PMID- 36731186
OWN - NLM
STAT- MEDLINE
DCOM- 20230223
LR  - 20230322
IS  - 1873-6750 (Electronic)
IS  - 0160-4120 (Linking)
VI  - 172
DP  - 2023 Feb
TI  - High-content analysis shows synergistic effects of low perfluorooctanoic acid 
      (PFOS) and perfluorooctane sulfonic acid (PFOA) mixture concentrations on human 
      breast epithelial cell carcinogenesis.
PG  - 107746
LID - S0160-4120(23)00019-3 [pii]
LID - 10.1016/j.envint.2023.107746 [doi]
AB  - Perfluoroalkyl substances (PFAS) have been associated with cancer, but the 
      potential underlying mechanisms need to be further elucidated and include studies 
      of PFAS mixtures. This mechanistic study revealed that very low concentrations 
      (500 pM) of the binary PFOS and PFOA mixture induced synergistic effects on human 
      epithelial breast cell (MCF-10A) proliferation. The cell proliferation was 
      mediated by pregnane X receptor (PXR) activation, an increase in cyclin D1 and 
      CDK6/4 levels, decrease in p21 and p53 levels, and by regulation of phosphor-Akt 
      and beta-catenin. The PFAS mixture also altered histone modifications, epigenetic 
      mechanisms implicated in tumorigenesis, and promoted cell migration and invasion 
      by reducing the levels of occludin. High-content screening using the cell 
      painting assay, revealed that hundreds of cell features were affected by the PFAS 
      mixture even at the lowest concentration tested (100 pM). The detailed phenotype 
      profiling further demonstrated that the PFAS mixture altered cell morphology, 
      mostly in parameters related to intensity and texture associated with 
      mitochondria, endoplasmic reticulum, and nucleoli. Exposure to higher 
      concentrations (>/=50 microM) of the PFOS and PFOA mixture caused cell death through 
      synergistic interactions that induced oxidative stress, DNA/RNA damage, and lipid 
      peroxidation, illustrating the complexity of mixture toxicology. Increased 
      knowledge about mixture-induced effects is important for better understanding of 
      PFAS' possible role in cancer etiology, and may impact the risk assessment of 
      these and other compounds. This study shows the potential of image-based 
      multiplexed fluorescence assays and high-content screening for development of new 
      approach methodologies in toxicology.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.
FAU - Pierozan, Paula
AU  - Pierozan P
AD  - Science for Life Laboratory, Department of Environmental Science, Stockholm 
      University, Stockholm 114 18, Sweden.
FAU - Kosnik, Marissa
AU  - Kosnik M
AD  - Science for Life Laboratory, Department of Environmental Science, Stockholm 
      University, Stockholm 114 18, Sweden.
FAU - Karlsson, Oskar
AU  - Karlsson O
AD  - Science for Life Laboratory, Department of Environmental Science, Stockholm 
      University, Stockholm 114 18, Sweden. Electronic address: 
      Oskar.Karlsson@aces.su.se.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230112
PL  - Netherlands
TA  - Environ Int
JT  - Environment international
JID - 7807270
RN  - 9H2MAI21CL (perfluorooctane sulfonic acid)
RN  - 947VD76D3L (perfluorooctanoic acid)
RN  - 0 (Alkanesulfonic Acids)
RN  - 0 (Fluorocarbons)
RN  - 0 (Environmental Pollutants)
SB  - IM
MH  - Humans
MH  - *Alkanesulfonic Acids/toxicity
MH  - *Fluorocarbons/toxicity
MH  - Epithelial Cells
MH  - Carcinogenesis
MH  - *Environmental Pollutants
OTO - NOTNLM
OT  - Breast cancer
OT  - Cell invasion
OT  - Cell painting
OT  - Chemical mixture
OT  - Cocktail effect
OT  - Epigenetics
OT  - High-content screening
OT  - Histone modifications
OT  - Mixture toxicology
OT  - NAMs
OT  - Oxidative stress
OT  - PFAS
OT  - PXR
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/02/03 06:00
MHDA- 2023/02/25 06:00
CRDT- 2023/02/02 18:04
PHST- 2022/11/04 00:00 [received]
PHST- 2023/01/04 00:00 [revised]
PHST- 2023/01/09 00:00 [accepted]
PHST- 2023/02/03 06:00 [pubmed]
PHST- 2023/02/25 06:00 [medline]
PHST- 2023/02/02 18:04 [entrez]
AID - S0160-4120(23)00019-3 [pii]
AID - 10.1016/j.envint.2023.107746 [doi]
PST - ppublish
SO  - Environ Int. 2023 Feb;172:107746. doi: 10.1016/j.envint.2023.107746. Epub 2023 
      Jan 12.