Di-2-ethylhexyl phthalate (DEHP), a plasticizer commonly used in the production of polyvinyl chloride plastics, has become an environmental pollutant. At the present time, the biological significance of phthalates in the environment is unknown. In the present studies, we observed that addition of DEHP to a stock diet of rats resulted in marked effects on incorporation of 14C-acetate into lipid by liver and kidney slices; other organs, such as heart, testes, and aorta, were unaffected. Incorporation of 14C-acetate into total lipid of liver (dpm/mg wet wt) from rats fed 0.5% or 1.0% DEHP for 10 or 18 days, respectively, was decreased to ca. 50% of control values. The decreased incorporation into liver lipid is not attributable to any one lipid fraction, inasmuch as incorporation into the phospholipid, sterol + diglyceride, free fatty acid, triglyceride, and sterol ester + hydrocarbon fractions was decreased 30-70% with respect to controls. In addition, the percent distribution of 14C-acetate among the individual phospholipids was ca. 25% lower in phosphatidyl choline of the DEHP-fed rats. In rats fed 0.5% DEHP, incorporation of 14C-acetate into total lipid of kidney was similar to control values, but incorporation into the triglyceride and sterol ester + hydrocarbon fraction was decreased 30-40%, whereas incorporation into the sterol + diglyceride fraction was increased 38%. Livers from DEHP-fed rats were ca. 20% larger than livers from control rats and, at the 0.5% level of DEHP feeding, testes wts were elevated; no significant changes were noted in wts of spleen, heart, aorta, kidney, or body wt gains in rats fed DEHP. These studies emphasize a subtle toxicity of phthalate esters not previously reported and emphasize the need for further biochemical studies to evaluate the effect of phthalates on biological systems.
Di-2-ethylhexyl phthalate (DEHP), a commonly used plasticizer, was found to be an inhibitor of the biosynthesis of hepatic nonsaponifiable lipids in the art. The addition of DEHP at levels of 0.5% or 1.0% to a stock diet of rats resulted in a decreased conversion of acetate-1-14C and mevalonate-5-3H into squalene, C30 sterols, and C27 sterols by liver minces or slices, in vitro. In studies conducted with 0.5% DEHP feeding from 2 to 11 days, the degree of inhibition was found to increase with the duration of DEHP feeding; the inhibition of 3H-mevalonate conversion to squalene and sterols developed more slowly, being reduced to ca. 70% control values in 11 days, whereas 14C-acetate conversion was reduced to ca. 35% of control values during the same period. 3H-mevalonate conversion to sterols and squalene was, however, found to be suppressable to the same extent as 14C-acetate conversion when diets containing 1.0% DEHP were fed for 18 days. The inhibitory effect of dietary DEHP on sterol and squalene biosynthesis from 14C-acetate and 3H-mevalonate by rat liver preparations is unlikely to be accounted for by the negative feedback of cholesterol secondary to hepatic sterol accumulation since, in these studies, hepatic total lipid and hepatic total sterol levels were similar in control and DEHP-fed rats.
The effect of various phthalate ester plasticizers on lipid metabolism in rats was studied in vivo and in vitro. Di-2-ethylhexyl phthalate (DEHP) and di-n-butyl phthalate (DBP) inhibited (30-70%) hepatic sterologenesis from 14C-acetate and 14C-mevalonate in liver minces from rats fed the phthalates at a level of 2.5 mmoles/100 g of chow diet for 21 days; inhibition of 14C-acetate incorporation into phospholipids, triglycerides, and steryl esters was reduced (35-70%) by DEHP and DBP feeding. In addition, serum cholesterol was lowered ca. 14 mg/dl with dietary DEHP or DBP but not with dimethyl phthalate (DMP). Hepatic total cholesterol levels were reduced significantly (31%, P<0.001) by DMP but not by DBP or DEHP. In other studies with DEHP fed at the 0.5% level in chow diets (1.3 mmoles/100 g), the incorporation (esterification) of 3H-oleate into di-and triglycerides was reduced ca. 40%. Furthermore, the addition of DEHP (2%, 5 mmoles/100 g) to a semisynthetic diet containing 10% fat (hydrogenated coconut oil) resulted in changes in serum lipoprotein composition. The percentage of serum cholesterol in LDL rose from 22% to 34% while that in HDL fell from 78% to 66%; these changes occurred without net changes in serum cholesterol levels. Possible mechanisms for the inhibitory effect of phthalates on hepatic lipid biosynthesis are discussed.
Circulating blood monocytes were isolated from normal and hypercholesterolemic swine, and the monocyte lipid compositions and lipid biosynthesis profiles were assessed. The data indicate that monocytes freshly isolated from hyperlipemic swine have increased phospholipid and cholesterol contents and have increased biosynthetic capability for synthesizing phospholipids, triglycerides, and cholesteryl esters, but not cholesterol. The profile of the stimulated lipid synthesis capability is similar to that of the swine aortic intima undergoing atherogenic change. These studies indicate that circulating blood monocytes in hyperlipemic swine, which are known to give rise to intimal foam cells in the early fatty streak lesion, can contribute to altered vessel lipid metabolism without a requirement for in situ modification by wall factors. 11 Although some studies have been performed with arterial (monocyte-derived macrophage) foam cells, 12 many of the macrophage studies to date have used macrophages elicited from peritoneum and lung or a macrophage cell line. 5101314 In our studies, we have focused on lipid metabolism in the freshly isolated blood monocyte, as this is the cellular entity that invades the vessel wall, and we previously reported that monocytes from hypercholesterolemic rabbits have a stimulated lipid synthesis profile that differs significantly from that of normolipemic blood monocytes and that resembles the lipid synthesis profile of atherosclerotic vessels. 15 In the present studies, we have successfully isolated monocytes from the blood of normal and hypercholesterolemic swine ]oleate, which resembles the lipid metabolic profile of cholesterol-enriched or lesioned aortic intima. The data suggest that monocytes invading the vessel wall from hypercholesterolemic plasma are capable of contributing to altered wall lipid metabolism without an obligatory requirement for in situ modification. Methods Animals and DietsPairs of male Yorkshire swine (6 weeks of age, 15-20 kg at initiation) were fed either normal hog chow or chow supplemented with 1.5% cholesterol and 19.5% lard 16 for periods of 15-20 weeks. Serum cholesterol levels ranged from 70 to 110 mg/dl in normal swine and between 400 and 600 mg/dl in the hyperlipemic swine. Details of euthanasia and tissue collection have been previously described.
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