Interindividual variation contributes to differential PCB 126 induced gene expression in primary breast epithelial cells and tissues

Stephanie M. Morin, Prabin Dhangada Majhi, Giovanna M. Crisi, Kelly J. Gregory, Renata Franca, Benjamin Schalet, Holly Mason, Jesse Thomas Casaubon, Qing Jackie Cao, Sandra Haddad, Grace Makari-Judson, D. Joseph Jerry, Sallie S. Schneider*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

PCB 126 is a pervasive, dioxin-like chemical pollutant which can activate the aryl hydrocarbon receptor (AhR). Despite being banned from the market, PCB 126 can be detected in breast milk to this day. The extent to which interindividual variation impacts the adverse responses to this chemical in the breast tissue remains unclear. This study aimed to investigate the impact of 3 nM PCB 126 on gene expression in a panel of genetically diverse benign human breast epithelial cell (HBEC) cultures and patient derived breast tissues. Six patient derived HBEC cultures were treated with 3 nM PCB 126. RNAseq was used to interrogate the impact of exposure on differential gene expression. Gene expression changes from the top critical pathways were confirmed via qRT-PCR in a larger panel of benign patient derived HBEC cultures, as well as in patient-derived breast tissue explant cultures. RNAseq analysis of HBEC cultures revealed a signature of 144 genes significantly altered by 3 nM PCB 126 treatment. Confirmation of 8 targets using a panel of 12 HBEC cultures and commercially available breast cell lines demonstrated that while the induction of canonical downstream target gene, CYP1A1, was consistent across our primary HBECs, other genes including AREG, S100A8, IL1A, IL1B, MMP7, and CCL28 exhibited significant variability across individuals. The dependence on the activity of the aryl hydrocarbon receptor was confirmed using inhibitors. PCB 126 can induce significant and consistent changes in gene expression associated with xenobiotic metabolism in benign breast epithelial cells. Although the induction of most genes was reliant on the AhR, significant variability was noted between genes and individuals. These data suggest that there is a bifurcation of the pathway following AhR activation that contributes to the variation in interindividual responses.

Original languageEnglish (US)
Article number113722
JournalEcotoxicology and Environmental Safety
Volume241
DOIs
StatePublished - Aug 2022
Externally publishedYes

Keywords

  • Amphiregulin
  • Aryl hydrocarbon receptor
  • Breast tissue
  • Interindividual variation
  • PCB 126
  • Patient derived explants

ASJC Scopus subject areas

  • Pollution
  • Public Health, Environmental and Occupational Health
  • Health, Toxicology and Mutagenesis

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