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

Cells. 2021 Sep 9;10(9):2367. doi: 10.3390/cells10092367.


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.

Keywords: DINCH; immunotoxicity; macrophage; plasticizer; proteomics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • DNA Damage / drug effects
  • DNA Repair / drug effects
  • Dicarboxylic Acids / metabolism*
  • Esters / metabolism*
  • Humans
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • NF-kappa B / metabolism
  • Oxidative Stress / drug effects*
  • Phthalic Acids / metabolism
  • Plasticizers / pharmacology*
  • Proteomics
  • Signal Transduction / drug effects
  • THP-1 Cells / drug effects*
  • THP-1 Cells / metabolism


  • Dicarboxylic Acids
  • Esters
  • NF-kappa B
  • Phthalic Acids
  • Plasticizers
  • phthalic acid