Toxicant Exposure and Brain Development

Although the developing brain is particularly vulnerable to a wide variety of environmental chemicals, little is known about the mechanisms underlying adverse effects following exposure. Normal brain development is orchestrated by precisely timed cellular and molecular events including proliferation, migration, differentiation, synaptogenesis, and programmed cell death (apoptosis). All these processes are potential targets for perturbation by exposures to environmental contaminants during critical developmental periods.

Our laboratory is currently investigating the impact of perinatal exposure to environmental agents on neurogenesis and neuronal differentiation in the developing brain. Both in vivo and in vitro models are being used to identify cellular targets and molecular mechanisms for neurotoxicity. The laboratory uses morphological and biochemical techniques to define toxicant effects on cell proliferation, neuronal migration, neurite development, synaptogenesis and apoptosis. We are also interested in correlating morphologic changes following toxicant exposure with alterations in expression of genes and proteins related to cytoskeletal dynamics, cell cycle control, and neurotrophic factor signaling .

Current projects involve several agents: endocrine disruptors, such as polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); abused substances (toluene and nicotine); and metals (mercury). The long term goal of our research is to determine the relationship between disrupted neuronal production or maturation and functional deficits produced by toxicant exposure during critical periods of brain development.

• Doran TM, Anderson EA, Latchney SE, Opanashuk LA, Nilsson BL. Turn Nucleation Perturbs Amyloid ß Self-Assembly and Cytotoxicity. J Mol Biol. 2012 Aug 10; 421(2-3):315-28.
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• Dever DP, Opanashuk LA. The aryl hydrocarbon receptor contributes to the proliferation of human medulloblastoma cells. Mol Pharmacol. 2012 May; 81(5):669-78.
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• Doran TM, Anderson EA, Latchney SE, Opanashuk LA, Nilsson BL. An Azobenzene Photoswitch Sheds Light on Turn Nucleation in Amyloid-ß Self-Assembly. ACS Chem Neurosci. 2012 Mar 21; 3(3):211-20.
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• Lee DW, Notter SA, Thiruchelvam M, Dever DP, Fitzpatrick R, Kostyniak PJ, Cory-Slechta DA, Opanashuk LA. Subchronic polychlorinated biphenyl (aroclor 1254) exposure produces oxidative damage and neuronal death of ventral midbrain dopaminergic systems. Toxicol Sci. 2012 Feb; 125(2):496-508.
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• Latchney SE, Lioy DT, Henry EC, Gasiewicz TA, Strathmann FG, Mayer-Pröschel M, Opanashuk LA. Neural precursor cell proliferation is disrupted through activation of the aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Stem Cells Dev. 2011 Feb; 20(2):313-26.
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• Janelsins MC, Roscoe JA, Berg MJ, Thompson BD, Gallagher MJ, Morrow GR, Heckler CE, Jean-Pierre P, Opanashuk LA, Gross RA. IGF-1 partially restores chemotherapy-induced reductions in neural cell proliferation in adult C57BL/6 mice. Cancer Invest. 2010 Jun; 28(5):544-53.
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• Fox DA, Opanashuk L, Zharkovsky A, Weiss B. Gene-chemical interactions in the developing mammalian nervous system: Effects on proliferation, neurogenesis and differentiation. Neurotoxicology. 2010 Sep; 31(5):589-97.
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• Singh KP, Casado FL, Opanashuk LA, Gasiewicz TA. The aryl hydrocarbon receptor has a normal function in the regulation of hematopoietic and other stem/progenitor cell populations. Biochem Pharmacol. 2009 Feb 15; 77(4):577-87.
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• Collins LL, Williamson MA, Thompson BD, Dever DP, Gasiewicz TA, Opanashuk LA. 2,3,7,8-Tetracholorodibenzo-p-dioxin exposure disrupts granule neuron precursor maturation in the developing mouse cerebellum. Toxicol Sci. 2008 May; 103(1):125-36.
