In vitro prediction of organ toxicity: the challenges of scaling and secondary mechanisms of toxicity

Hengstler, Jan G.; Sjögren, Anita; Zink, Daniele; Hornberg, Jorrit J.

doi:10.1007/s00204-020-02669-7

Cited by 27 publications

(24 citation statements)

References 35 publications

(54 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Substances used, their concentration and incubation time are presented in Table 1 (Tab. 1) (References in Table 1: Hengstler et al, 2020[ 21 ]; Aduen et al, 1994[ 1 ]; Nelson et al, 2011[ 34 ]; Divakaruni et al, 2014[ 14 ]; Cooper et al, 1989[ 9 ]; Davies and Anderson, 1997[ 12 ]).…”

Section: Methodsmentioning

confidence: 99%

Continuous, non-invasive monitoring of oxygen consumption in a parallelized microfluidic in vitro system provides novel insight into the response to nutrients and drugs of primary human hepatocytes

Busche

Rabl

Fischer

et al. 2022

EXCLI Journal; 21:Doc144; ISSN 1611-2156

View full text Add to dashboard Cite

Oxygen plays a fundamental role in cellular energy metabolism, differentiation and cell biology in general. Consequently, in vitro oxygen sensing can be used to assess cell vitality and detect specific mechanisms of toxicity. In 2D in vitro models currently used, the oxygen supply provided by diffusion is generally too low, especially for cells having a high oxygen demand. In organ-on-chip systems, a more physiologic oxygen supply can be generated by establishing unidirectional perfusion. We established oxygen sensors in an easy-to-use and parallelized organ-on-chip system. We demonstrated the applicability of this system by analyzing the influence of fructose (40 mM, 80 mM), ammonium chloride (100 mM) and Na-diclofenac (50 µM, 150 µM, 450 µM, 1500 µM) on primary human hepatocytes (PHH). Fructose treatment for two hours showed an immediate drop of oxygen consumption (OC) with subsequent increase to nearly initial levels. Treatment with 80 mM glucose, 20 mM lactate or 20 mM glycerol did not result in any changes in OC which demonstrates a specific effect of fructose. Application of ammonium chloride for two hours did not show any immediate effects on OC, but qualitatively changed the cellular response to FCCP treatment. Na-diclofenac treatment for 24 hours led to a decrease of the maximal respiration and reserve capacity. We also demonstrated the stability of our system by repeatedly treating cells with 40 mM fructose, which led to similar cell responses on the same day as well as on subsequent days. In conclusion, our system enables in depth analysis of cellular respiration after substrate treatment in an unidirectional perfused organ-on-chip system.

show abstract

Section: Methodsmentioning

confidence: 99%

Continuous, non-invasive monitoring of oxygen consumption in a parallelized microfluidic in vitro system provides novel insight into the response to nutrients and drugs of primary human hepatocytes

Busche

Rabl

Fischer

et al. 2022

EXCLI Journal; 21:Doc144; ISSN 1611-2156

View full text Add to dashboard Cite

show abstract

“…All studies face a similar challenge, which is the choice of concentrations for in vitro testing (Leist et al, 2017[ 10 ]). This question has recently been discussed in an editorial of the Archives of Toxicology, where the authors pointed out that in vitro tests are usually performed at a concentration range around and above the plasma peak concentrations (C max ) of a drug in humans (Hengstler et al, 2020[ 8 ]). A typical strategy is to test relatively high concentrations, often 20- or even 200-fold higher than the human plasma C max .…”

Section: ⁯⁯⁯⁯⁯mentioning

confidence: 99%

“…compounds, whose toxicity depends on specific metabolic pathways may require higher scaling factors than compounds that do not require bio-activation. Moreover, scaling may also depend on the mechanism of toxicity (Hengstler et al, 2020[ 8 ]). To gain more insight into the requirements of optimal scaling it is not helpful to test only one or two concentrations, e.g.…”

Section: ⁯⁯⁯⁯⁯mentioning

confidence: 99%

Which concentrations are optimal for in vitro testing?

Albrecht

2020

EXCLI Journal; 19:Doc1172; ISSN 1611-2156

View full text Add to dashboard Cite

“…The existence of non-monotonic responses by EDCs (in which their effects change, in an inverted U or U-shape) also makes the work of researchers very difficult, since it is necessary to be aware that a high dose of EDC is not always it is the most toxic, but it can be a lower dose-this event makes difficult to define the safe dose of a given compound (Diamanti-Kandarakis et al, 2009;Vandenberg et al, 2012;Couderq et al, 2020). Indeed, one of the greatest challenges in toxicology is the choice of concentrations for in vitro testing, an issue that has been discussed recently (Leist et al, 2017;Albrecht, 2020;Hengstler et al, 2020). Currently, the use of relatively high concentrations (20 to 200 times higher than in vivo blood concentrations (C max ) is agreed upon, as these high concentrations lead to better accuracy results than lower concentrations.…”

Section: Introductionmentioning

confidence: 99%

“…Overall, higher concentrations in the culture medium are required to observe cell damage compared to the C max that is known to cause adverse effects in vivo (in vitro-in vivo scaling factor). Thus, it is advised to use a concentration range close to and above the maximum concentrations observed in human plasma (Hengstler et al, 2020). Furthermore, most EDCs remain understudied, which constituted a major force of investigation but, highlight the need for more emergent investigations to discover the toxicological effects.…”

Section: Introductionmentioning

confidence: 99%

Regulation mechanisms of endocrine disruptors on vasodilation and vasoconstriction: Insights from ex vivo models

Lorigo¹,

Cairrão²

2022

Biocell

View full text Add to dashboard Cite

Cardiovascular diseases (CVD) are one of the leading causes of death worldwide. The knowledge and understanding of CVD are based on the study of vascular physiology and how the smooth muscle cells and tissues perform their different functions. Exposure to endocrine disruptors (EDCs), such as phytoestrogens, polycyclic aromatic hydrocarbons, flame retardants, plasticizers, pesticides, and cosmetics, is an integral and fundamental part of human exposure. Humans are exposed to EDCs by multiple pathways including air, food, water, and consumer products. However, this exposure can lead to several adverse effects on human health, including on the cardiovascular (CV) system. The negative impact that EDC toxicity has on human CV health is a serious problem that must not be overlooked. In this point of view, we proposed the use of the human umbilical artery as a human model to study the direct effects of EDCs on the vascular level. Several works where these cells were directly exposed to EDC's were presented to highlight this well-established model as a great strategy to be used. In the future, we emphasize the need to continue to carry out different investigations using HUA to unveil and understand the vascular toxicity of EDCs and improve human CV health.

show abstract

In vitro prediction of organ toxicity: the challenges of scaling and secondary mechanisms of toxicity

Cited by 27 publications

References 35 publications

Continuous, non-invasive monitoring of oxygen consumption in a parallelized microfluidic in vitro system provides novel insight into the response to nutrients and drugs of primary human hepatocytes

Continuous, non-invasive monitoring of oxygen consumption in a parallelized microfluidic in vitro system provides novel insight into the response to nutrients and drugs of primary human hepatocytes

Which concentrations are optimal for in vitro testing?

Regulation mechanisms of endocrine disruptors on vasodilation and vasoconstriction: Insights from ex vivo models

Contact Info

Product

Resources

About