Abstract
In an effort to replace, reduce and refine animal experimentation, there is an unmet need to advance current in vitro models that offer features with physiological relevance and enhanced predictivity of in vivo toxicological output. Hepatic toxicology is key following chemical, drug and nanomaterials (NMs) exposure, as the liver is vital in metabolic detoxification of chemicals as well as being a major site of xenobiotic accumulation (i.e., low solubility particulates). With the ever-increasing production of NMs, there is a necessity to evaluate the probability of consequential adverse effects, not only in health but also in clinically asymptomatic liver, as part of risk stratification strategies. In this study, two unique disease initiation and maintenance protocols were developed and utilised to mimic steatosis and pre-fibrotic NASH in scaffold-free 3D liver microtissues (MT) composed of primary human hepatocytes, hepatic stellate cells, Kupffer cells and sinusoidal endothelial cells. The characterized diseased MT were utilized for the toxicological assessment of a panel of xenobiotics. Highlights from the study included: 1. Clear experimental evidence for the pre-existing liver disease is important in the augmentation of xenobiotic-induced hepatotoxicity and 2. NMs are able to activate stellate cells. The data demonstrated that pre-existing disease is vital in the intensification of xenobiotic-induced liver damage. Therefore, it is imperative that all stages of the wide spectrum of liver disease are incorporated in risk assessment strategies. This is of significant consequence, as a substantial number of the general population suffer from sub-clinical liver injury without any apparent or diagnosed manifestations.
Highlights
The expanded commercial utilisation of engineered nanomaterials (NMs), which undoubtedly leads to increased exposure to users and consumers, highlighting the necessity to better evaluate the potential safety of these substances (Johnston et al 2012; Kermanizadeh et al 2015; 2018; Vance et al 2015)
The pre-fibrotic non-alcoholic steatohepatitis (NASH) condition was induced with 3D InSightTM Human Liver NASH2.0 Basal Medium (CS07–305-01; InSphero) containing supraphysiological carbohydrate (6.6 mM glucose, 10 mM fructose) and insulin (0.85 nM) levels supplemented by high-dose lowdensity lipoprotein (LDL) and LPS)
The standard multi-cellular model (3D InSightTM Human Liver MT), was the starting point for the disease initiation models of steatosis and NASH induced by two different treatment schemes: a) steatosis— medium with supraphysiological glucose concentration or b) NASH—diabetic conditions at elevated sugar and insulin levels
Summary
The expanded commercial utilisation of engineered nanomaterials (NMs), which undoubtedly leads to increased exposure to users and consumers, highlighting the necessity to better evaluate the potential safety of these substances (Johnston et al 2012; Kermanizadeh et al 2015; 2018; Vance et al 2015). In addition to occupational and consumer NM exposure, which is inhaled and ingested, a number of nanomedicines have been developed for intravenous administration, resulting in intentional direct entry of materials into the blood (Balasubramanian et al 2010; Kermanizadeh et al 2018). The combined presence of a potent innate immune response along with the tendency for the hepatic cells to be routinely exposed to xenobiotics can result in substantial liver inflammation after exposure to hepatotoxins. The organ is understood to be a major storage organ for non-soluble xenobiotics (Lee et al 2013; Lipka et al 2010; Modrzynska et al 2018) as exemplified in a recent study in which NM aggregates were detectable in the liver sinusoids (often in the KCs) up to 180 days post exposure (Modrzynska et al 2018)
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