Gene Expression Changes Induced in Mouse Liver by Di(2-ethylhexyl) Phthalate

• Published in: Toxicology and applied pharmacology 2002-12, Vol.185 (3), p.180-196
• Main Authors: Wong, Jean S., Gill, Sarjeet S.
• Format: Article
• Language: English
• Subjects: 11-beta-Hydroxysteroid Dehydrogenases; Affymetrix; Amidohydrolases; Animals; Aryl Hydrocarbon Hydroxylases - metabolism; Biological and medical sciences; Blotting, Northern; Carrier Proteins - metabolism; Cell Adhesion Molecules - biosynthesis; Cell Adhesion Molecules - genetics; Chemical and industrial products toxicology. Toxic occupational diseases; complement component; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450 Family 2; development; di(2-ethylhexyl) phthalate (DEHP); Diethylhexyl Phthalate - toxicity; Eating - physiology; endocrine disruptor; fasting; Gene Expression Regulation - drug effects; Gene Expression Regulation, Enzymologic - drug effects; GPI-Linked Proteins; Hydroxysteroid Dehydrogenases - metabolism; Immunity - physiology; immunosuppression; liver; Liver - drug effects; Liver - enzymology; Liver - metabolism; Male; Medical sciences; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; microarray; Northern blot; Oligonucleotide Array Sequence Analysis; oxidative stress; Oxidative Stress - genetics; peroxisome proliferator; pheromone; Phospholipid Transfer Proteins; plasticizer; reproduction; Reproduction - drug effects; RNA, Messenger - biosynthesis; Sexual Maturation - physiology; steroid hormone metabolism; Steroid Hydroxylases - metabolism; stress; testis; Testis - drug effects; Testis - metabolism; Toxicology; Various organic compounds; xenobiotic detoxification; Xenobiotics - metabolism
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1006/taap.2002.9540

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. 11βHSDI 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, GSTθ2, and Id2. Collectively, our data validate the concern for DEHP as a reproductive developmental toxicant.