Bisphenol A Inhibits the Transporter Function of the Blood-Brain Barrier by Directly Interacting with the ABC Transporter Breast Cancer Resistance Protein (BCRP).

Elin Engdahl,Daniel J Rigden,Maarten D M Van Schijndel,Joëlle Rüegg,Anna Herland,Dimitrios Voulgaris,Kerry A Ramsbottom,Michela Di Criscio

doi:10.3390/ijms22115534

Abstract

The breast cancer resistance protein (BCRP) is an important efflux transporter in the blood-brain barrier (BBB), protecting the brain from a wide range of substances. In this study, we investigated if BCRP function is affected by bisphenol A (BPA), a high production volume chemical used in common consumer products, as well as by bisphenol F (BPF) and bisphenol S (BPS), which are used to substitute BPA. We employed a transwell-based in vitro cell model of iPSC-derived brain microvascular endothelial cells, where BCRP function was assessed by measuring the intracellular accumulation of its substrate Hoechst 33342. Additionally, we used in silico modelling to predict if the bisphenols could directly interact with BCRP. Our results showed that BPA significantly inhibits the transport function of BCRP. Additionally, BPA was predicted to bind to the cavity that is targeted by known BCRP inhibitors. Taken together, our findings demonstrate that BPA inhibits BCRP function in vitro, probably by direct interaction with the transporter. This effect might contribute to BPA’s known impact on neurodevelopment.

Highlights

To investigate the effect of bisphenol A (BPA), bisphenol S (BPS), and bisphenol F (BPF) on breast cancer resistance protein (BCRP) function in the blood-brain barrier (BBB), we used a human in vitro BBB model of iPSC-derived human-induced brain microvascular endothelial-like cells (BMECs) grown on transwell® permeable supports. The advantage of this model is the generation of barrier-forming cells that have an in vivo-like resistance, termed transepithelial electrical resistance (TEER) [32,33], as well as expression of proteins characteristic for human BBB, e.g., tight junction proteins and BBB transporters such as the BCRP [34,35,36,37,38]
We investigated the effect of BPA, BPS, and BPF on BCRP function and found that 500 nM BPA inhibits BCRP efflux transportation in a human BBB in vitro model
BPF and BPS showed the same trend as BPA, neither BPF nor BPS

Summary

Introduction

The blood-brain barrier (BBB) is the interface between systemic blood circulation and the central nervous system (CNS). This tight barrier consists of endothelial cells of the capillary walls in a complex network with astrocytes and pericytes. By controlling the flux of nutrients, metabolites, and drugs between the blood and CNS, the BBB is the gatekeeper of brain functionality. Impairment of BBB function contributes to the pathology of neurological conditions, including multiple sclerosis, stroke, epilepsy, and Alzheimer’s disease [1,2,3,4,5]. BBB integrity has been implicated in playing a role in neurodevelopmental disorders, such as autism spectrum disorder [6]

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