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<h5 class="section-title" id="d14655294e222">Introduction</h5>
<p id="P1">The BCRP/
<i>ABCG2</i> efflux transporter protects the developing fetus by limiting the transplacental
transfer
of drugs and chemicals and prevents the apoptosis of trophoblasts. The purpose of
this study was to determine whether hypoxia-related signaling alters placental BCRP
expression and function
<i>in vitro</i> and in human pregnancies.
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<h5 class="section-title" id="d14655294e233">Methods</h5>
<p id="P2">Human BeWo choriocarcinoma cells were treated with the hypoxia mimetic,
cobalt chloride
(CoCl
<sub>2</sub>), or 3% oxygen for 24-48 h. Activation of HIF-1α signaling and regulation
of BCRP
was assessed using qPCR, ELISA, western blotting and a fluorescent substrate transport
assay. In addition, healthy term placentas from high altitude pregnancies with chronic
hypoxia were assessed for BCRP expression.
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<h5 class="section-title" id="d14655294e241">Results</h5>
<p id="P3">CoCl
<sub>2</sub> and 3% oxygen increased HIF-1α protein signaling and decreased the mRNA
and protein
expression of BCRP by 30-75% in BeWo cells. Reduced BCRP expression corresponded with
impaired efflux activity during hypoxia as evidenced by accumulation of the substrate
Hoechst 33342. A number of transcription factors known to regulate BCRP, including
AHR, NRF2 and PPARγ, were also coordinately down-regulated by 3% oxygen in BeWo cells.
Moreover, women who gave birth at a high altitude (3100 m) exhibited signs of chronic
placental hypoxia, including enhanced protein expression of the HIF-1α target GLUT1,
and had reduced BCRP levels in microvillous membranes compared to women at a moderate
altitude (1600 m).
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<h5 class="section-title" id="d14655294e249">Discussion</h5>
<p id="P4">This study provides novel insight into the regulation of the placental
BCRP transporter
by hypoxia, which may be important for exposure of the fetus to chemicals during early
development and in hypoxia-related pregnancy disorders.
</p>
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<img alt="" class="figure" src="/document_file/239cf26e-85b5-4862-ad3a-e8971eb5d19c/PubMedCentral/image/nihms-847720-f0001.jpg"/>
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