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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
[Display omitted] •Human iPSC-derived NSCs undergoing differentiation possess some metabolic competence.•CPF entered the cells and was biotrasformed into its two main metabolites (CPFO and TCP).•After repeated exposure, very limited bioaccumulation of CPF was observed.•Treatment with CPF decreased n...
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Published in: | Reproductive toxicology (Elmsford, N.Y.) N.Y.), 2020-12, Vol.98, p.174-188 |
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creator | Di Consiglio, Emma Pistollato, Francesca Mendoza-De Gyves, Emilio Bal-Price, Anna Testai, Emanuela |
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•Human iPSC-derived NSCs undergoing differentiation possess some metabolic competence.•CPF entered the cells and was biotrasformed into its two main metabolites (CPFO and TCP).•After repeated exposure, very limited bioaccumulation of CPF was observed.•Treatment with CPF decreased neurite outgrowth, synapse number and electrical activity.•Treatment with CPF increased BDNF levels and the percentage of astrocytes.
For some complex toxicological endpoints, chemical safety assessment has conventionally relied on animal testing. Apart from the ethical issues, also scientific considerations have been raised concerning the traditional approach, highlighting the importance for considering real life exposure scenario. Implementation of flexible testing strategies, integrating multiple sources of information, including in vitro reliable test methods and in vitro biokinetics, would enhance the relevance of the obtained results. Such an approach could be pivotal in the evaluation of developmental neurotoxicity (DNT), especially when applied to human cell-based models, mimicking key neurodevelopmental processes, relevant to human brain development.
Here, we integrated the kinetic behaviour with the toxicodynamic alterations of chlorpyrifos (CPF), such as in vitro endpoints specific for DNT evaluation, after repeated exposure during differentiation of human neural stem cells into a mixed culture of neurons and astrocytes. The upregulation of some cytochrome P450 and glutathione S-transferase genes during neuronal differentiation and the formation of the two major CPF metabolites (due to bioactivation and detoxification) supported the metabolic competence of the used in vitro model. The alterations in the number of synapses, neurite outgrowth, brain derived neurotrophic factor, the proportion of neurons and astrocytes, as well as spontaneous electrical activity correlated well with the CPF ability to enter the cells and be bioactivated to CPF-oxon. Overall, our results confirm that combining in vitro biokinetics and assays to evaluate effects on neurodevelopmental endpoints in human cells should be regarded as a key strategy for a quantitative characterization of DNT effects. |
doi_str_mv | 10.1016/j.reprotox.2020.09.010 |
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•Human iPSC-derived NSCs undergoing differentiation possess some metabolic competence.•CPF entered the cells and was biotrasformed into its two main metabolites (CPFO and TCP).•After repeated exposure, very limited bioaccumulation of CPF was observed.•Treatment with CPF decreased neurite outgrowth, synapse number and electrical activity.•Treatment with CPF increased BDNF levels and the percentage of astrocytes.
For some complex toxicological endpoints, chemical safety assessment has conventionally relied on animal testing. Apart from the ethical issues, also scientific considerations have been raised concerning the traditional approach, highlighting the importance for considering real life exposure scenario. Implementation of flexible testing strategies, integrating multiple sources of information, including in vitro reliable test methods and in vitro biokinetics, would enhance the relevance of the obtained results. Such an approach could be pivotal in the evaluation of developmental neurotoxicity (DNT), especially when applied to human cell-based models, mimicking key neurodevelopmental processes, relevant to human brain development.
