Placental BCRP transporter reduces cadmium accumulation and toxicity in immortalized human trophoblasts

Ranran Zhang; Lauren Walker; Xia Wen; Cathleen Doherty; Ludwik Gorczyca; Brian Buckley; Emily S Barrett; Lauren M Aleksunes

doi:10.1016/j.reprotox.2023.108466

Placental BCRP transporter reduces cadmium accumulation and toxicity in immortalized human trophoblasts

Reprod Toxicol. 2023 Oct:121:108466. doi: 10.1016/j.reprotox.2023.108466. Epub 2023 Sep 1.

Authors

Ranran Zhang¹, Lauren Walker², Xia Wen³, Cathleen Doherty⁴, Ludwik Gorczyca⁵, Brian Buckley⁴, Emily S Barrett⁶, Lauren M Aleksunes⁷

Affiliations

¹ Department of Biostatistics and Epidemiology, Rutgers University, Piscataway, NJ 08854, USA.
² Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA.
³ Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA; Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA.
⁴ Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA.
⁵ Joint Graduate Program in Toxicology, Rutgers University, Piscataway, NJ 08854, USA.
⁶ Department of Biostatistics and Epidemiology, Rutgers University, Piscataway, NJ 08854, USA; Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA.
⁷ Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA; Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA. Electronic address: aleksunes@eohsi.rutgers.edu.

PMID: 37660740
PMCID: PMC10591833 (available on 2024-10-01)
DOI: 10.1016/j.reprotox.2023.108466

Abstract

Cadmium (Cd) is a ubiquitous environmental metal detectable in most pregnant women. Animal and human studies demonstrate that in utero exposure to Cd reduces birth weight and impairs perinatal growth due to placental toxicity. BCRP is a prominent transporter that can efflux xenobiotics from the placenta. This study sought to investigate Cd transport and toxicity in cultured human BeWo trophoblasts with reduced expression and function of the placental barrier transporter BCRP. Knockdown (KD) of BCRP protein expression and function in BeWo trophoblasts increased the intracellular accumulation of Cd by 100% following treatment with 1 μM CdCl₂. No change in the expression of Cd uptake transporters was observed between control and BCRP-KD cells. Reduced BCRP expression impaired viability of BeWo cells exposed to CdCl₂ for 48 hr (BCRP-KD IC₅₀: 11 μM, control cells IC₅₀: 18 μM). Moreover, BCRP-KD cells were more sensitive to CdCl₂-induced cytotoxicity compared to control BeWo cells. CdCl₂ treatment strongly induced the expression of the metal-binding protein metallothionein (MT) in both control and BCRP-KD cells, with significantly greater MT upregulation in Cd-treated BCRP-KD cells. These data suggest that the BCRP transporter reduces Cd accumulation in syncytiotrophoblasts, which may be one mechanism to reduce subsequent toxicity to the placenta and developing fetus.

Keywords: BCRP; BeWo; Cadmium; Efflux; Metal; Toxicity; Transporter.

Abstract

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