Gene expression changes induced by di(2-ethylhexyl) phthalate and caloric restriction.

摘要

Previous animal studies provide evidence of male reproductive toxicity of the most widely used plasticizer, di(2-ethylhexyl) phthalate (DEHP). To better understand the effects of DEHP exposure, we utilized microarray technology to identify novel DEHP targets in the liver and testis of sexually mature male C57BL/6 mice treated with dietary DEHP. In the liver, expression changes were observed in genes involved in pheromone transport, xenobiotic detoxification, and steroid hormone metabolism. Further studies were conducted on identified steroid hormone metabolizing genes 3β-hydroxysteroid dehydrogenases (HSD3b) and Cyp2b. Expression of HSD3b2, HSD3b3, and HSD3b5 and HSD3b4 were suppressed in the liver and testis, respectively. Cyp2b, which hydroxylates testosterone in the liver, was highly inducible by DEHP treatment. The liver-testis axis provides the connection between DEHP's impairment of steroid hormone metabolism and its testicular toxicity. DEHP's increase in metabolism of testosterone in the liver results in lowered levels of circulating testosterone, which ultimately leads to deleterious effects in the testis. In contrast to the liver, our microarray study in the testis revealed almost all genes to be upregulated by only 3 fold or less. One plausible explanation for these observations is that many of these genes may not be induced transcriptionally, but were likely a response of increase in Sertoli:germ cell ratio. We conclude that long-term high dose DEHP inflicts toxicity on the testis via a mechanism distinct from that of the liver.; It is intriguing that many genes targeted by DEHP in the liver were also regulated by caloric restriction. Since both DEHP and caloric restriction mediate through the peroxisome proliferator receptor α (PPARα), a comprehensive study was conducted to determine the overlap in the transcript profiles of caloric restriction and exogenous agonists of lipid-activated nuclear receptors in the mouse liver. Genes regulated by both caloric restriction and these receptors include those necessary for lipid metabolism, decreasing risk factors for coronary heart disease, and regulating cell growth.