Session 24: Stress and Toxicity -------------------------------------------------------------------------------- Student suggestions about the introductory film loop for the course: It should contain something on the instructor's background (name, research focus, qualifications, impetus for teaching mammalian toxicology); description of what mammalian toxicology is about; course objectives and focus; course structure. -------------------------------------------------------------------------------- Stress and toxicity: Role of heat shock proteins. ( http://ehpnet1.niehs.nih.gov/docs/1998/Suppl-6/1319-1323wijeweera/abstract.html) Role of adrenal axis. Role of CNS, adrenal medulla, neurotransmitters. Role of renal blood flow control. Role of leptin axes. Disease. Oxidative stress. -------------------------------------------------------------------------------- Readings/references: Types of stress in mammalian cells: http://www.csa.ru/Inst/gorb_dep/inbios/SSE/2_4type.htm A primer on Oxidative Stress: http://www.agronomy.psu.edu/courses/AGRO518/Oxygen.htm Diagram of pathways: http://www.sigma-aldrich.com/sigma-aldrich/image/sg_ls_cs_slide30.jpg Summary reactive oxygen and nitrogen species: http://www.fedem.org/revista/n8/imagenes/image008.jpg Hepatotoxicity slide presentation: http://www.le.ac.uk/pa/msc/heptox.pdf Thiols in oxidative stress: http://www.pharmanac.net/pdf_documentation/ OSATDITPAPBLIHIP.pdf A definition of oxidative stress: http://www.bb.iastate.edu/~jat/glutchp.html DNA damage in oxidative stress: http://www.dojindo.com/newsletter/review_vol2.html Mitochondrial dysfunction: http://www.mrc-dunn.cam.ac.uk/research/dysfunction.html Oxidative stress and calcium: http://www.grc.nia.nih.gov/branches/lns/linka.htm A doctor's primer on antioxidants: http://www.thedoctorslounge.net/education/tutorials/antioxidants/antioxidants1.htm Oxidative stress in optical systems: http://www.djo.harvard.edu/meei/OA/lat/INDEX.html Slide presentation on Vitamin E and oxidative stress: http://qcom.etsu.edu/nutrition/vit%20e%20presentation/ tsld002.htm Abstract of a Review: http://ehpnet1.niehs.nih.gov/docs/1998/ 106p375-384kelly/abstract.html Abstract of an article on radiation associations: http://www.lowdose.org/pubs/ehp/docs/klaunigabstract.html -------------------------------------------------------------------------------- Stress Internal stimuli (loss of homeostasis, chemical signal imbalance) External stimuli (environmental -- heat, light, pressure, sound, biological interactions between organisms, interpersonal/behavioral) Note either source of stimulus can be acute or chronic. Stress gives rise to supra- or ab-normal systemic activities. At the cell level these may involve heat shock protein expression, changes in membrane potentials and ion balance, changes in cellular metabolism, changes in gene expression, changes in receptor numbers, etc. At the tissue level, these translate into changes in chemical or hormonal sensitivity, "irritability," capacity to respond or function. At the system level the changes give rise to alterations in excitability and chemical signal output. Examples include: Adrenal axis/adrenal cortex >>> CRH, cortisol, DHEAS levels rise thereby increasing blood glucose levels, enhancing lipolysis, suppressing immune functions among other end results. Adrenal medulla >>> norepinephrine & epinephrine rise thereby altering blood pressure and cardiac rate. Kidney >>> responds to vasopressin by increasing water retention; responds to a fall in renal perfusion by increasing renin output resulting in rises in angiotensin I & II and aldosterone (from the adrenal cortex, glomerulosa layer) with subsequent increases in sodium retention and blood pressure. CNS >>> may increase output of opiate peptides to suppress nociceptive stimuli; may decrease NPY and other peptides while increasing CART, CRH, and other peptides in the leptin pathways resulting in suppression of apetite; may increase output of vasopressin, dopamine, serotonin or other neurotransmitters causing alterations in both sympathetic and parasympathetic nerve transduction pathways. Thyroid >>> may increase output of thyroxine causing generalized increases in metabolic rate and increased thermal output; under chronic stress the reverse may occur; thermal control is compromised under both situations. Immune system >>> interleukins, CRH, bradykinin, and prostaglandins may all be released causing alterations in adrenal, thyroid, CNS and other functions. Note that the kinins and prostaglandins may stimulate smooth muscle contractions of the vascular endothelium or even organ walls -- stomach, intestine, uterus (Clearly infection