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Toxicol Sci. 2018 Dec 21. doi: 10.1093/toxsci/kfy303. [Epub ahead of print]

Placental BCRP/ABCG2 transporter prevents fetal exposure to the estrogenic mycotoxin zearalenone.

Author information

1
Joint Graduate Program in Toxicology, Rutgers University School of Graduate Studies, 170 Frelinghuysen Rd, Piscataway, NJ, USA.
2
Environmental and Occupational Health Sciences Institute, Rutgers University, 170 Frelinghuysen Rd, Piscataway, NJ, USA.
3
Department of Environmental and Occupational Health, School of Public Health, Rutgers University 170 Frelinghuysen Rd, Piscataway, NJ, USA.
4
Department of Pharmacology and Toxicology, Rutgers University, 170 Frelinghuysen Rd, Piscataway, NJ, USA.

Abstract

In the placenta, the BCRP/ABCG2 efflux transporter limits the maternal-to-fetal transfer of drugs and chemicals. Previous research has pointed to the estrogenic mycotoxin zearalenone as a potential substrate for BCRP. Here, we sought to assess the role of the BCRP transporter in the transplacental disposition of zearalenone during pregnancy. In vitro transwell transport assays employing BCRP/Bcrp-transfected MDCK cells and BeWo trophoblasts with reduced BCRP expression were used to characterize the impact of BCRP on the bidirectional transport of zearalenone. In both models, the presence of BCRP protein increased the basolateral-to-apical transport and reduced the apical-to-basolateral transport of zearalenone over a 2 h period. In vivo pharmacokinetic analyses were then performed using pregnant wild-type and Bcrp-/- mice after a single tail vein injection of zearalenone. Zearalenone and its metabolite α-zearalenol were detectable in serum, placentas, and fetuses from all animals, and β-zearalenol was detected in serum and fetuses, but not placentas. There were no significant differences in the maternal serum concentrations of any analytes between the two genotypes. In Bcrp-/- mice, the free fetal concentrations of zearalenone, α-zearalenol, and β-zearalenol were increased by 115%, 84%, and 150%, respectively, when compared to wild-type mice. Concentrations of free zearalenone and α-zearalenol were elevated 145% and 78% in Bcrp-/- placentas, respectively, when compared to wild-type placentas. Taken together, these data indicate that the placental BCRP transporter functions to reduce the fetal accumulation of zearalenone, which may impact susceptibility to developmental toxicities associated with in utero zearalenone exposure.

PMID:
30576553
DOI:
10.1093/toxsci/kfy303

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