Modes of Action and Species-Specific Effects of Di-(2-ethylhexyl)Phthalate in the Liver

Abstract

The industrial plasticizer di-(2-ethylhexyl)phthalate (DEHP) is used in manufacturing of a wide variety of polyvinyl chloride (PVC)-containing medical and consumer products. The biological action of DEHP is very similar to chemicals that are collectively known as peroxisome proliferators (PPs). PPs are a structurally diverse group of compounds characterized as nongenotoxic rodent carcinogens. This review focuses on the effect of DEHP in liver, a primary target organ for the pleiotropic effects of DEHP and other PPs. Specifically, liver parenchymal cells, identified herein as hepatocytes, are a major cell type that are responsive to exposure to PPs, including DEHP; however, other cell types in the liver may also play a role. The PP-induced increase in the number and size of peroxisomes in hepatocytes, so called 'peroxisome proliferation' that results in elevation of fatty acid metabolism, is a hallmark response to these compounds in the liver. A link between peroxisome proliferation and tumor formation has been a predominant, albeit questioned, theory to explain the cause of a hepatocarcinogenic effect of PPs. Other molecular events, such as induction of cell proliferation, decreased apoptosis, oxidative DNA damage, and selective clonal expansion of the initiated cells have been also been proposed to be critically involved in PP-induced carcinogenesis in liver. Considerable differences in the metabolism and molecular changes induced by DEHP in the liver, most predominantly the activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)α, have been identified between species. Both sexes of rats and mice develop adenomas and carcinomas after prolonged feeding with DEHP; however, limited DEHP-specific human data are available, even though exposure to DEHP and other phthalates is common in the general population. This likely constitutes the largest gap in our knowledge on the potential for DEHP to cause liver cancer in humans. Overall, it is believed that the sequence of key events that are relevant to DEHP-induced liver carcinogenesis in rodents involves the following events whereby the combination of the molecular signals and multiple pathways, rather than a single hallmark event (such as induction of PPARα and peroxisomal genes, or cell proliferation) contribute to the formation of tumors: (i) rapid metabolism of the parental compound to primary and secondary bioactive metabolites that are readily absorbed and distributed throughout the body; (ii) receptor-independent activation of hepatic macrophages and production of oxidants; (iii) activation of PPARα in hepatocytes and sustained increase in expression of peroxisomal and non-peroxisomal metabolismrelated genes; (iv) enlargement of many hepatocellular organelles (peroxisomes, mitochondria, etc.); (v) rapid, but transient increase in cell proliferation, and a decrease in apoptosis; (vi) sustained

Time course investigation of PPARα- and Kupffer cell-dependent effects of WY-14,643 in mouse liver using microarray gene expression

“…These compounds have been the subject of debate for several decades because of their carcinogenicity in rodents (Lalwani et al, 1981) and uncertain risk to humans (Klaunig et al, 2003;Rusyn et al, 2006). A number of peroxisome proliferator-induced events leading up to carcinogenesis, including increased cell replication, oxidative damage and tumorigenesis itself require activation of nuclear receptor peroxisome proliferators-activated receptor alpha (PPARα) (Peters et al, 1997;Rusyn et al, 2004).…”

“…A wide range of nuclear receptor-independent effects of PPARa-agonists in rodent liver have been reported and some of these were attributed to activation of the Kupffer cells (Rusyn et al, 2006). Therefore, delineating the relative contribution of receptor-independent anddependent molecular events is important for human health risk assessment of these agents, which is currently based largely on the inter-species differences in PPARα activation and signaling (Peters et al, 2005).…”

Interference of pollutants with PPARs: endocrine disruption meets metabolism

“…Earlier studies have indeed shown that both in utero and adult exposure to phthalates have various effects on endocrine functions, in some cases mediated by PPARs. 17,19,40,49,66 Embryogenesis is a very sensitive period and several studies Figure 1 Schematic representation of the effects of MEHP on adipogenesis through selective PPARg modulation. MEHP, compared to the specific PPARg agonist rosiglitazone, only partially abolishes the interaction between PPARg and the corepressor NCoR.…”

Sustained formation of α-(4-pyridyl-1-oxide)-N-tert-butylnitrone radical adducts in mouse liver by peroxisome proliferators is dependent upon peroxisome proliferator-activated receptor-α, but not NADPH oxidase

“…A number of indirect confirmations for peroxisome proliferator-initiated increases in reactive oxygen species have been collected over past two decades; however, the causative relevance of some of this evidence to the carcinogenic effect of peroxisome proliferators has been questioned and contrasting views have been presented (reviewed in [29]). Therefore, we provide direct in vivo evidence for sustained production of oxidants after treatment with peroxisome proliferators, as well as information on whether POBN radical adducts are produced by PPARα-dependent mechanisms, both of which are critical for understanding the mode of action of these agents.…”