Placental BCRP/ABCG2Transporter Prevents Fetal Exposure to the Estrogenic Mycotoxin Zearalenone

Abstract

In the placenta, the breast cancer resistance protein (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 Madine-Darby canine kidney 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 À/À mice after a single tail vein injection of zearalenone. Zearalenone and its metabolite a-zearalenol were detectable in serum, placentas, and fetuses from all animals, and b-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 À/À mice, the free fetal concentrations of zearalenone, a-zearalenol, and bzearalenol were increased by 115%, 84%, and 150%, respectively, when compared with wild-type mice. Concentrations of free zearalenone and a-zearalenol were elevated 145% and 78% in Bcrp À/À placentas, respectively, when compared with 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.

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

“…In addition, the estrogenic mycotoxin zearalenone was first described as an ABCG2 substrate by Xiao et al [66], who observed decreased intracellular accumulation as well as increased resistance to the cytotoxicity mediated by this compound in ABCG2 -overexpressing cells. The same research group later confirmed the specific involvement of murine and human ABCG2 in bidirectional transport assays and revealed that foetal exposure to this mycotoxin was increased in Abcg2- knockout mice [145]. Murine and human ABCG2 is also involved in the efflux of the mycotoxin ochratoxin A in cell culture models [84].…”

ZIKV disrupts placental ultrastructure and drug transporter expression in mice

“…However, no effects were observed in ICompetent animals at a low ZIKV titer or in Abcg1 in any experimental setting. As such, ZIKV also likely increases the fetal accumulation of Bcrp substrates (antibiotics, antiretrovirals, sulfonylureas, folate, mercuric species, estrogenic mycotoxins, carcinogens phototoxic compounds, among others) and disrupts placental lipid homeostasis (lipids, cholesterol, cytotoxic oxysterols) by reducing placental Abca1 expression(25,(66)(67)(68)(69).…”

Breast cancer resistance protein (Bcrp/Abcg2) is selectively modulated by lipopolysaccharide (LPS) in the mouse yolk sac

“…In the pharmacological and toxicological context, results obtained at GD15.5 suggest that LPS-induced upregulation of Bcrp in the amnion facing-mesothelium, favors the entry of Bcrp substrates into the embryo/fetal compartment. In this context, Bcrp substrates of clinical importance comprise 1) xenobiotics: including antibiotics, antiretrovirals, sulfonylureas, nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), and 2) toxicants : including select mercuric species, estrogenic mycotoxins, carcinogens phototoxic compounds [ 19 , [28] , [29] , [30] , [31] ]. We have previously demonstrated a decrease in placental Bcrp expression in mice exposed to LPS in the same experimental design and dose regimens [ 32 ].…”