Genomic and proteomic responses to environmentally relevant exposures to dieldrin: indicators of neurodegeneration?

Abstract

Dieldrin is a persistent organochlorine pesticide that induces neurotoxicity in the vertebrate central nervous system and impairs reproductive processes in fish. This study examined the molecular events produced by subchronic dietary exposures to 2.95 mg dieldrin/kg feed in the neuroendocrine brain of largemouth bass, an apex predator. Microarrays, proteomics, and pathway analysis were performed to identify genes, proteins, and cell processes altered in the male hypothalamus. Fifty-four genes were induced, and 220 genes were reduced in steady-state levels (p < 0.001; fold change greater than +/- 1.5). Functional enrichment analysis revealed that the biological gene ontology categories of stress response, nucleotide base excision repair, response to toxin, and metabolic processes were significantly impacted by dieldrin. Using isobaric tagging for relative and absolute quantitation, 90 proteins in the male hypothalamus were statistically evaluated for changes in protein abundance. Several proteins altered by dieldrin are known to be associated with human neurodegenerative diseases, including apolipoprotein E, microtubule-associated tau protein, enolase 1, stathmin 1a, myelin basic protein, and parvalbumin. Proteins altered by dieldrin were involved in oxidative phosphorylation, differentiation, proliferation, and cell survival. This study demonstrates that a subchronic exposure to dieldrin alters the abundance of messenger RNAs and proteins in the hypothalamus that are associated with cell metabolism, cell stability and integrity, stress, and DNA repair.

FIG. 1.

Disease processes that involve genes (p < 0.01) regulated by dieldrin. Green indicates a downregulation in the mRNA and red indicates an induction in mRNA level. Proteins in figure follow nomenclature rules for mammalian proteins because pathways are based on mammalian data. 101F6, cytochrome b-561 domain containing 2; ABCF2, ATP-binding cassette, subfamily F (GCN20), member 2 (predicted); AMACR, alpha-methylacyl-CoA racemase; APCS, serum amyloid P-component; APOH, apolipoprotein H; ATF2, activating transcription factor 2; ATP2B1, ATPase, Ca++ transporting, plasma membrane 1; Bmp7, bone morphogenetic protein 7; C1D, nuclear DNA-binding protein; Calu, calumenin; CDK10, cyclin-dependent kinase (CDC2-like) 10; CDW92, CDW92 antigen; CEBPD, CCAAT/enhancer-binding protein (C/EBP), delta; CENPE, centromere protein E (predicted); CLDN1, claudin 1; CYCS, cytochrome c, somatic; DLG2, discs, large homolog 2 (Drosophila); ESR2, estrogen receptor 2 beta; FGF12, fibroblast growth factor 12; FLJ10140, tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (predicted); GTR2, Ras-related GTP binding C (predicted); HLA-DRB3, major histocompatibility complex, class II, DR beta 3; HRMT1L2, heterogeneous nuclear ribonucleoprotein methyltransferase-like 2 (Saccharomyces cerevisiae); HSPC167, CDK5 regulatory subunit associated protein 1; KLKB1, kallikrein B, plasma 1; KRT15, type I keratin KA15; MDK, midkine; MGC9788, 3-hydroxybutyrate dehydrogenase, type 1; MYO9B, myosin Ixb; NAPB, similar to N-ethylmaleimide-sensitive fusion protein attachment protein beta; NPC2, Niemann-Pick type C2; OXCT1, similar to 3-oxoacid CoA transferase 1; P2RY12, purinergic receptor P2Y, G-protein coupled 12; PFKL, phosphofructokinase, liver, B-type; PLP1, proteolipid protein; POMC, pro-opiomelanocortin; PPAP2B, phosphatidic acid phosphatase type 2B; PPGB, protective protein for beta-galactosidase; RDH11, retinol dehydrogenase 11; RFT1, RFT1 homolog (predicted); SERPINB9, similar to SPI6; SH3BGRL3, SH3 domain binding glutamic acid–rich protein-like 3 (predicted); SNAP25, synaptosome-associated protein 25 kDa; SNM1, DNA cross-link repair 1A, PSO2 homolog (S. cerevisiae) (predicted); SOAT1, sterol O-acyltransferase 1; SRPR, hypothetical LOC569063; TACC1, transforming, acidic coiled-coil containing protein 1; TACSTD1, tumor-associated calcium signal transducer 1; TPRT, prenyl (solanesyl) diphosphate synthase, subunit 1.

FIG. 2.

Relative fold changes for genes analyzed by microarray (white bars; n = 4) and real-time PCR (black bars; n = 4) in the male hypothalamus. Abbreviations are as follows: ar = androgen receptor; esrβb = estrogen receptor beta b; gpx = glutathione peroxidase; gst = glutathione-s-transferase; hsp70= heat-shock protein 70; npc2 = Niemann-Pick Disease C2.