Effects of Defined Mixtures of Persistent Organic Pollutants (POPs) on Pre-lethal Cytotoxicity in the Human A-498 Kidney Cell Line In Vitro

Amber, Mazia; Xie, Yuling; Berntsen, Hanne Friis; Zimmer, Karin Elisabeth; Ropstad, Erik; Verhaegen, Steven; Connolly, Lisa

doi:10.1007/s12403-021-00396-7

Cited by 4 publications

(4 citation statements)

References 36 publications

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“…Using cell reporter assays, this mixture was found to antagonize the androgen receptor transactivation and nuclear translocation [13], to inhibit the transactivation activity of the aryl hydrocarbon receptor [14], and to induce cytotoxicity while it enhances nerve-growth-factor-induced neurite outgrowth in PC12 cells at high concentrations [15]. Microscopic high content analysis (HCA) revealed that some sub-mixtures affected cell number, nuclear area, and mitochondrial membrane potential in A-498 human kidney cells [16].…”

Section: Introductionmentioning

confidence: 99%

A Realistic Mixture of Persistent Organic Pollutants Affects Zebrafish Development, Behavior, and Specifically Eye Formation by Inhibiting the Condensin I Complex

Guerrero-Limón

Nivelle

Bich-Ngoc

et al. 2023

Toxics

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Persistent organic pollutants (POPs) are posing major environmental and health threats due to their stability, ubiquity, and bioaccumulation. Most of the numerous studies of these compounds deal with single chemicals, although real exposures always consist of mixtures. Thus, using different tests, we screened the effects on zebrafish larvae caused by exposure to an environmentally relevant POP mixture. Our mixture consisted of 29 chemicals as found in the blood of a Scandinavian human population. Larvae exposed to this POP mix at realistic concentrations, or sub-mixtures thereof, presented growth retardation, edemas, retarded swim bladder inflation, hyperactive swimming behavior, and other striking malformations such as microphthalmia. The most deleterious compounds in the mixture belong to the per- and polyfluorinated acids class, although chlorinated and brominated compounds modulated the effects. Analyzing the changes in transcriptome caused by POP exposure, we observed an increase of insulin signaling and identified genes involved in brain and eye development, leading us to propose that the impaired function of the condensin I complex caused the observed eye defect. Our findings contribute to the understanding of POP mixtures, their consequences, and potential threats to human and animal populations, indicating that more mechanistic, monitoring, and long-term studies are imperative.

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Section: Introductionmentioning

confidence: 99%

A Realistic Mixture of Persistent Organic Pollutants Affects Zebrafish Development, Behavior, and Specifically Eye Formation by Inhibiting the Condensin I Complex

Guerrero-Limón

Nivelle

Bich-Ngoc

et al. 2023

Toxics

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“…In addition, several sub-mixtures were designed, containing either chlorinated (Cl), brominated (Br), or perfluorinated compounds (PFAA) to be able to assign specific effects to one of these classes [17]. The total POP mixture was shown to antagonize the androgen receptor transactivation and nuclear translocation [18], inhibit the transactivation activity of the aryl hydrocarbon receptor [19], and to enhance the nervegrowth-factor-induced neurite outgrowth in PC12 cells at high concentration [18][19][20][21]. It also induces cytotoxicity and some of the sub-mixtures affect the number of cells, nuclear area and mitochondrial membrane potential in human A-498 kidney cells [21].…”

Section: Introductionmentioning

confidence: 99%

“…The total POP mixture was shown to antagonize the androgen receptor transactivation and nuclear translocation [18], inhibit the transactivation activity of the aryl hydrocarbon receptor [19], and to enhance the nervegrowth-factor-induced neurite outgrowth in PC12 cells at high concentration [18][19][20][21]. It also induces cytotoxicity and some of the sub-mixtures affect the number of cells, nuclear area and mitochondrial membrane potential in human A-498 kidney cells [21]. Recently, zebrafish larvae exposed to this POP mix at realistic concentrations, or sub-mixtures thereof, presented growth retardation, edemas, retarded swim bladder inflation, and hyperactive swimming behavior [22].…”

