The Emerging Plasticizer Alternative DINCH and Its Metabolite MINCH Induce Oxidative Stress and Enhance Inflammatory Responses in Human THP-1 Macrophages

Alexandra Schaffert,Kristin Schubert,Matthias Blüher,Josi Arnold,Martin Von Bergen,Isabel Karkossa

doi:10.3390/cells10092367

Abstract

The use of the plasticizer bis(2-ethylhexyl)phthalate (DEHP) and other plasticizers in the manufacture of plastic products has been restricted due to adverse health outcomes such as obesity, metabolic syndrome, and asthma, for which inflammation has been described to be a driving factor. The emerging alternative plasticizer 1,2-cyclohexanedioic acid diisononyl ester (DINCH) still lacks information regarding its potential effects on the immune system. Here, we investigated the effects of DINCH and its naturally occurring metabolite monoisononylcyclohexane-1,2-dicarboxylic acid ester (MINCH) on the innate immune response. Human THP-1 macrophages were exposed to 10 nM–10 μM DINCH or MINCH for 4 h, 16 h, and 24 h. To decipher the underlying mechanism of action, we applied an untargeted proteomic approach that revealed xenobiotic-induced activation of immune-related pathways such as the nuclear factor κB (NF-κB) signaling pathway. Key drivers were associated with oxidative stress, mitochondrial dysfunction, DNA damage repair, apoptosis, and autophagy. We verified increased reactive oxygen species (ROS) leading to cellular damage, NF-κB activation, and subsequent TNF and IL-1β release, even at low nM concentrations. Taken together, DINCH and MINCH induced cellular stress and pro-inflammatory effects in macrophages, which may lead to adverse health effects.

Highlights

As part of the innate immune system, macrophages are found in most organs and tissues of the body [1]
To analyze the cytotoxic effects in human macrophages, THP-1 cells were treated with increasing concentrations of DINCH or its metabolite MINCH for 4, 16, and 24 h
Among the Receptor affected pathways, we found immune-related such naling, and Induction, which were increased by treatment with as nuclear factor κB (NF-κB) signaling, Toll-like Receptor signaling, CD40 Signaling, Acute Phase Response individual time points when compared to the LPS-stimulated conSignaling, and Induction, which were increased by treatment trol

Summary

Introduction

As part of the innate immune system, macrophages are found in most organs and tissues of the body [1]. They are critical for modulating immune responses and release chemokines and cytokines upon activation [1]. The plasticizers, has previously been described to modulate immune responses and enhance susceptibility to pathogens or promote chronic inflammation in tissues, which is associated with concomitant diseases such as cardiovascular diseases, type 2 diabetes, asthma, and allergies [2,3]. Plasticizers can leach from these plastic products and expose humans through air, food, or skin contact [5]. Several plasticizers are considered harmful to human health by acting as endocrine disruptors (EDCs), interfering directly with receptors or signaling molecules, and modulating hormone production or transport [6]

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