Here, we integrated the kinetic behaviour with the toxicodynamic alterations of chlorpyrifos (CPF), such as in vitro endpoints specific for DNT evaluation, after repeated exposure during differentiation of human neural stem cells into a mixed culture of neurons and astrocytes. The upregulation of some cytochrome P450 and glutathione S-transferase genes during neuronal differentiation and the formation of the two major CPF metabolites (due to bioactivation and detoxification) supported the metabolic competence of the used in vitro model. The alterations in the number of synapses, neurite outgrowth, brain derived neurotrophic factor, the proportion of neurons and astrocytes, as well as spontaneous electrical activity correlated well with the CPF ability to enter the cells and be bioactivated to CPF-oxon. Overall, our results confirm that combining in vitro biokinetics and assays to evaluate effects on neurodevelopmental endpoints in human cells should be regarded as a key strategy for a quantitative characterization of DNT effects.</description><identifier>ISSN: 0890-6238</identifier><identifier>EISSN: 1873-1708</identifier><identifier>DOI: 10.1016/j.reprotox.2020.09.010</identifier><identifier>PMID: 33011216</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Biokinetics ; Chlorpyrifos ; Developmental neurotoxicity ; Human iPSC-derived neural stem cells ; Repeated exposure</subject><ispartof>Reproductive toxicology (Elmsford, N.Y.), 2020-12, Vol.98, p.174-188</ispartof><rights>2020 The Authors</rights><rights>Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.</rights><rights>2020 The Authors 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c537t-58d4874352a8db2199916210ff2f279f8835db2ec080ff6f221e40738e7b7e993</citedby><cites>FETCH-LOGICAL-c537t-58d4874352a8db2199916210ff2f279f8835db2ec080ff6f221e40738e7b7e993</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33011216$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Di Consiglio, Emma</creatorcontrib><creatorcontrib>Pistollato, Francesca</creatorcontrib><creatorcontrib>Mendoza-De Gyves, Emilio</creatorcontrib><creatorcontrib>Bal-Price, Anna</creatorcontrib><creatorcontrib>Testai, Emanuela</creatorcontrib><title>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</title><title>Reproductive toxicology (Elmsford, N.Y.)</title><addtitle>Reprod Toxicol</addtitle><description>[Display omitted]
•Human iPSC-derived NSCs undergoing differentiation possess some metabolic competence.•CPF entered the cells and was biotrasformed into its two main metabolites (CPFO and TCP).•After repeated exposure, very limited bioaccumulation of CPF was observed.•Treatment with CPF decreased neurite outgrowth, synapse number and electrical activity.•Treatment with CPF increased BDNF levels and the percentage of astrocytes.
For some complex toxicological endpoints, chemical safety assessment has conventionally relied on animal testing. Apart from the ethical issues, also scientific considerations have been raised concerning the traditional approach, highlighting the importance for considering real life exposure scenario. Implementation of flexible testing strategies, integrating multiple sources of information, including in vitro reliable test methods and in vitro biokinetics, would enhance the relevance of the obtained results. Such an approach could be pivotal in the evaluation of developmental neurotoxicity (DNT), especially when applied to human cell-based models, mimicking key neurodevelopmental processes, relevant to human brain development.
Here, we integrated the kinetic behaviour with the toxicodynamic alterations of chlorpyrifos (CPF), such as in vitro endpoints specific for DNT evaluation, after repeated exposure during differentiation of human neural stem cells into a mixed culture of neurons and astrocytes. The upregulation of some cytochrome P450 and glutathione S-transferase genes during neuronal differentiation and the formation of the two major CPF metabolites (due to bioactivation and detoxification) supported the metabolic competence of the used in vitro model. The alterations in the number of synapses, neurite outgrowth, brain derived neurotrophic factor, the proportion of neurons and astrocytes, as well as spontaneous electrical activity correlated well with the CPF ability to enter the cells and be bioactivated to CPF-oxon. Overall, our results confirm that combining in vitro biokinetics and assays to evaluate effects on neurodevelopmental endpoints in human cells should be regarded as a key strategy for a quantitative characterization of DNT effects.