title: Delayed temporal increase of hepatic Hsp70 in ApoE knockout mice after prenatal arsenic exposure.
abstract: Prenatal arsenic exposure accelerates atherosclerosis in ApoE(-/-) mice by unknown mechanism. Arsenic is a hepatotoxicant, and liver disease increases atherosclerosis risk. Prenatal arsenic exposure may predispose to liver disease by priming for susceptibility to other environmental insults. Earlier microarray analyses showed prenatal arsenic exposure increased Hsc70 (HspA8) and Hsp70 (HspA1a) mRNAs in livers of 10-week-old mice. We determined effects of prenatal arsenic exposure on hepatic Hsp70 and Hsc70 expression by Western blot and on DNA methylation by methyl acceptance assay during prenatal and postnatal development. Pregnant ApoE(-/-) mice were given drinking water containing 85 mg/l NaAsO(2) (49 ppm arsenic) from gestation day (GD) 8 to 18. Hsp70 and Hsc70 expression and DNA methylation were determined in GD18 fetuses and 3-, 10-, and 24-week-old mice. Hsc70 expression was unchanged at all ages. Hsp70 induction was observed at 3 and 10 weeks, but was unchanged in GD18 fetuses and 24-week livers of mice. Global DNA methylation increased with age; arsenic had no effects. Bisulfite sequencing of DNA from livers of 10-week-old mice showed Hsp70 promoter region methylation was unchanged, but methylation was increased within the transcribed region. Hsf1 and Nrf2 nuclear translocation were investigated as potential mechanisms of Hsp70 induction and found unaltered. Putative binding sites were identified in HSP70 for in utero arsenic exposure-suppressed microRNAs suggesting a possible mechanism. Thus, prenatal arsenic exposure causes delayed temporal hepatic Hsp70 induction, suggesting a transient state of stress in livers which can predispose the mice to developing liver disease.
authors.affiliation: Department of Pharmacology & Toxicology, University of Louisville, Louisville, Kentucky 40202, USA.
authors.forename: Ntube N O
authors.initials: NN
authors.lastname: Ngalame
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Micciche
authors.forename: Marilyn E
authors.initials: ME
authors.lastname: Feil
authors.forename: J Christopher
authors.initials: JC
authors.lastname: States
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D018053:Arsenites / Q000633:toxicity*; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics; D015153:Blotting, Western; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D008099:Liver / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D017670:Sodium Compounds / Q000633:toxicity*; D014157:Transcription Factors / Q000378:metabolism; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D001057:Apolipoproteins E; D018053:Arsenites; D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017670:Sodium Compounds; D014157:Transcription Factors; D014874:Water Pollutants, Chemical; C017947:sodium arsenite