Down-regulation of the placental BCRP/ABCG2 transporter in response to hypoxia signaling

Lissa N. Francois, Ludwik Gorczyca, Jianyao Du, Kristin M. Bircsak, Elizabeth Yen, Xia Wen, Mei Juan Tu, Aiming Yu, Nicholas P. Illsley, Stacy Zamudio, Lauren M. Aleksunes

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Introduction The BCRP/ABCG2 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 in vitro and in human pregnancies. Methods Human BeWo choriocarcinoma cells were treated with the hypoxia mimetic, cobalt chloride (CoCl2), 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. Results CoCl2 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). Discussion 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.

Original languageEnglish (US)
Pages (from-to)57-63
Number of pages7
JournalPlacenta
Volume51
DOIs
StatePublished - Mar 1 2017

Fingerprint

Down-Regulation
Oxygen
Pregnancy
Fetus
Choriocarcinoma
Peroxisome Proliferator-Activated Receptors
Proteins
Trophoblasts
Hypoxia
ATP Binding Cassette Transporter, Sub-Family G, Member 2
Placenta
Transcription Factors
Western Blotting
Enzyme-Linked Immunosorbent Assay
Parturition
Apoptosis
Messenger RNA
Membranes
Pharmaceutical Preparations

Keywords

  • ABCG2
  • BCRP
  • Hypoxia
  • Placenta
  • Transporter

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology
  • Developmental Biology

Cite this

Francois, L. N., Gorczyca, L., Du, J., Bircsak, K. M., Yen, E., Wen, X., ... Aleksunes, L. M. (2017). Down-regulation of the placental BCRP/ABCG2 transporter in response to hypoxia signaling. Placenta, 51, 57-63. https://doi.org/10.1016/j.placenta.2017.01.125

Down-regulation of the placental BCRP/ABCG2 transporter in response to hypoxia signaling. / Francois, Lissa N.; Gorczyca, Ludwik; Du, Jianyao; Bircsak, Kristin M.; Yen, Elizabeth; Wen, Xia; Tu, Mei Juan; Yu, Aiming; Illsley, Nicholas P.; Zamudio, Stacy; Aleksunes, Lauren M.

In: Placenta, Vol. 51, 01.03.2017, p. 57-63.

Research output: Contribution to journalArticle

Francois, LN, Gorczyca, L, Du, J, Bircsak, KM, Yen, E, Wen, X, Tu, MJ, Yu, A, Illsley, NP, Zamudio, S & Aleksunes, LM 2017, 'Down-regulation of the placental BCRP/ABCG2 transporter in response to hypoxia signaling', Placenta, vol. 51, pp. 57-63. https://doi.org/10.1016/j.placenta.2017.01.125
Francois, Lissa N. ; Gorczyca, Ludwik ; Du, Jianyao ; Bircsak, Kristin M. ; Yen, Elizabeth ; Wen, Xia ; Tu, Mei Juan ; Yu, Aiming ; Illsley, Nicholas P. ; Zamudio, Stacy ; Aleksunes, Lauren M. / Down-regulation of the placental BCRP/ABCG2 transporter in response to hypoxia signaling. In: Placenta. 2017 ; Vol. 51. pp. 57-63.
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abstract = "Introduction The BCRP/ABCG2 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 in vitro and in human pregnancies. Methods Human BeWo choriocarcinoma cells were treated with the hypoxia mimetic, cobalt chloride (CoCl2), 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. Results CoCl2 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). Discussion 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.",
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AU - Francois, Lissa N.

AU - Gorczyca, Ludwik

AU - Du, Jianyao

AU - Bircsak, Kristin M.

AU - Yen, Elizabeth

AU - Wen, Xia

AU - Tu, Mei Juan

AU - Yu, Aiming

AU - Illsley, Nicholas P.

AU - Zamudio, Stacy

AU - Aleksunes, Lauren M.

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N2 - Introduction The BCRP/ABCG2 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 in vitro and in human pregnancies. Methods Human BeWo choriocarcinoma cells were treated with the hypoxia mimetic, cobalt chloride (CoCl2), 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. Results CoCl2 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). Discussion 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.

AB - Introduction The BCRP/ABCG2 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 in vitro and in human pregnancies. Methods Human BeWo choriocarcinoma cells were treated with the hypoxia mimetic, cobalt chloride (CoCl2), 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. Results CoCl2 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). Discussion 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.

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