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

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 CdCl. 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 CdCl for 48 hr (BCRP-KD IC: 11 μM, control cells IC: 18 μM). Moreover, BCRP-KD cells were more sensitive to CdCl-induced cytotoxicity compared to control BeWo cells. CdCl 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.