Polychlorinated biphenyl (PCB) congeners with multiple ortho chlorine substituents are potent sensitizers of the ryanodine receptor (RyR) and this activity is thought to contribute to the developmental neurotoxicity associated with perinatal PCB exposure. Many of these congeners display axial chirality and are present in industrial PCB mixtures as a racemate (a 1:1 ratio of both atropisomers). However, the ratio of the two enantiomers changes in vivo, probably due to enantioselective processes involving cytochrome (CYP) P450 enzymes. Emerging data suggest significant variability in the enantiomeric enrichment of chiral PCBs in the human population. This, when considered in light of our preliminary data demonstrating that PCB atropisomers differentially sensitize the ryanodine receptor (RyR), raises the question of whether enantiomeric enrichment influences the risk for adverse neurodevelopmental outcomes following PCB exposure. We propose three specific aims to test the hypothesis that chiral PCB congeners undergo enantioselective biotransformation catalyzed by P450 enzymes and that these differences in biotransformation influence neurodevelopmental endpoints.
In Aim 1, the enantiospecificity of RyR-mediated mechanisms of developmental neurotoxicity will be characterized in vitro. The effects of pure PCB atropisomers on dendritic morphology will be quantified in primary rat hippocampal neuron-glia co-cultures and correlated with cellular PCB levels. The molecular mechanisms responsible for enantiospecific activation of RyR1 and RyR2 channel complexes will be investigated using biochemical, biophysical and cellular analyses.
In Aim 2, the species and isoform-dependent enantioselective binding and metabolism of pure PCB atropisomers by P450 enzymes will be investigated using murine and human microsomes and tissue slices, as well as recombinant human P450 enzymes. The P450 isoforms responsible for the enantioselective metabolism of PCBs in microsomes will be identified using P450 inhibitors.
Aim 3 will confirm, in vivo, that metabolism by P450 enzymes is responsible for enantiomeric enrichment of PCBs and that PCB 136 atropisomers cause enantioselective RyR-mediated developmental neurotoxicity. First, a pharmacokinetic model will be developed, in mice, to examine the role of metabolism in the enantioselective disposition of PCBs. Subsequent studies will determine whether perinatal exposure to chiral PCBs causes enantiomeric enrichment-dependent effects on hippocampal expression and function of RyR and dendritic arborization. These studies will make a fundamental contribution to understanding the risk associated with human exposure to chiral PCB congeners that are highly toxic to the developing nervous system and will provide an insight into the role of chirality in the disposition and toxicity of many chiral pollutants, such as pesticides and plasticizers. Given the extensive polymorphism in human CYP genes, the proposed studies may also suggest future investigations into gene-environment interactions that modulate susceptibility to PCB developmental neurotoxicity.

Public Health Relevance

Developmental exposures to chiral polychlorinated biphenyls (PCBs) may cause neurodevelopmental toxicity by interfering with dendritic growth and plasticity via mechanisms involving the enantiospecific sensitization of ryanodine receptors. The goal of the proposed research is to investigate how differences in the enantioselective disposition of chiral PCBs in pregnant mice influence neurodevelopmental endpoints in exposed offspring. Because the enantiomer ratio of chiral PCBs is highly variable in human populations, the proposed studies will make a fundamental contribution to understanding the risk associated with human exposure to chiral PCB congeners that are highly toxic to the developing nervous system and will provide an insight into the role of chirality in the disposition and toxicity of a broad range of other organic pollutants, such as many pesticides and plasticizers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES017425-03
Application #
8206663
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (03))
Program Officer
Kirshner, Annette G
Project Start
2010-01-26
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$407,078
Indirect Cost
$69,283
Name
University of Iowa
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Fritsch, Erika B; Stegeman, John J; Goldstone, Jared V et al. (2015) Expression and function of ryanodine receptor related pathways in PCB tolerant Atlantic killifish (Fundulus heteroclitus) from New Bedford Harbor, MA, USA. Aquat Toxicol 159:156-66
Lesiak, Adam; Zhu, Mingyan; Chen, Hao et al. (2014) The environmental neurotoxicant PCB 95 promotes synaptogenesis via ryanodine receptor-dependent miR132 upregulation. J Neurosci 34:717-25
Ekuase, Edugie J; Lehmler, Hans-Joachim; Robertson, Larry W et al. (2014) Binding interactions of hydroxylated polychlorinated biphenyls (OHPCBs) with human hydroxysteroid sulfotransferase hSULT2A1. Chem Biol Interact 212:56-64
Wu, Xianai; Kammerer, Austin; Lehmler, Hans-Joachim (2014) Microsomal oxidation of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) results in species-dependent chiral signatures of the hydroxylated metabolites. Environ Sci Technol 48:2436-44
Stamou, Marianna; Wu, Xianai; Kania-Korwel, Izabela et al. (2014) Cytochrome p450 mRNA expression in the rodent brain: species-, sex-, and region-dependent differences. Drug Metab Dispos 42:239-44
Yang, Dongren; Kania-Korwel, Izabela; Ghogha, Atefeh et al. (2014) PCB 136 atropselectively alters morphometric and functional parameters of neuronal connectivity in cultured rat hippocampal neurons via ryanodine receptor-dependent mechanisms. Toxicol Sci 138:379-92
Fritsch, Erika B; Connon, Richard E; Werner, Inge et al. (2013) Triclosan impairs swimming behavior and alters expression of excitation-contraction coupling proteins in fathead minnow (Pimephales promelas). Environ Sci Technol 47:2008-17
Niknam, Yassaman; Feng, Wei; Cherednichenko, Gennady et al. (2013) Structure-activity relationship of selected meta- and para-hydroxylated non-dioxin like polychlorinated biphenyls: from single RyR1 channels to muscle dysfunction. Toxicol Sci 136:500-13
Lu, Zhe; Kania-Korwel, Izabela; Lehmler, Hans-Joachim et al. (2013) Stereoselective formation of mono- and dihydroxylated polychlorinated biphenyls by rat cytochrome P450 2B1. Environ Sci Technol 47:12184-92
Kania-Korwel, Izabela; Lehmler, Hans-Joachim (2013) Assigning atropisomer elution orders using atropisomerically enriched polychlorinated biphenyl fractions generated by microsomal metabolism. J Chromatogr A 1278:133-44

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