Environmental Toxicology and Pharmacology 5 (1998) 105 – 112
Ortho substituted polychlorinated biphenyls elevate intracellular [Ca
2 +
]
in human granulocytes
Ø.A. Voie *, F. Fonnum
Norwegian Defence Research Establishment, Diision for Enironmental Toxicology, P.O. Box 25, N-2007, Kjeller, Norway
Received 23 April 1997; received in revised form 8 October 1997; accepted 13 October 1997
Abstract
The perturbation of Ca
2 +
-homeostasis in human granulocytes exposed to ortho and non ortho substituted polychlorinated
biphenyls (PCB) was investigated. Ortho substituted PCB congeners increased intracellular free calcium, [Ca
2 +
]i, in a concentra-
tion-dependent manner. The increase in [Ca
2 +
]i was inversely proportional to the total surface area of the ortho substituted
congeners. The effect of ortho substituted PCB congeners was dependent upon external Ca
2 +
and phospholipase C activation,
except for a tetra-ortho substituted congener, 2,2,6,6-TeCB, that was not phospholipase C-dependent. We suppose that PCBs
activate phospholipase C which leads to the production of ins(1,4,5)P3. This will release Ca
2 +
from intracellular stores and
subsequently activation of Ca
2 +
release activated Ca
2 +
channels (CRAC) in the plasma membrane. It is also possible that PCBs
activate CRAC in a more direct manner. Our findings show that ortho substituted PCB congeners stimulate [Ca
2 +
]i elevation in
human granulocytes, and this could in part account for the effects of PCB on the immune system. © 1998 Elsevier Science B.V.
All rights reserved.
Keywords: Polychlorinated biphenyls (PCB); Granulocytes; Ca
2 +
; Protein kinase C; Phospholipase C
1. Introduction
Polychlorinated biphenyls (PCB) are stable lipophilic
compounds which possess a strong biomagnification
ability and have become widespread environmental pol-
lutants. PCBs have been used as isolating and cooling
liquids in electrical components. These compounds
show a complex spectrum of biological and toxicologi-
cal properties (Van den Berg et al., 1993). Effects such
as cytochrome P450 1A1 induction, hepatomegaly,
thymic atrophy and reduced body weight gain are all
mediated by coplanar PCB congeners through a com-
mon receptor, the Ah receptor (Nebert, 1989; Safe,
1990). Little attention has been paid to di-, tri- and
tetra-ortho PCB congeners. It has been shown that
these congeners, which are abundantly present in the
environment, cause other biological and toxic effects
such as P450 2B induction, hepatotoxicity, carcinogen-
ity, neurotoxicity and immunotoxicity (Parkinson et al.,
1983; Davis and Safe, 1990; Silberhorn et al., 1990;
Seegal et al., 1991). Toxic effects of PCBs on phago-
cytic cells of experimental animals have been reported
(Loose et al., 1978). Thomas and Hinsdill (1978), have
found that exposure of mice to PCBs enhanced suscep-
tibility to endotoxin shock, and reduced the ability of
the animals to clear the injected microorganisms. A
di-ortho PCB congener (2,2,4,4-TeCB) was recently
found to alter neutrophil function by both stimulating
degranulation and by superoxide production in rats
(Brown and Ganey, 1995). Mature granulocytes consist
of neutrophils (5 ×10
9
cells/l blood), eosinophils (2 ×
10
8
cells/l blood) and basophils (4 ×10
7
cells/l blood)
and are developed from a common pluripotent stem cell
(Cline, 1975). To achieve its mission of localizing and
destroying micro-organisms, the neutrophil must be
* Corresponding author. Tel.: +47 63807824; fax: +47 63807811;
e-mail: oyvind-albert.voie@ffi.no
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