, limited reproducibility, and lack of perfusable vascular and collecting duct systems. This review gives an overview of our current understanding of nephrogenesis that enabled the generation of kidney organoids. Next, the potential applications of kidney organoids are discussed followed by future perspectives. This review proposes that advancement in kidney organoid research will be facilitated through our increasing knowledge on nephrogenesis and combining promising techniques such as organ-on-a-chip models.

Comparison of zebrafish in vitro and in vivo developmental toxicity assessments of perfluoroalkyl acids (PFAAs)

2020 ◽  
Vol 84 (3) ◽  
pp. 125-136
Author(s):  
Ola Wasel ◽  
Kathryn M. Thompson ◽  
Yu Gao ◽  
Amy E. Godfrey ◽  
Jiejun Gao ◽  
...  
Keyword(s):  
Developmental Toxicity ◽  
Perfluoroalkyl Acids

The Synthesis and Preliminary Pharmacological Evaluation of a Series of Substituted 4'-Phenoxypropyl Analogues of the Atypical Antipsychotic Clozapine

2010 ◽  
Vol 63 (1) ◽  
pp. 116 ◽  
Author(s):  
Ben Capuano ◽  
Ian T. Crosby ◽  
Fiona M. McRobb ◽  
Anna Podloucka ◽  
David A. Taylor ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Antipsychotic Agents ◽  
Pharmacological Effects ◽  
Lead Compound ◽  
Substituted Phenols ◽  
Biochemical Effects ◽  
Primary Focus

Herein we report the synthesis, characterization, and preliminary pharmacological activity of a new series of substituted 4′-phenoxypropyl tricyclic analogues of clozapine as potential antipsychotic agents for the treatment of schizophrenia. The lead compound (3) for this investigation was designed based on a revised model derived from the structural hybridization of the commercial therapeutics clozapine (1) and haloperidol (2). The compounds described in this paper probe the biochemical effects of introducing a variety of electron-withdrawing and electron-donating substituents with the primary focus on the para-position of the introduced distal aromatic ring. The target compounds were readily prepared in three steps using the key intermediate lactam (8-chloro-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine-11-one, 9), piperazine and commercially available substituted phenols. The chemistry and structural characterization of this series of substituted 4′-phenoxypropyl analogues of clozapine are described. Preliminary in vitro results on the pharmacological effects of the ring substituents on affinity for dopamine D4 and serotonin 5-HT2A receptors are discussed. Psychosis-related in vivo animal behavioural data for compounds identified with potential from the receptor binding screen are also presented.

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