Page 719 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

684 SECTION | IX Gases, Solvents and Other Industrial Toxicants

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FIGURE 51.2 The proposed molecular mechanism of action of 2,3,7,8-tetrachorinated dibenzo-p-dioxin (TCDD) and TCDD-like chemicals.
Schematic representation of functioning of the AhR (aryl hydrocarbon receptor) pathway. After entering the cell, the TCDD-like compounds bind to a
protein complex in the cytoplasm consisting of AhR, Hsp90, AIP. Upon ligand binding AIP is released, exposing nuclear localization signal on AhR
and leading to translocation of AhR from the cytoplasm to the nucleus. Within the nucleus, Hsp90 are released and AhR heterodimerizes with the
Aryl Receptor Nuclear Translocator (ARNT). The AhR-ARNT complex then binds to multiple enhancer elements in the promotor region of the
responsive genes in the AhR battery such as CYP1A. Source: Adapted from Denison, M.S., Nagy, S.R., 2003. Activation of the aryl hydrocarbon
receptor by structurally diverse exogenous and endogenous chemicals. Ann. Rev. Pharmacol. Toxicol. 43, 309 334.

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cells, while coplanar PCB had no effect even at 100 μM Madison, 1994). The congener 2,2 -DCB, but not 4,4 -
(Kodavanti and Tilson, 2000). Experiments with several DCB, inhibited both cytosolic (nNOS) and membrane
pharmacological agents revealed that the effects of PCBs (eNOS) forms of NOS (Sharma and Kodavanti, 2002).
are additive with glutamate, and none of the channel (glu- These in vitro studies clearly demonstrated that second
tamate, calcium, and sodium) antagonists blocked the messenger systems involved in the development of the
response of 2,2 -DCB (Kodavanti et al., 1994). nervous system, LTP, and learning and memory are sensi-
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Immunoblots of PKC-alpha and epsilon indicated that tive targets for the ortho-substituted PCBs and related
noncoplanar ortho-PCB decreased the cytosolic form and chemicals. Fig. 51.3 illustrates the intracellular signaling
increased the membrane form significantly at 25 μM events affected by these chemicals (ortho-PCBs and com-
(Yang and Kodavanti, 2001). Subsequent SAR studies mercial PCB mixtures) at low micromolar concentrations
indicated that congeners that are noncoplanar increased and shorter exposure periods, where cytotoxicity is not
PKC translocation, while coplanar congeners did not (for evident. These signaling pathways include calcium
review, see Kodavanti and Tilson, 1997, 2000). This was homeostasis and PKC translocation. The rise of intracellu-
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further strengthened by observations with structurally lar free Ca is slow, but steady following exposure. This
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similar chemicals such as polychlorinated diphenyl ethers free Ca rise could be due to increased calcium influx,
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(Kodavanti et al., 1996). Nitric oxide (NO), which is pro- inhibited Ca buffering mechanisms, and/or calcium
duced by nitric oxide synthase (NOS), is a gaseous neuro- release from intracellular stores by the products of mem-
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transmitter. NO has an important role as a retrograde brane phospholipases. This increase in free Ca could
messenger in long-term potentiation (LTP), learning and cause translocation of PKC. The coplanar non-ortho-
memory processes, and endocrine function (Schuman and PCBs have marginal effects on calcium homeostasis and