</description><subject>Biokinetics</subject><subject>Chlorpyrifos</subject><subject>Developmental neurotoxicity</subject><subject>Human iPSC-derived neural stem cells</subject><subject>Repeated exposure</subject><issn>0890-6238</issn><issn>1873-1708</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNqFUd1u0zAUjhCIlcErTH6BdLbTxs4NAlX8TJoEEnBtOfZJekpiV7aT0bfkkeasbIIrrmyd8_0dfUVxxeiaUVZfH9YBjsEn_2vNKadr2qwpo8-KFZOiKpmg8nmxorKhZc0reVG8ivFAKd2IRrwsLqqKMsZZvSp-37gEfdAJXU9a9D_RQUITiXaWoCMzpuBJTJNFiCR5ArMeJp2AWJhh8McRXNIDcTA9pEGD6ZSJdjJgSXsiZj_4cDwF7HxcBPfTqB3Br992pYWAc0Yt3CwRE4zEwDBEMrm86_2SyWLXQcgmmDN6lyPc6WDj2dBl2hK0HzD_HrivixedHiK8-fNeFj8-fvi--1zefvl0s3t_W5ptJVK5lXYjxabaci1ty1nTNKzmjHYd77hoOimrbZ6DoTLP6o5zBhsqKgmiFdA01WXx9qx7nNoRrMkJ8xHqGHDU4aS8RvXvxuFe9X5WQggu5SJQnwVM8DEG6J64jKqlY3VQjx2rpWNFG5U7zsSrv52faI-lZsC7MwDy_TNCUNEguFwIBjBJWY__87gHlnnE5A</recordid><startdate>202012</startdate><enddate>202012</enddate><creator>Di Consiglio, Emma</creator><creator>Pistollato, Francesca</creator><creator>Mendoza-De Gyves, Emilio</creator><creator>Bal-Price, Anna</creator><creator>Testai, Emanuela</creator><general>Elsevier Inc</general><general>Pergamon In Cooperation With The Reproductive Toxicology Center</general><scope>6I.</scope><scope>AAFTH</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>202012</creationdate><title>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</title><author>Di Consiglio, Emma ; Pistollato, Francesca ; Mendoza-De Gyves, Emilio ; Bal-Price, Anna ; Testai, Emanuela</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c537t-58d4874352a8db2199916210ff2f279f8835db2ec080ff6f221e40738e7b7e993</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Biokinetics</topic><topic>Chlorpyrifos</topic><topic>Developmental neurotoxicity</topic><topic>Human iPSC-derived neural stem cells</topic><topic>Repeated exposure</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Di Consiglio, Emma</creatorcontrib><creatorcontrib>Pistollato, Francesca</creatorcontrib><creatorcontrib>Mendoza-De Gyves, Emilio</creatorcontrib><creatorcontrib>Bal-Price, Anna</creatorcontrib><creatorcontrib>Testai, Emanuela</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Reproductive toxicology (Elmsford, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Di Consiglio, Emma</au><au>Pistollato, Francesca</au><au>Mendoza-De Gyves, Emilio</au><au>Bal-Price, Anna</au><au>Testai, Emanuela</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>Reproductive toxicology (Elmsford, N.Y.)</jtitle><addtitle>Reprod Toxicol</addtitle><date>2020-12</date><risdate>2020</risdate><volume>98</volume><spage>174</spage><epage>188</epage><pages>174-188</pages><issn>0890-6238</issn><eissn>1873-1708</eissn><abstract>[Display omitted]
•Human iPSC-derived NSCs undergoing differentiation possess some metabolic competence.•CPF entered the cells and was biotrasformed into its two main metabolites (CPFO and TCP).•After repeated exposure, very limited bioaccumulation of CPF was observed.•Treatment with CPF decreased neurite outgrowth, synapse number and electrical activity.•Treatment with CPF increased BDNF levels and the percentage of astrocytes.
For some complex toxicological endpoints, chemical safety assessment has conventionally relied on animal testing. Apart from the ethical issues, also scientific considerations have been raised concerning the traditional approach, highlighting the importance for considering real life exposure scenario. Implementation of flexible testing strategies, integrating multiple sources of information, including in vitro reliable test methods and in vitro biokinetics, would enhance the relevance of the obtained results. Such an approach could be pivotal in the evaluation of developmental neurotoxicity (DNT), especially when applied to human cell-based models, mimicking key neurodevelopmental processes, relevant to human brain development.
Here, we integrated the kinetic behaviour with the toxicodynamic alterations of chlorpyrifos (CPF), such as in vitro endpoints specific for DNT evaluation, after repeated exposure during differentiation of human neural stem cells into a mixed culture of neurons and astrocytes. The upregulation of some cytochrome P450 and glutathione S-transferase genes during neuronal differentiation and the formation of the two major CPF metabolites (due to bioactivation and detoxification) supported the metabolic competence of the used in vitro model. The alterations in the number of synapses, neurite outgrowth, brain derived neurotrophic factor, the proportion of neurons and astrocytes, as well as spontaneous electrical activity correlated well with the CPF ability to enter the cells and be bioactivated to CPF-oxon. Overall, our results confirm that combining in vitro biokinetics and assays to evaluate effects on neurodevelopmental endpoints in human cells should be regarded as a key strategy for a quantitative characterization of DNT effects.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>33011216</pmid><doi>10.1016/j.reprotox.2020.09.010</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Biokinetics Chlorpyrifos Developmental neurotoxicity Human iPSC-derived neural stem cells Repeated exposure |
title | 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 |
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