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• Elder A, Gelein R, Silva V, Feikert T, Opanashuk L, Carter J, Potter R, Maynard A, Ito Y, Finkelstein J, Oberdörster G. Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ Health Perspect. 2006 Aug; 114(8):1172-8.
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• Lee DW, Gelein RM, Opanashuk LA. Heme-oxygenase-1 promotes polychlorinated biphenyl mixture aroclor 1254-induced oxidative stress and dopaminergic cell injury. Toxicol Sci. 2006 Mar; 90(1):159-67.
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• Barlow BK, Lee DW, Cory-Slechta DA, Opanashuk LA. Modulation of antioxidant defense systems by the environmental pesticide maneb in dopaminergic cells. Neurotoxicology. 2005 Jan; 26(1):63-75.
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• Lee DW, Opanashuk LA. Polychlorinated biphenyl mixture aroclor 1254-induced oxidative stress plays a role in dopaminergic cell injury. Neurotoxicology. 2004 Dec; 25(6):925-39.
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• Williamson MA, Gasiewicz TA, Opanashuk LA. Aryl hydrocarbon receptor expression and activity in cerebellar granule neuroblasts: implications for development and dioxin neurotoxicity. Toxicol Sci. 2005 Feb; 83(2):340-8.
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• LoPachin RM, He D, Reid ML, Opanashuk LA. 2,5-Hexanedione-induced changes in the monomeric neurofilament protein content of rat spinal cord fractions. Toxicol Appl Pharmacol. 2004 Jul 1; 198(1):61-73.
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• Filbrandt CR, Wu Z, Zlokovic B, Opanashuk L, Gasiewicz TA. Presence and functional activity of the aryl hydrocarbon receptor in isolated murine cerebral vascular endothelial cells and astrocytes. Neurotoxicology. 2004 Jun; 25(4):605-16.
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• Opanashuk LA, He DK, Lehning EJ, LoPachin RM. Gamma-diketone peripheral neuropathy III. Neurofilament gene expression. Neurotoxicology. 2001 Apr; 22(2):215-20.
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• Haas KZ, Sperber EF, Opanashuk LA, Stanton PK, Moshé SL. Resistance of immature hippocampus to morphologic and physiologic alterations following status epilepticus or kindling. Hippocampus. 2001; 11(6):615-25.
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• Opanashuk LA, Pauly JR, Hauser KF. Effect of nicotine on cerebellar granule neuron development. Eur J Neurosci. 2001 Jan; 13(1):48-56.
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• LoPachin RM, Lehning EJ, Opanashuk LA, Jortner BS. Rate of neurotoxicant exposure determines morphologic manifestations of distal axonopathy. Toxicol Appl Pharmacol. 2000 Sep 1; 167(2):75-86.
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• Chiu FC, Opanashuk LA, He DK, Lehning EJ, LoPachin RM. gamma-diketone peripheral neuropathy. II. Neurofilament subunit content. Toxicol Appl Pharmacol. 2000 Jun 1; 165(2):141-7.
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• Opanashuk LA, Mark RJ, Porter J, Damm D, Mattson MP, Seroogy KB. Heparin-binding epidermal growth factor-like growth factor in hippocampus: modulation of expression by seizures and anti-excitotoxic action. J Neurosci. 1999 Jan 1; 19(1):133-46.
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• Opanashuk LA, Hauser KF. Opposing actions of the EGF family and opioids: heparin binding-epidermal growth factor (HB-EGF) protects mouse cerebellar neuroblasts against the antiproliferative effect of morphine. Brain Res. 1998 Aug 31; 804(1):87-94.
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• Hauser KF, Harris-White ME, Jackson JA, Opanashuk LA, Carney JM. Opioids disrupt Ca2+ homeostasis and induce carbonyl oxyradical production in mouse astrocytes in vitro: transient increases and adaptation to sustained exposure. Exp Neurol. 1998 May; 151(1):70-6.
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• Opanashuk LA, Finkelstein JN. Relationship of lead-induced proteins to stress response proteins in astroglial cells. J Neurosci Res. 1995 Dec; 42(5):623-32.
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• Opanashuk LA, Finkelstein JN. Induction of newly synthesized proteins in astroglial cells exposed to lead. Toxicol Appl Pharmacol. 1995 Mar; 131(1):21-30.
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