ES/RP 531 Fundamentals of Environmental Toxicology Fall 2005 ESRP531 Lect 12 Neurotox.doc Page 1 of 21 October 5, 2005 Lecture 12: Neurotoxicity I I. Introduction: The Importance Neurotoxicity in the Context of Environmental Toxicology A. Of all the environmental contaminants, the pesticides are perhaps the most studied from the perspective of environmental chemistry and toxicology 1. With respect to the mode of action, i.e., how toxicity is manifested through biochemical interactions, pesticides are well studied because they must work against pests yet provide a margin of safety to the user. 2. For the most part, the pesticides that have been most environmentally contentious are toxicants with biochemical modes of action in the nervous system. a. Nearly all of the pesticides with pharmacodynamics (toxicodynamic) action at the level of the nervous system are insecticides. 1. The ultimate biochemical receptors are at different sites on the nerve cell. II. Normal Nervous System Physiology A. Because nerve physiology is interfered with by insecticides, a discussion of normal nerve physiology is necessary to understand mode of action of commonly used insecticides B. General Overview 1. The nervous system provides rapid coordination of sensory and mechanical functions (i.e., muscle movement) and interacts (i.e., carries information to) with the endocrine and immune system. 2. Consists of electrically excitable cells (neurons) that can generate electrical signals long distances without degrading the strength of the signal. 3. Functions similarly among all animals. 4. Basic structures of the neuron a. Soma (cell body containing the nucleus and providing metabolic maintenance of the cell) b. Dendrites (receive and carry signals toward the soma) c. Axon (carries signals away from the soma) d. Supporting cells (glial cells, myelin sheath) C. Nerve Cell Morphology 1. A single nerve cell is called a neuron. 2. A neuron consists of: a. Cell body (soma) containing the nucleus and numerous thin fibers extending from it. 1. The cell body provides metabolic maintenance of the neuron. b. The fibers consist of a single long one called the axon extending in one direction and numerous shorter ones called the dendrites that are heavily branched. (See Figure 1) c. The entire nerve cell, including the cell body, axon, and dendrites, is surrounded by a membrane that also acts as electrical insulation. This insulating membrane is called the myelin sheath.ES/RP 531 Fundamentals of Environmental Toxicology Fall 2005 ESRP531 Lect 12 Neurotox.doc Page 2 of 21 Figure 1. Nerve cell morphology (adapted from Scientific American) d. The axon terminates at other nerve cells without touching them; 1. Instead there is a small gap called the synapse between nerve cell axons and dendrites. (See Figures 1 & 3) D. Organization of the Nervous System 1. Sensory neurons a. Transmit information collected from external stimuli b. Respond to endogenous stimuli 2. Interneurons a. Link other neurons within the central nervous system (i.e., brain and nerve cord) b. Networked to exchange information and perform complex “computations” leading to behavior (or thought) 3. Motor neurons a. Carry information (instructional signals) to effector organs 1. An effector is a cell, tissue, or organ that acts to change the condition of an organism in response to neuronal or hormonal signals (for ex., contraction of muscles; sections by glands). 4. Supportive Cells a. Provide structural, insulative, and metabolic functions to the neuron. E. Transmission of Nerve Signals: Overview (see Figure 2) 1. The plasma membrane of the soma and its dendrites receive “signals” from the terminals of other neurons. a. As will be explained later, these signals are in the form of neurotransmitter chemicals (most common form) or as electrical current (less common form), but all signaling is transduced to electrical information. 2. All the signals received by one soma from other axons are integrated in a region called the axon hillock. The received electrical signals are actually membrane voltage changes.ES/RP 531 Fundamentals of Environmental Toxicology Fall 2005 ESRP531 Lect 12 Neurotox.doc Page 3 of 21 a. Sufficient input will initiate a large enough change in the plasma membrane voltage potential to generate an action potential. b. The action potential is what is commonly thought of as the nerve impulse or signal that travels outward from the axon hillock down the axon to its terminus adjacent to different neurons dendrites. Figure 2. General overview of nerve cell and signal transmission pathway. Drawing from Randall, D., W. Burggren, and K. French. 2002. Eckert Animal Physiology: Mechanisms and Adaptations, 5th Ed. W.H. Freeman, NY. F. Electrical Physiology of the Nerve Cell 1. The nerve signal conducts down the length of the axon in a one-way direction (See Figure 3). a. The nerve signal is actually an electrical signal that travels along the length of the axon until it reaches the synapse where the axon and dendrite are separated. 2. The ability of the nerve cell to conduct electrical signals down its axon is due to two factors: a. Permeability of the membrane to ions 1. Cell membrane is semipermeable; allows some ions to freely diffuse across it, but other ions cannot; b. The membrane electrical potential (i.e., the membrane potential) 1. Membrane potential is the charge separation, or potential difference, across the membrane inside surface and the outside surface. 3. Cell membrane and the resting potential (Figure 4) a. The membrane potential existing prior to conduction of the nerve impulse is called the resting potential. b. Cell membrane is freely permeable to potassium but not to sodium; c. In addition to sodium and potassium, chloride and organic anions are present; (See Table 1 for ion concentrations inside and outside of the membrane. d. The difference in distribution of the ions at equilibrium creates the resting potential, which is about –60 to -70 mV (millivolts) of electrical potential; 1. The inside of the cell is negative with respect to the outside, i.e., it is POLARIZED.ES/RP 531 Fundamentals of Environmental Toxicology Fall 2005 ESRP531 Lect 12 Neurotox.doc Page 4 of 21 Figure 3. Nerve cell axon terminates prior to physically touching the dendrites. The gap is called the synapse. The nerve signal is transmitted