Section: Introductionmentioning

confidence: 99%

A realistic mixture of ubiquitous persistent organic pollutants affects bone and cartilage development in zebrafish by interaction with nuclear receptor signaling

Guerrero-Limón,

Zappia,

Muller

2024

PLoS ONE

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"Persistent organic pollutants (POPs)" have a plethora of deleterious effects on humans and the environment due to their bioaccumulative, persistent, and mimicking properties. Individually, each of these chemicals has been tested and its effects measured, however they are rather found as parts of complex mixtures of which we do not fully grasp the extent of their potential consequences. Here we studied the effects of realistic, environmentally relevant mixtures of 29 POPs on cartilage and bone development using zebrafish as a model species. We observed developmental issues in cartilage, in the form of diverse malformations such as micrognathia, reduced size of the Meckel’s and other structures. Also, mineralized bone formation was disrupted, hence impacting the overall development of the larvae at later life stages. Assessment of the transcriptome revealed disruption of nuclear receptor pathways, such as androgen, vitamin D, and retinoic acid, that may explain the mechanisms of action of the compounds within the tested mixtures. In addition, clustering of the compounds using their chemical signatures revealed structural similarities with the model chemicals vitamin D and retinoic acid that can explain the effects and/or enhancing the phenotypes we witnessed. Further mechanistic studies will be required to fully understand this kind of molecular interactions and their repercussions in organisms. Our results contribute to the already existing catalogue of deleterious effects caused by exposure to POPs and help to understand the potential consequences in at risk populations.

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“…A compromise characterized by pragmatic and operational efficiency entails targeted assessments of specific chemicals that closely emulate human samples. , A prominent example is the design of a mixture of 29 persistent organic pollutants, whose design was derived from estimated human daily intakes . This mixture has been tested in diverse cellular bioassay, − and strong mixture effects were observed; however, due to a lack of single chemical data, consistency with mixture models could not be checked.…”

Section: Introductionmentioning

confidence: 99%

Toxicological Study of Human Exposure to Mixtures of Chemicals: Challenges and Approaches

Nian,

Braun,

Escher

et al. 2024

Environ. Sci. Technol. Lett.

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Humans are exposed to highly diverse mixtures of complex and often unknown compositions, which may adversely impact their health. There is a lack of guidance on how to design toxicological studies of chemical mixtures. This paper aims to evaluate the weaknesses and strengths of chemical mixture studies and to propose the practical design of mixture effect studies including chemical selection, dosing considerations, and determination of toxicological mechanisms of mixtures. The design of mixture effect studies should be optimized to yield relevant information on real-life mixture effects (1) by selecting appropriate chemicals based on the association between chemical effects and diseases using information from epidemiological studies and "chemical-disease" associations from toxicological databases and/or animal studies; (2) by testing mixture ratios and concentrations derived from biomonitoring data; (3) by evolving from binary mixtures and those with a low number of components to complex and diverse mixtures with as many components as practically possible; (4) by applying multiomics and high-throughput screening approaches to increase the number of testable individual chemicals and mixture scenarios; and (5) by implementing computational mixture models in the experiment planning phase and to interpret the outcomes to examine the toxicological mechanisms of "multiple exposure-multiple targets". We urge to move mixture investigation from answering academic questions such as mixture interaction models at high effect and concentration levels to mixture scenarios that are relevant for today's human exposure, i.e., low concentration, low effect but high complexity mixtures.

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Effects of Defined Mixtures of Persistent Organic Pollutants (POPs) on Pre-lethal Cytotoxicity in the Human A-498 Kidney Cell Line In Vitro

Cited by 4 publications

References 36 publications

A Realistic Mixture of Persistent Organic Pollutants Affects Zebrafish Development, Behavior, and Specifically Eye Formation by Inhibiting the Condensin I Complex

A Realistic Mixture of Persistent Organic Pollutants Affects Zebrafish Development, Behavior, and Specifically Eye Formation by Inhibiting the Condensin I Complex

A realistic mixture of ubiquitous persistent organic pollutants affects bone and cartilage development in zebrafish by interaction with nuclear receptor signaling

Toxicological Study of Human Exposure to Mixtures of Chemicals: Challenges and Approaches

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