Effects of phthalic acid esters on the liver and thyroid.

Abstract

The effects, over periods from 3 days to 9 months of administration, of diets containing di-2-ethylhexyl phthalate are very similar to those observed in rats administered diets containing hypolipidemic drugs such as clofibrate. Changes occur in a characteristic order commencing with alterations in the distribution of lipid within the liver, quickly followed by proliferation of hepatic peroxisomes and induction of the specialized P450 isoenzyme(s) catalyzing w oxidation of fatty acids. There follows a phase of mild liver damage indicated by induction of glucose-6-phosphatase activity and a loss of glycogen, eventually leading to the formation of enlarged lysosomes through autophagy and the accumulation of lipofuscin. Associated changes are found in the kidney and thyroid. The renal changes are limited to the proximal convoluted tubules and are generally similar to changes found in the liver. The effects on the thyroid are more marked. Although the levels of thyroxine in plasma fall to about half normal values, serum triiodothyronine remains close to normal values while the appearance of the thyroid varies, very marked hyperactivity being noted 7 days after commencement of treatment, this is less marked at 14 days, but even after 9 months treatment there is clear cut evidence for hyperactivity with colloid changes which indicate this has persisted for some time. Straight chain analogs of di-2-ethylhexyl phthalate, di-n-hexyl phthalate and di-n-oxtyl phthalate differ entirely in their short-term effects on the liver and kidney but have similar effects on the thyroid.The short-term in vivo hepatic effects of the three phthalate esters can be reproduced in hepatocytes in tissue culture. All three phthalate esters, as well as clofibrate, have early marked effects on the metabolism of fatty acids in isolated hepatocytes. The nature of these changes is such as to increase storage of lipid in the liver. A hypothesis is presented to explain the progress from these initial metabolic effects to the final formation of liver tumors.

Involvement of Thyroxine in Ovarian Toxicity of Di-(2-ethylhexyl) Phthalate

“…When T 4 was administered to thyroidectomized rats, the increases in the hormone levels and in the number of developed follicles were suppressed at levels equating those of intact rats. Circulating levels of thyroid hormone were obviously low in the rats receiving DEHP 13,14) , and in our present study, the serum T 4 level was significantly lowered by treatment with 2,000 mg DEHP (P<0.05) in intact rats, whereas the T 4 level tended to be decreased by 2,000 mg DEHP in hypox rats, although the decrease was without statistical significance (Fig. 1).…”

“…DEHP is also known to suppress enzyme activity in the liver of rats 13,14) . When fed with diets containing DEHP, the serum thyroxine (T 4 ) levels declined to about half of those of control rats 3 d after the initiation of intake of DEHP in diet 13) .…”

“…When fed with diets containing DEHP, the serum thyroxine (T 4 ) levels declined to about half of those of control rats 3 d after the initiation of intake of DEHP in diet 13) . Administration of T 4 to intact and thyroidectomized rats significantly increased the circulating levels of thyroid hormones, and the increase of thyroid hormone levels was suppressed by DEHP administered simultaneously with T 4 14) .…”

Environmental Thyroid Disruptors and Human Endocrine Health

“…www.intechopen.com Rodent studies found histopathological changes in the rat thyroid glands after exposure to di(2-ethylhexyl) phthalate (DEHP), di-noctyl phthalate (DnOP) and di-n-hexyl phthalate (DnHP), corresponding to thyroid hyperactivity (Hinton et al, 1986;Howarth et al, 2001;Mitchell et al, 1985;Poon et al, 1997;Price et al, 1988). Long-term treatment with high doses of DEHP resulted in basophilic deposits in the colloid and enlargement of the lysosomes (Mitchell et al, 1985).…”

Disruption of Thyroid Hormone Function by Environmental Pollutants

“…Wenzel et al 134) found that DEHP and other phthalates enhance iodine uptake in rat thyroid follicular cells. In rats fed DEHP-contaminated diets, histological changes in the thyroid and a decrease in plasma T 4 were seen, but T 3 level remained unchanged, [135][136][137][138] while rats intravenously receiving DEHP showed increased concentrations of serum T 4 and T 3 . 139) Exposure of male rats to DBP by oral gavage also caused a reduction in T 4 and T 3 levels in a dose-dependent manner.…”