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The effects of di-2 ethylhexyl phthalate (DEHP) over periods of 3 days to 9 months were examined in both male and female rats using biochemical, histological and ultrastructural techniques. Responses occurred in a characteristic order. Initial effects included : changes in the. distribution of lipid in the liver, proliferation of hepatic peroxisomes and induction of laurate hydroxylases. More slowly developing changes were (1) hypertrophy of the hepatocytes, (2) centrilobular loss of glycogen and (3) a fall in glucose-6-phosphatase activity. After 9 months of treatment, accumulation of lipid-loaded lysosomes were observed. All these changes were observed in rats treated with 1000 or 200 mg/kg/day of DEHP, but rats treated with 50 mg/kg/day of DEHP did not show the later changes. In addition to these sustained alterations, two transient changes were observed. Male rats, treated with 1000 mg/kg/day of DEHP showed changes in the biliary system as shown by electron microscopy, by examination of bile flow, bile enzymes and proteins. Furthermore, a burst of mitosis occurred immediately after commencement of treatment of DEHP, the magnitude and time of which was dose-dependent. Changes in female rats were qualitatively similar, but quantitatively smaller, than in male rats. Mature male rats treated for 3 or 13 days with either DEHP or the hypolipidaemic drugs fenofibrate or clofibrate, showed similar changes to young rats with the exception of the mitotic burst which did not occur in these animals. The initial short term effects of DEHP and the straight chain analogues, di-n-octyl phthalate (DN0P) and di-n- hexyl phthalate (DNHP) in vivo and their respective esters, MEHP and MNHP, were reproduced in cultured hepatocytes. There was induction of peroxisomal enzymes in response to treatment with DEHP or MEHP but little or no induction after treatment with DNOP, MNOP or MNHP. Accumulation of lipid was seen after 24 hours of treatment With MEHP, MNOP and MNHP. However, the mitotic burst was not reproduced in cultured hepatocytes treated with MEHP, neither was there a fall in glucose-6-phosphatase activity. There was no increase in H[2]O[2] production either in vitro in cultured hepatocytes treated with MEHP, or in vivo as measured by catalase compound I in perfused liver from rats treated with DEHP in the diet. There was no evidence for mutagenic activity of DEHP or MEHP in the Ames Test. Treatment of isolated hepatocytes with MEHP, straight chain phthalate esters or clofibrate, resulted in early marked pertubations in lipid metabolism, namely, an increase in production of neutral fats and generally in fatty acid oxidation. This may explain the increased storage of lipid, in the liver. There was a marked difference in response between hepatocytes isolated from fed and fasted rats, the latter being more sensitive to all compounds. Indeed with fed rats there was, in some cases, a slight decrease in fatty acid oxidation. The effects on lipid metabolism were observed at concentrations which produced peroxisome proliferation in cultured cells.

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