ABC- and SLC-Transporters in Murine and Bovine Mammary Epithelium - Effects of Prochloraz

Abstract

Some chemicals are ligands to efflux transporters which may result in high concentrations in milk. Limited knowledge is available on the influence of maternal exposure to chemicals on the expression and function of transporters in the lactating mammary gland. We determined gene expression of ABC and SLC transporters in murine mammary tissue of different gestation and lactation stages, in murine mammary cells (HC11) featuring resting and secreting phenotypes and in bovine mammary tissue and cells (BME-UV). Effects on transporter expression and function of the imidazole fungicide prochloraz, previously reported to influence BCRP in mammary cells, was investigated on transporter expression and function in the two cell lines. Transporters studied were BCRP, MDR1, MRP1, OATP1A5/OATP1A2, OCTN1 and OCT1. Gene expressions of BCRP and OCT1 in murine mammary glands were increased during gestation and lactation, whereas MDR1, MRP1, OATP1A5 and OCTN1 were decreased, compared to expressions in virgins. All transporters measured in mammary glands of mice were detected in bovine mammary tissue and in HC11 cells, while only MDR1 and MRP1 were detected in BME-UV cells. Prochloraz treatment induced MDR1 gene and protein expression in both differentiated HC11 and BME-UV cells and increased protein function in HC11 cells, resulting in decreased accumulation of the MDR1 substrate digoxin. In conclusion, our results demonstrate that murine (HC11) and bovine (BME-UV) mammary epithelial cells can be applied to characterize expression and function of transporters as well as effects of contaminants on the mammary transporters. An altered expression, induced by a drug or toxic chemical, on any of the transporters expressed in the mammary epithelial cells during lactation may modulate the well-balanced composition of nutrients and/or secretion of contaminants in milk with potential adverse effects on breast-fed infants and dairy consumers.

Neurotoxic assessment of Microcystin-LR, cylindrospermopsin and their combination on the human neuroblastoma SH-SY5Y cell line

“…These facts support that MC-LR damage could only evolve if it is transported into the nervous system through OATPs or other different transporters (Feurstein et al, 2009;. However, the presence of these transporters in the nervous system is scarce and, in some cases, their number can vary with the ACCEPTED MANUSCRIPT differentiation process (Rozman et al, 2017;Yagdiran et al, 2016). Thus, the low MC-LR-toxicity in those cell lines (primary murine WBC, primary murine CGNs cells, primary hippocampal neurons, RAW246.7 murine macrophage-like cells, BV-2 cells, N2a cells, GT1-7 cells and SH-SY5Y cells) and the increment in the EC 50 value in the differentiated SH-SY5Y cells from our study, compared with the undifferentiated ones, could be due to this fact.…”

Transporters in the Mammary Gland—Contribution to Presence of Nutrients and Drugs into Milk

“…Considerable efforts are being made to predict the presence of drugs in milk based on pharmacokinetic parameters [16,47]. Furthermore, milk residues of toxins or chemicals can alter the expression of transporters which, in turn, mediate the transference of these undesirable compounds into milk [30]. Milk composition strongly affects xenobiotic uptake and concentration.…”

Staphylococcus aureus and Lipopolysaccharide Modulate Gene Expressions of Drug Transporters in Mouse Mammary Epithelial Cells Correlation to Inflammatory Biomarkers

“…The primers were synthetized by Cybergene (Huddinge, Sweden). Sequences of the other murine primers used are reported in [ 9 ].…”

“…ATP-binding cassette (ABC-) and Solute Carrier (SLC-) superfamilies are the two major classes of transporters. Individual members of these superfamilies, such as BCRP, MDR1, MRP1, OATP1A2 (the human orthologue of the mouse Oatp1a5), OCTN1 and OCT1 are expressed in apical and basolateral membranes of epithelial cells in the mammary gland with differential expression during the pregnancy-lactation cycle, as reported in rodents, cows and humans [ 6 – 9 ]. BCRP, which is highly expressed in the mammary gland epithelium during lactation, has a high impact on drug transport into milk [ 10 – 15 ].…”

“…We have previously characterized gene expressions of transporters in mammary gland of mice at different lactation stages and in HC11 cells. Gene expressions of Csn2 (β-casein) , Bcrp , Mdr1 , Mrp1 , Oatp1a5 , Octn1 and Oct1 were altered during gestation and lactation in mice mammary glands and in HC11 cells the expression patterns were affected by differentiation [ 9 , 39 ].…”