Int. J. Environ. Res. Public Health 2009, 6 3134 and taken up by the proximal tubular cells [48,49]. Moreover, under certain conditions [e.g., cell–cell interactions], metal-induced synthesis of metallothionein may also have an immunosuppressive effect on T-cell function [50]. The toxic effects of mercury on the kidney are well characterized and include acute tubular necrosis and reduced glomerular filtration rate. In small doses, the S3 segment in the cortico-medullary area is the primary target site. As the dose of mercury is increased, the injury spreads to involve the S1 and S2 segments of the proximal tubules [51]. A more recent study has shown that Cd nephrotoxicity is also associated with alterations in the localization of the tight junction protein claudin-2 in the proximal tubule [52]. Additional studies have shown that N-cadherin and its associated proteins may be involved in the nephrotoxic responses to other metals such as Hg [36,53] and bismuth (Bi) [54]. The biochemical mode of action for Hg toxicity has been postulated to involve interaction of Hg with thiol groups of proteins (R–S–Hg+; R–S–Hg–S–R; R<S2>Hg) [55] via either binding or precipitation of SH groups [56]. Hg has a relatively large thiol association constant, thereby enabling this reaction [57]. Despite the thermodynamic stability of metal–SH complexes, they are generally kinetically labile, and hence are rapidly mobile in most biological systems [58]. Although mercuric ions bind only about 1% of the SH groups on the surface of red blood cells, this binding action is substantial enough to inhibit sugar transport and energy production [59]. Consistent with its thiol binding properties, Hg has been shown to preferentially distribute in the lysosomal fraction of rat cells [57] and interact with phospholipid membranes (specifically phosphatidylserine and phosphatidylcholine) [57,60,61]. Furthermore, while Hg can inhibit enzymes with SH groups, and interact with membrane proteins, it can also substitute for zinc in certain zinc- activated enzymes (e.g., carboxypeptidase) [62] or replace metallothionein-bound Zn, Cu, and Cd. The ability of Hg to interact with phospholipids and specific enzyme systems may help explain the cell degeneration, apoptosis and necrosis, and overall toxicity observed in immune system cells. The effects of I-Hg on transduction at cellular membrane channels have been investigated through studies of Hg2+. In a study on the effects of inorganic Hg on cell membranes, Liang et al. [63] found that Hg2+ induced channelopathies in guinea pig sensory cells by impairing K+ channels and changing the permeability of the cell membrane. Leong et al. [64], for example, found that Hg2+ ions suppressed neuronal somata sprouting, thus inhibiting neurite growth in snails. It has been reported that inorganic and organic mercury block voltage-activated Ca2+ channels in nerve terminals and disrupt ligand-gated ion channels [65,66]. These and other experimental animal studies demonstrate a wide range of biological effects from exposure to different species of Hg [67–70]. Enlarged kidneys are indicative of renal inflammation and proliferative lesions following chronic exposure to Cd [71] or As [72]. The increased kidney injury from Cd and As co-exposure might be due to increased oxidative stress. It has been proposed that both Cd [73–77] and As [76,77] may produce oxidative stress as a cellular mechanism of toxicity. Other recent studies have shown that alterations in the activity of focal adhesion kinase may play a key role in the malignant transformation of cells by arsenic [78,79]. In this regard, Cd and As co-exposure produces significantly more lipid peroxidation in liver and kidney than either inorganic given alone [80]. In regard to aetiology of porcine nephropathy, the production of multiple toxins as is sometimes the environmental situation, presents a problem that has not been sufficiently investigated. Co-incidence of