Cytotoxicity by endocrine disruptors through effects on ER Ca2+ transporters, aberrations in Ca2+ signalling pathways and ER stress

Abstract

Concerns regarding man-made organic chemicals pervading our ecosystem and having adverse and detrimental effects upon organisms, including man, have now been studied for several decades. Since the 1970s, some environmental pollutants were identified as having endocrine disrupting affects. These endocrine disrupting chemicals (EDC) were initially shown to have estrogenic or anti-estrogenic properties and some were also shown to bind to a variety of hormone receptors. However, since the 1990s it has also been identified that many of these EDC additionally, have the ability of causing abnormal alterations in Ca²⁺ signalling pathways (also commonly involved in hormone signalling), leading to exaggerated elevations in cytosolic [Ca²⁺] levels, that is known to cause activation of a number of cell death pathways. The major emphasis of this review is to present a personal perspective of the evidence for some types of EDC, specifically alkylphenols and brominated flame retardants (BFRs), causing direct effects on Ca²⁺ transporters (mainly the SERCA Ca²⁺ ATPases), culminating in acute cytotoxicity and cell death. Evidence is also presented to indicate that this Ca²⁺ATPase inhibition, which leads to abnormally elevated cytosolic [Ca²⁺], as well as a decreased luminal ER [Ca²⁺], which triggers the ER stress response, are both involved in acute cytotoxicity.