Di(2-ethylhexyl) phthalate-induced toxicity and peroxisome proliferator-activated receptor alpha: a review

Abstract

The plasticizer di(2-ethylhexyl) phthalate (DEHP) has been widely used in the manufacture of polyvinyl chloridecontaining products such as medical and consumer goods. Humans can easily be exposed to it because DEHP is ubiquitous in the environment. Recent research on the adverse effects of DEHP has focused on reproductive and developmental toxicity in rodents and/or humans. DEHP is a representative of the peroxisome proliferators. Therefore, peroxisome proliferator-activated receptor alpha (PPARα)-dependent pathways are the expected mode of action of several kinds of DEHP-induced toxicities. In this review, we summarize DEHP kinetics and its mechanisms of carcinogenicity and reproductive and developmental toxicity in relation to PPARα. Additionally, we give an overview of the impacts of science policy on exposure sources.

Environmentally-relevant exposure to diethylhexyl phthalate (DEHP) alters regulation of double-strand break formation and crossover designation leading to germline dysfunction in Caenorhabditis elegans

“…Of note, the embryonic lethality and the incidence of males observed following exposure to 100 μM DEHP are not as elevated as in null mutants in which key events for achieving accurate meiotic chromosome segregation, such as chromosome synapsis or recombination, are abrogated [37,38]. This may be due, at least in part, to inter-individual differences in the metabolism of DEHP, as previously observed in mice and humans [39].…”

Sentinels of synthetics – a comparison of phthalate exposure between common bottlenose dolphins (Tursiops truncatus) and human reference populations

“…The geometric mean concentration of MEHP for bottlenose dolphins was significantly higher than NHANES concentrations [ 16 ]. MEHP is a metabolite of di-(2-ethylhexyl) phthalate (DEHP), which is primarily used to increase the flexibility of plastic (e.g., polyvinyl chloride, food packaging, wire covering, toys, medical tubing; [ 3 , 50 , 60 ]). DEHP can also be found in cosmetics, personal care products, oil and paint [ 3 ], although studies have suggested this is due to migration from the plastic containers housing these products [ 14 , 61 ].…”

“…DEHP can also be found in cosmetics, personal care products, oil and paint [ 3 ], although studies have suggested this is due to migration from the plastic containers housing these products [ 14 , 61 ]. Because of weak bonds with the corresponding substrate, DEHP can be easily leached into food and the environment [ 3 , 60 ].…”

“…Hydrolysis occurs in the liver through mechanisms involving the alpha-mediated enzymes of the peroxisome proliferator-activated receptor (PPAR⍺) and efficiency can vary among individuals. Metabolites of DEHP (e.g., MEHP, MEOHP, MEHHP) can bind to PPAR⍺ and disrupt normal kidney, liver, heart, and reproductive function [ 60 ]. In humans, higher MEHP concentrations have been associated with myriad health impacts including decreased oocyte counts [ 70 ], early pregnancy loss [ 71 ], reduced sperm quality [ 72 ], and abnormal reproductive development [ 73 ], among others.…”

“…In humans, higher MEHP concentrations have been associated with myriad health impacts including decreased oocyte counts [ 70 ], early pregnancy loss [ 71 ], reduced sperm quality [ 72 ], and abnormal reproductive development [ 73 ], among others. These phthalate-associated health impacts may be due to interference in steroid, sex, or thyroid hormone circulation, but the occurrence and magnitude of endocrine disruption seem to vary by phthalate ester type, degree of exposure, sex, pregnancy, and age [ 3 – 5 , 8 – 12 , 60 , 74 – 79 ]. While epidemiological studies in humans and experimental studies in laboratory rodents indicate potential health risks for bottlenose dolphins, we found that direct comparisons to human studies were hindered as most papers reported concentrations were adjusted for creatinine or specific gravity.…”