Gene expression changes induced in mouse liver by di(2-ethylhexyl) phthalate.
Increasing chemical use necessitates a better understanding of how pollutants, such as di(2-ethylhexyl) phthalate (DEHP), a peroxisome proliferator and a phthalate plasticizer, affect human health. To understand the effects of DEHP exposure, we utilized microarray technology to identify novel DEHP targets in livers of male C57BL/6 mice treated with 1.0% dietary DEHP for 13 weeks. We identified 51 DEHP-regulated genes; these genes are involved in, but not limited to, peroxisome proliferation, xenobiotic detoxification, oxidative stress response, immune function, steroid hormone metabolism, testis development, and pheromone transport. The reproductive toxicity mechanism of DEHP may be due to its effects on steroid hormone metabolism and sexual development. Confirmation of microarray results with Northern blots demonstrated that both low- and high-dose DEHP treatments altered the expression of genes associated with testis development and steroid hormone synthesis. Vanin-1, a regulator of testis development, was upregulated after exposure to 0.2 and 1.0% DEHP by 1.8- and 2.9-fold, respectively. Several genes involved in hormone metabolism were also regulated by DEHP. 11betaHSDI was downregulated 1.8- and 3.1-fold by 0.2 and 1.0% DEHP, respectively, while HSD3b5 was suppressed similarly by 0.2% DEHP, 1.5-fold, and more severely by 1.0% DEHP, 8.0-fold. Interestingly, food restriction had a similar effect to DEHP on several genes, including HSD3b5. In addition, steroidogenic gene cyp7B1 was downregulated while phospholipid transfer protein and cyp2B9 were induced. Genes peripherally associated with steroid hormones were also affected: ALDH3, GSTtheta2, and Id2. Collectively, our data validate the concern for DEHP as a reproductive developmental toxicant.
Wong
Jean S
JS
Department of Cell Biology and Neuroscience, University of California, Riverside 92521, USA.
Gill
Sarjeet S
SS
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000581:Amidohydrolases; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D004435:Eating / Q000502:physiology; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism; D007109:Immunity / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000235:genetics; D049294:Phospholipid Transfer Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D012098:Reproduction / Q000187:drug effects; D012741:Sexual Maturation / Q000502:physiology; D013250:Steroid Hydroxylases / Q000378:metabolism; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism
D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D008565:Membrane Proteins; D049294:Phospholipid Transfer Proteins; D012333:RNA, Messenger; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D004051:Diethylhexyl Phthalate; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D013250:Steroid Hydroxylases; C115867:oxysterol 7-alpha-hydroxylase; D001189:Aryl Hydrocarbon Hydroxylases; C121503:Cyp2b9 protein, mouse; D000072467:Cytochrome P450 Family 2; D000581:Amidohydrolases; C022314:pantetheinase