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Emerging toxicants as endocrine disruptors: what are the issues?
Comparative Biochemistry and Physiology, Part A 151 (2008) S2 – S10
Contents lists available at ScienceDirect
Comparative Biochemistry and Physiology, Part A j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c b p a
25 th Congress of the new European Society of Comparative Biochemistry and Physiology Ravenna (Italy) - Sept 7-11, 2008 New challenges in integrative physiology and biochemistry: from molecular mechanisms to environmental adaptation
Physiology and toxicology of endocrine regulation including intracellular responses SESSION OPENING LECTURE 1. Emerging toxicants as endocrine disruptors: what are the issues? T.W. Moon (Department of Biology and Centre for Advanced Research in Environmental Genomics, University of Ottawa, Ottawa, Canada) We read daily of new toxicants appearing in our environment and evidence is accumulating that even a limited exposure to some chemicals may impact ecosystem and human health. Our analytical instrumentation is moving back the boundaries of what toxicants can be measured meaning that exposure-levels have moved from the ppm to the ppb. Toxicology has become less of a ‘kill-and-count’ science and more one of looking for subtle effects that could modify the fitness of organisms in their environment. To address issues facing regulators that must answer the ultimate question “does toxicant X pose a risk”, we must begin to fillin the gap between our very sensitive newly identified molecular biomarkers and the traditional toxicity endpoints that are easily understood in a regulatory paradigm. I will discuss using research from both my group and the literature some of these issues using pharmaceuticals and nanomaterials. Human pharmaceuticals are found in the aquatic environment as a result of increased prescription rates and the inability of waste water treatment plants to remove many of these compounds. Their pseudopersistent nature means that aquatic species including fish may be exposed at some point to a variety of human drugs. Drugs are designed specifically against cellular targets many of which are highly conserved within vertebrates. Our work addresses whether fish exposed to aquatic pharmaceuticals respond as expected or whether unintended effects occur as a means of assessing the risk of such compounds to aquatic species. Two groups of drugs are studied—fibrates (lipid lowering) and fluoxetine (SSRI, selective serotonin reuptake inhibitor). Early studies demonstrated that fibrates (gemfibrozil) bioconcentrate, reduce testosterone levels and challenge the oxidative defenses
of goldfish when presented at concentrations reported in the environment. Furthermore, fibrates interfere with in vitro agonist-induced steroidogenesis using preparations of rainbow trout head-kidney cells and goldfish testis fragments. However, the point at which fibrates interfere depends upon the tissue; potentially P450-c21 and P450-b21 are affected in head-kidney cells while in the testis fragments entry of cholesterol into the mitochondria (StAR, PBR) is the target. Using realtime PCR, mRNA abundance was unaffected suggesting these drugs act at the protein level. Fluoxetine (FLX) acts to increase the availability of serotonin (5-HT) at post-synaptic neurons and thus has downstream affects on both reproduction and feeding. Dosing goldfish with FLX (5 ug/g) resulted in a significant decrease in food intake and fish mass, and using a goldfish-carp array (www.auratus.ca) hypothalamic mRNA for the dopamine transporter and isotocin were both down-regulated which may at least in part account for changes observed in estrogen content in goldfish and decreases in egg production in other fish. Thus fish exposed to human pharmaceuticals may experience effects not unlike those seen in humans but do such exposures affect overall performance. A new and potentially even more subtle emerging toxicant group the nanomaterials will also be discussed. Supported by the NSERC Canada, Canadian Water Network and BEST in Science (ON) operating grants. doi:10.1016/j.cbpa.2008.05.044
ORAL PRESENTATIONS 2. Multidrug resistance transporter in the midgut gland and the brain of crustaceans U. Bickmeyer, A.-K. Lüders, R. Saborowski (Alfred Wegener Institute for Polar and Marine Research, Helgoland, Germany)
Contents lists available at ScienceDirect
Comparative Biochemistry and Physiology, Part A j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c b p a
25 th Congress of the new European Society of Comparative Biochemistry and Physiology Ravenna (Italy) - Sept 7-11, 2008 New challenges in integrative physiology and biochemistry: from molecular mechanisms to environmental adaptation
Physiology and toxicology of endocrine regulation including intracellular responses SESSION OPENING LECTURE 1. Emerging toxicants as endocrine disruptors: what are the issues? T.W. Moon (Department of Biology and Centre for Advanced Research in Environmental Genomics, University of Ottawa, Ottawa, Canada) We read daily of new toxicants appearing in our environment and evidence is accumulating that even a limited exposure to some chemicals may impact ecosystem and human health. Our analytical instrumentation is moving back the boundaries of what toxicants can be measured meaning that exposure-levels have moved from the ppm to the ppb. Toxicology has become less of a ‘kill-and-count’ science and more one of looking for subtle effects that could modify the fitness of organisms in their environment. To address issues facing regulators that must answer the ultimate question “does toxicant X pose a risk”, we must begin to fillin the gap between our very sensitive newly identified molecular biomarkers and the traditional toxicity endpoints that are easily understood in a regulatory paradigm. I will discuss using research from both my group and the literature some of these issues using pharmaceuticals and nanomaterials. Human pharmaceuticals are found in the aquatic environment as a result of increased prescription rates and the inability of waste water treatment plants to remove many of these compounds. Their pseudopersistent nature means that aquatic species including fish may be exposed at some point to a variety of human drugs. Drugs are designed specifically against cellular targets many of which are highly conserved within vertebrates. Our work addresses whether fish exposed to aquatic pharmaceuticals respond as expected or whether unintended effects occur as a means of assessing the risk of such compounds to aquatic species. Two groups of drugs are studied—fibrates (lipid lowering) and fluoxetine (SSRI, selective serotonin reuptake inhibitor). Early studies demonstrated that fibrates (gemfibrozil) bioconcentrate, reduce testosterone levels and challenge the oxidative defenses
of goldfish when presented at concentrations reported in the environment. Furthermore, fibrates interfere with in vitro agonist-induced steroidogenesis using preparations of rainbow trout head-kidney cells and goldfish testis fragments. However, the point at which fibrates interfere depends upon the tissue; potentially P450-c21 and P450-b21 are affected in head-kidney cells while in the testis fragments entry of cholesterol into the mitochondria (StAR, PBR) is the target. Using realtime PCR, mRNA abundance was unaffected suggesting these drugs act at the protein level. Fluoxetine (FLX) acts to increase the availability of serotonin (5-HT) at post-synaptic neurons and thus has downstream affects on both reproduction and feeding. Dosing goldfish with FLX (5 ug/g) resulted in a significant decrease in food intake and fish mass, and using a goldfish-carp array (www.auratus.ca) hypothalamic mRNA for the dopamine transporter and isotocin were both down-regulated which may at least in part account for changes observed in estrogen content in goldfish and decreases in egg production in other fish. Thus fish exposed to human pharmaceuticals may experience effects not unlike those seen in humans but do such exposures affect overall performance. A new and potentially even more subtle emerging toxicant group the nanomaterials will also be discussed. Supported by the NSERC Canada, Canadian Water Network and BEST in Science (ON) operating grants. doi:10.1016/j.cbpa.2008.05.044
ORAL PRESENTATIONS 2. Multidrug resistance transporter in the midgut gland and the brain of crustaceans U. Bickmeyer, A.-K. Lüders, R. Saborowski (Alfred Wegener Institute for Polar and Marine Research, Helgoland, Germany)