PMID- 32764792
OWN - NLM
STAT- MEDLINE
DCOM- 20201008
LR  - 20201008
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 15
IP  - 8
DP  - 2020
TI  - AhR-activating pesticides increase the bovine ABCG2 efflux activity in 
      MDCKII-bABCG2 cells.
PG  - e0237163
LID - 10.1371/journal.pone.0237163 [doi]
LID - e0237163
AB  - In bovine mammary glands, the ABCG2 transporter actively secretes xenobiotics 
      into dairy milk. This can have significant implications when cattle are exposed 
      to pesticide residues in feed. Recent studies indicate that the fungicide 
      prochloraz activates the aryl hydrocarbon receptor (AhR) pathway, increasing 
      bovine ABCG2 (bABCG2) gene expression and efflux activity. This could enhance the 
      accumulation of bABCG2 substrates in dairy milk, impacting pesticide risk 
      assessment. We therefore investigated whether 13 commonly used pesticides in 
      Europe are inducers of AhR and bABCG2 activity. MDCKII cells expressing mammary 
      bABCG2 were incubated with pesticides for up to 72 h. To reflect an in vivo 
      situation, applied pesticide concentrations corresponded to the maximum residue 
      levels (MRLs) permitted in bovine fat or muscle. AhR activation was ascertained 
      through CYP1A mRNA expression and enzyme activity, measured by qPCR and 
      7-ethoxyresorufin-Omicron-deethylase (EROD) assay, respectively. Pesticide-mediated 
      increase of bABCG2 efflux activity was assessed using the Hoechst 33342 
      accumulation assay. For all assays, the known AhR-activating pesticide prochloraz 
      served as a positive control, while the non-activating tolclofos-methyl provided 
      the negative control. At 10-fold MRL concentrations, chlorpyrifos-methyl, 
      diflufenican, ioxynil, rimsulfuron, and tebuconazole significantly increased 
      CYP1A1 mRNA levels, CYP1A activity, and bABCG2 efflux activity compared to the 
      vehicle control. In contrast, dimethoate, dimethomorph, glyphosate, iprodione, 
      methiocarb and thiacloprid had no impact on AhR-mediated CYP1A1 mRNA levels, 
      CYP1A activity or bABCG2 efflux. In conclusion, the MDCKII-bABCG2 cell model 
      proved an appropriate tool for identifying AhR- and bABCG2-inducing pesticides. 
      This provides an in vitro approach that could reduce the number of animals 
      required in pesticide approval studies.
FAU - Kuhnert, Lydia
AU  - Kuhnert L
AUID- ORCID: 0000-0002-9779-2440
AD  - Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary 
      Medicine, University Leipzig, Leipzig, Germany.
FAU - Giantin, Mery
AU  - Giantin M
AD  - Division of Veterinary Pharmacology and Toxicology, Department of Comparative 
      Biomedicine and Food Science, University of Padua, Agripolis Legnaro (Padua), 
      Italy.
FAU - Dacasto, Mauro
AU  - Dacasto M
AD  - Division of Veterinary Pharmacology and Toxicology, Department of Comparative 
      Biomedicine and Food Science, University of Padua, Agripolis Legnaro (Padua), 
      Italy.
FAU - Halwachs, Sandra
AU  - Halwachs S
AD  - Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary 
      Medicine, University Leipzig, Leipzig, Germany.
FAU - Honscha, Walther
AU  - Honscha W
AD  - Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary 
      Medicine, University Leipzig, Leipzig, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200807
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 2)
RN  - 0 (Fungicides, Industrial)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 0 (Recombinant Proteins)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily G, Member 2/agonists/*metabolism
MH  - Animal Testing Alternatives/*methods
MH  - Animals
MH  - Cattle
MH  - Dogs
MH  - Fungicides, Industrial/*toxicity
MH  - Germany
MH  - Lactation/drug effects
MH  - Madin Darby Canine Kidney Cells
MH  - Receptors, Aryl Hydrocarbon/*agonists/metabolism
MH  - Recombinant Proteins/metabolism
MH  - Toxicity Tests, Chronic/*methods
PMC - PMC7413513
COIS- MSD Animal Health Innovation GmbH provided financial support in the form of 
      salary to author SH during the time of the manuscript preparation. There are no 
      patents, products in development or marketed products to declare. This does not 
      alter our adherence to PLOS ONE policies on sharing data and materials.
EDAT- 2020/08/09 06:00
MHDA- 2020/10/09 06:00
PMCR- 2020/08/07
CRDT- 2020/08/09 06:00
PHST- 2019/12/23 00:00 [received]
PHST- 2020/07/21 00:00 [accepted]
PHST- 2020/08/09 06:00 [entrez]
PHST- 2020/08/09 06:00 [pubmed]
PHST- 2020/10/09 06:00 [medline]
PHST- 2020/08/07 00:00 [pmc-release]
AID - PONE-D-19-35569 [pii]
AID - 10.1371/journal.pone.0237163 [doi]
PST - epublish
SO  - PLoS One. 2020 Aug 7;15(8):e0237163. doi: 10.1371/journal.pone.0237163. 
      eCollection 2020.