Bisphenol A Binds to Protein Disulfide Isomerase and Inhibits Its Enzymatic and Hormone-Binding Activities

Abstract

Bisphenol A [2,2-bis-(4-hydroxyphenyl) propane; BPA] is a versatile industrial material for plastic products, but is increasingly being recognized as a pervasive industrial pollutant as well. Accumulating evidence indicates that the environmental contaminant BPA is one of the endocrine-disrupting chemicals that potentially can adversely affect humans as well as wildlife. To define the molecular aspects of BPA action, we first investigated the molecules with which it physically interacts. High BPA-binding activity was detected in the P2 membrane fraction prepared from rat brains. As determined by SDS-PAGE analysis, the molecular mass of a BPA-binding protein purified from the rat brain P2 fraction was 53 kDa. The N-terminal amino acid sequence of the purified BPA-binding protein was identical with that of the rat protein disulfide isomerase (PDI), which is a multifunctional protein that is critically involved in the folding, assembly, and shedding of many cellular proteins via its isomerase activity in addition to being considered to function as an intracellular hormone reservoir. The Kd value of BPA binding to recombinant rat PDI was 22.6 +/- 6.6 microm. Importantly, the binding activity of L-T3 and 17beta-estradiol hormones to PDI was competitively inhibited by BPA in addition to abolishing its isomerase activities. In this paper we report that the ubiquitous and multifunctional protein PDI is a target of BPA and propose that binding to PDI and subsequent inhibition of PDI activity might be mechanistically responsible for various actions of BPA.

NTP‐CERHR expert panel report on the reproductive and developmental toxicity of bisphenol A

“…PDI is believed to act as a buffer for these hormones in cells. PDI is of interest because bisphenol A has been reported to bind to the T 3 binding sites of PDI with 10 to 100-fold lower affinity than T 3 (Hiroi, 2006) and inhibit the binding of T 3 to PDI when bound. PDI immunoreactivity was increased in the neocortex of bisphenol A treated fetuses from GD 12.5-GD 16.5 and in subplate cells at GD 14.5.…”

Bisfenol A’ya Maruz Bırakılmış Sıçanlarda İmmun Hücre sayısı, Plazma İmmunglobulin İçeriği ve INF-γ Gen Ekspresyonu

“…BPA changed immune response as it increased gene expression of INF-γ and increased IgG and IgA. In some studies [4,26,27] reported that BPA has multiple actions on patterns of cytokine and antibody production, response to infection, and autoimmune disease progression, T cell subsets, B cell functions, and dendritic cell and macrophage biology. The immunological activities of BPA may be mediated through estrogen receptor signaling, arylhydrocarbon receptor, and the peroxisome proliferator-activated receptor family of nuclear receptors [5] .…”

“…In the last two decades an increasing interest can be observed on biological effects of this compound. Most studies on endocrine disrupters including bisphenol A have been focused on reproductive toxicology and carcinogenesis [2][3][4][5] . It acts as endocrine disrupter with estrogenic activities in the body.…”

Apoptosis-inducing activity of endocrine-disrupting chemicals in cultured PC12 cells

“…It has been suggested previously that BPA functions either estrogenically or anti-estrogenically when binding in vitro to estrogen receptor α in competition with estradiol [11]. The relative binding affinity of BPA to estrogen receptor α is known to be more than 1000 times weaker than that of estradiol.…”

“…Bisphenol A (BPA) is a small estrogenic monomer that is polymerized to produce polycarbonate plastic resins that are used to line metal cans [11,12]. BPA is also used in other types of plastic, such as polyvinyl chloride (PVC), used in the manufacture of medical tubing, toys and water pipes, and polyethylene terephthalate (PET), which is used in soda and mineral water bottles.…”