Integrating biokinetics and in vitro studies to evaluate developmental neurotoxicity induced by chlorpyrifos in human iPSC-derived neural stem cells undergoing differentiation towards neuronal and glial cells

Consiglio, Emma Di; Pistollato, Francesca; Gyves, Emilio Mendoza-de; Bal‐Price, Anna; Testai, Emanuela

doi:10.1016/j.reprotox.2020.09.010

Cited by 16 publications

(26 citation statements)

References 140 publications

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“…Concentrations considered for the analysis of selected DNT endpoints are relevant to human exposure based on concentrations found in human samples, as shown for the six previously tested chemicals [ 31 , 58 ] and the four new ones investigated in this study (see Table 1 and Supplementary Table S1). The nominal concentrations tested in this study are also in the range of concentrations described in previously published in vitro studies (e.g., [ 25 , [59] , [60] , [61] , [62] ]).…”

Section: Resultsmentioning

confidence: 91%

Combining in vitro assays and mathematical modelling to study developmental neurotoxicity induced by chemical mixtures

Herrmann

Carpi

Gyves

et al. 2021

Reproductive Toxicology

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Highlights Mixtures of similar MoA chemicals increased BDNF levels and neurite outgrowth. Mixtures of similar MoA chemicals decreased synapse formation and electrical activity. Synergistic effects on synaptogenesis features was predicted by mathematical modelling. Some of the DNT effects observed in hiPSC-neurons/astrocytes recapitulate ASD features. In vitro assays combined with mathematical modelling enable DNT testing of chemical mixtures.

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Section: Resultsmentioning

confidence: 91%

Combining in vitro assays and mathematical modelling to study developmental neurotoxicity induced by chemical mixtures

Herrmann

Carpi

Gyves

et al. 2021

Reproductive Toxicology

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“…The tested nominal concentrations were between 18.45 and 37.1 μM ( Di Consiglio et al, 2020 ). We performed BMD modeling and assessed the results by considering the intervals between the BMDL and the BMDU and the distance of the BMDL from the lowest experimental concentration.…”

Section: Resultsmentioning

confidence: 99%

“…Data from an in vitro biokinetic and toxicodynamic study ( Di Consiglio et al, 2020 ) were the basis to perform a human QIVIVE. In this study, the time courses of CPF and its toxic metabolite CPF-oxon (CPFO) concentrations were measured in the medium and in the cell lysate of human-induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs) undergoing differentiation and repeatedly exposed for 14 days to CPF.…”

Section: Methodsmentioning

confidence: 99%

In Vitro–In Vivo Extrapolation by Physiologically Based Kinetic Modeling: Experience With Three Case Studies and Lessons Learned

et al. 2022

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Physiologically based kinetic (PBK) modeling has been increasingly used since the beginning of the 21st century to support dose selection to be used in preclinical and clinical safety studies in the pharmaceutical sector. For chemical safety assessment, the use of PBK has also found interest, however, to a smaller extent, although an internationally agreed document was published already in 2010 (IPCS/WHO), but at that time, PBK modeling was based mostly on in vivo data as the example in the IPCS/WHO document indicates. Recently, the OECD has published a guidance document which set standards on how to characterize, validate, and report PBK models for regulatory purposes. In the past few years, we gained experience on using in vitro data for performing quantitative in vitro–in vivo extrapolation (QIVIVE), in which biokinetic data play a crucial role to obtain a realistic estimation of human exposure. In addition, pharmaco-/toxicodynamic aspects have been introduced into the approach. Here, three examples with different drugs/chemicals are described, in which different approaches have been applied. The lessons we learned from the exercise are as follows: 1) in vitro conditions should be considered and compared to the in vivo situation, particularly for protein binding; 2) in vitro inhibition of metabolizing enzymes by the formed metabolites should be taken into consideration; and 3) it is important to extrapolate from the in vitro measured intracellular concentration and not from the nominal concentration to the tissue/organ concentration to come up with an appropriate QIVIVE for the relevant adverse effects.

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“…In silico analysis also provides useful information about the pharmacokinetics of chemicals that cause OS [116] as well as their ability to induce ROS [117,118] and their quantitative structure-activity relationships [119]. Integration of in silico, in vitro, and/or in vivo studies will also facilitate prediction of the toxicities of OSrelated chemicals [120][121][122][123].…”

Section: Oxidative Medicine and Cellular Longevitymentioning

confidence: 99%

Oxidative Stress as a Common Key Event in Developmental Neurotoxicity

Nishimura

Kanda

Sone

et al. 2021

Oxidative Medicine and Cellular Longevity

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The developing brain is extremely sensitive to many chemicals. Perinatal exposure to neurotoxicants has been implicated in several neurodevelopmental disorders, including autism spectrum disorder, attention-deficit hyperactive disorder, and schizophrenia. Studies of the molecular and cellular events related to developmental neurotoxicity have identified a number of “adverse outcome pathways,” many of which share oxidative stress as a key event. Oxidative stress occurs when the balance between the production of free oxygen radicals and the activity of the cellular antioxidant system is dysregulated. In this review, we describe some of the developmental neurotoxins that target the antioxidant system and the mechanisms by which they elicit stress, including oxidative phosphorylation in mitochondria and plasma membrane redox system in rodent models. We also discuss future directions for identifying adverse outcome pathways related to oxidative stress and developmental neurotoxicity, with the goal of improving our ability to quickly and accurately screen chemicals for their potential developmental neurotoxicity.

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Integrating biokinetics and in vitro studies to evaluate developmental neurotoxicity induced by chlorpyrifos in human iPSC-derived neural stem cells undergoing differentiation towards neuronal and glial cells

Abstract: Graphical abstract

Cited by 16 publications

References 140 publications

Combining in vitro assays and mathematical modelling to study developmental neurotoxicity induced by chemical mixtures

Combining in vitro assays and mathematical modelling to study developmental neurotoxicity induced by chemical mixtures

In Vitro–In Vivo Extrapolation by Physiologically Based Kinetic Modeling: Experience With Three Case Studies and Lessons Learned

Oxidative Stress as a Common Key Event in Developmental Neurotoxicity

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