is an environmental stressor.) Note several normal biological processes utilize stress as a signal. Disease has been mentioned. Should toxins alter any of the steps involved in these signalling pathways and intracellular signal cascades, they have the potential to either block or exascerbate the stressful condition. The birth process involves stress on both the offspring and the mother. In the offspring near term the maturing thyroid axis and general rapid growth of the fetus brings on a generalized anoxic stress. Generalized "crowding" by the maternal organs including the pelvic bones stimulate the fetal adrenal axis to produce CRH, ACTH, and resultant increased cortisol (and DHEAS). Placental CRH is also rising at this time and helps reinforce this stimulus of the fetal adrenal axis. The adrenal steroids alter the metabolism of steroids and prostaglandins in the placenta. Progesterone production falls in favor of estrogen production while the placental inactivation of prostaglandins that normally occurs during pregnancy is inactivated. The increased estrogens, and decreased progesterone levels favor increases in oxytocin receptor numbers in the maternal myometrial cells. They also increase the maternal systemic stimulation of the posterior pituitary production of oxytocin and the myometrial cells' formation of gap junctions. The oxytocin actions both directly and mediated by formation of prostaglandins in myometrial cells stimulate coordinated contractions of the maternal myometrium and ultimately lead to completion of parturition. Other systems also contribute to the process: pudendal nerve compression during late pregnancy decreases output of norepinephrine which normally decreases myometrial contractility; opiates are increased dramatically during birth to act as endogenous pain suppressors. Additional mechanisms may also contribute in this case. For example, progesterone levels which peak at or near term for most mammals may act via glucocorticoid receptors during the latter part of pregnancy to alter glucose metabolism, immune responses, and possibly even help decrease expression of prostaglandin inactivating enzymes, though this latter mechanism has yet to be shown. Shock is another, if extreme, example of systemic stress that may be accelerated or induced by toxicant actions. Generally breakdown of kidney function or of osmotic tissue barriers leads to decrease in blood pressure, decline in cardiac rate and output, a decrease in oxygen and glucose perfusion of the brain and other organs, CNS depression, respiratory depression, and systemic failure. Any toxicant accelerating this chain of events may cause shock if given in high enough dose. -------------------------------------------------------------------------------- Currently, the major path for actions of toxicants in causing tissue effects not related to uptake by particular receptors or via indirect impacts on cellular metabolism or cell division, involves the concept of oxidative stress. This is covered in some depth in Hodgson and Smart, Introduction to Biochemical Toxicology, 3rd Ed, 2001, John Wiley & Sons, Inc.: New York, NY, 235-253. Specific elements of the concept are covered in the links provided at the beginning of this session. The concept entails the idea that cells are damaged as a result of the breakdown in balance of reduction and oxidation within the cells. If oxidative conditions arise as a result of the unchecked intracellular production of peroxide or superoxide radicals, or reactive nitrogen species, these molecules can covalently alter other molecules, including macromolecules, within the cell. Oxidized lipids or proteins will compromise membrane functions so mitochondrial or cell membrane potentials may be altered. Intracellular signalling may also stimulate production of "cell death" signals causing the initiation of the events leading to apoptotic cell death. The production and redox cycling of glutathione plays a key role in maintaining intracellular oxidative balance. Adequate levels of other reductive species such as retinoids, ascorbic acid, tocopherol, and reduced nicotine adenine dinucleotides help maintain the balance. Overabundance of metals like iron or copper can be problematic. While any toxicant that requires rapid P450 mediated metabolism increases the endogenous risks for overproduction of superoxide and peroxide species that may act as proximal reactive intermediates in causing cellular oxidation or macromolecular modification. Unless the reductase activities and other repair processes can keep up the cell, minimally, and/or the tissue involved may undergo damage from oxidative stress.