In Vitro Effects of Environmentally Relevant Polybrominated Diphenyl Ether (PBDE) Congeners on Calcium Buffering Mechanisms in Rat Brain

Abstract

Polybrominated diphenyl ethers (PBDEs) are widely used as additive flame-retardants and have been detected in human blood, adipose tissue, and breast milk. Developmental and long-term exposures to these chemicals may pose a human health risk, especially to children. We have previously demonstrated that polychlorinated biphenyls (PCBs), which are structurally similar to PBDEs and cause neurotoxicity, perturb intracellular signaling events including calcium homeostasis and protein kinase C translocation, which are critical for neuronal function and development of the nervous system. The objective of the present study was to test whether environmentally relevant PBDE congeners 47 and 99 are also capable of disrupting Ca(2+) homeostasis. Calcium buffering was determined by measuring (45)Ca(2+)-uptake by microsomes and mitochondria, isolated from adult male rat brain (frontal cortex, cerebellum, hippocampus, and hypothalamus). Results show that PBDEs 47 and 99 inhibit both microsomal and mitochondrial (45)Ca(2+)-uptake in a concentration-dependent manner. The effect of these congeners on (45)Ca(2+)-uptake is similar in all four brain regions though the hypothalamus seems to be slightly more sensitive. Among the two preparations, the congeners inhibited (45)Ca(2+)-uptake in mitochondria to a greater extent than in microsomes. These results indicate that PBDE 47 and PBDE 99 congeners perturb calcium signaling in rat brain in a manner similar to PCB congeners, suggesting a common mode of action of these persistent organic pollutants.

A mechanistic view of polybrominated diphenyl ether (PBDE) developmental neurotoxicity

“…Similar results were also obtained with BDE-47 in mouse cerebellar granule neurons (Costa, Tagliaferri, et al, unpublished). Kodavanti and Ward (2005) later showed that DE-71 (8–22 μM) inhibited Ca 2+ uptake in microsomes, and particularly in mitochondria isolated from rat brain, and Coburn et al (2008) confirmed these findings with BDE-47 and BDE-99.…”

Characterization of Ca2+Signalling in Postnatal Mouse Retinal Ganglion Cells: Involvement of OPA1 in Ca2+Clearance

“…The role of mitochondria as Ca 2+ -buffering systems has been demonstrated in several models by many studies (see for example [42,43]). Furthermore, this was shown to be true also for retinal cells, especially for amacrine cells.…”

Scientific Opinion on Polybrominated Diphenyl Ethers (PBDEs) in Food

“…BDE-47 induced oxidative stress in hippocampal neurons in parallel to a reduced expression level of antioxidative proteins and enzymes (GSH, SOD, GSH-Px), which might lead to induction of apoptosis (He et al, 2008a). In addition, alterations in calcium homeostasis were observed in mitochondria prepared from rat brain (Coburn et al, 2008) and SHSY5Y cells (He et al, 2009b). …”

“…Cytotoxicity as measured by MTT reduction was detected in the neuroblastoma cell line SK-N-MC (Tagliaferri et al, 2010) and the human astrocytoma cell line (132-1N1) (Madia et al, 2004). In addition, alterations in neural migration/differentiation of human neural progenitor cells (Schreiber et al, 2010) and modulations of calcium uptake determined in rat mitochondria (Coburn et al, 2008) have been reported. Large-scale proteomic analyses with non-toxic and cytotoxic concentrations showed that BDE-99 alters the expression of cytoskeletal proteins already at low concentrations in cerebellar cortical cells isolated from rat fetuses on GD21 (Sprague-Dawley rats).…”