Inhibition of sterologenesis in brain and liver of fetal and suckling rats from dams fed di‐2‐ethylhexyl phthalate plasticizer

Abstract

The effect of di-2-ethylhexyl phthalate (DEHP) on lipid metabolism was studied in liver and brain from fetal rats taken 3 days before parturition from dams receiving dietary DEHP during gestation. In fetuses from rats receiving 0.5% or 1.0% DEHP in a stock diet, the incorporation of 14C-acetate and labeled mevalonate (3H or 14C) into the C27 sterols, C30 sterols, and squalene fractions of brain tissue incubated in vitro was significantly reduced between the confidence limits P <0.05 to P <0.001. When liver from fetuses was incubated with labeled mevalonate, incorporation of label into the C27 sterol and C30 sterol fractions was significantly reduced as well (P <0.02 to P <0.001), whereas incorporation of labeled mevalonate into the squalene fraction was not significantly altered. The incorporation of 14C-acetate into total hepatic lipids of the fetal rats was also studied, and statistically significant reductions in incorporation were observed in the lanosterol fraction (P <0.001), the combined fraction of sterol esters + squalene (P <0.02), and the combined fraction of cholesterol + diglycerides (P <0.01). No significant changes were observed in the incorporation of 14C-acetate into phospholipids, free fatty acids, or triglycerides. In 8-day old suckling rats delivered from dams fed 0.5% DEHP for the last 16 days of gestation and maintained on the same diet during the nursing period, the incorporation of 14C-mevalonate into hepatic C27 sterols, in vitro, was significantly depressed (P <0.05) whereas in corporation into C30 sterols and squalene was similar to control values. In these same suckling rats, body weights were significantly lower in the control group (21.7 vs. 18.8 g, P <0.01), whereas liver weight as a % of body weight was significantly higher (P <0.01) in rats nursing from the DEHP-fed dams. The results ind'teate that the inhibitory effect of dietary DEHP on lipid metabolism in the mature rat is transmitted across the placental barrier to the developing fetus and that the abnormal pattern of lipid metabolism in rats delivered from DEHP-fed females is only partially restored to normal during the suckling periods.

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“…Plasma lipid-related markers such as total cholesterol (TCH), high density lipoprotein cholesterol (HDL-C) triglyceride (TG) of all treatment groups on the DEHP diet were significantly lower than Control. DEHP has been found to inhibit lipid and sterol synthesis in rats [24,25], but there was no significant improvement by D-allose and D-allulose administration. The relationship between sterol synthesis and oxidative stress is unclear.…”

Effects of Phthalic Acid Esters (PAEs) on the Neonate and Aspects of Teratogenic Actions

“…In neonatal rats previously injected with MEHP, very little PAE was detected in their livers (19). Bell et al (49) suggested that DEHP can cross the placental barrier, as evidenced by inhibition of sterologenesis in the brain and in the liver of fetal and suckling rats from dams previously fed with this phthalate. Subsequent reports (50) indicated that fetuses taken by caesarean section from pregnant rats fed DEHP (beginning 5 to 10 days after conception) exhibited an impairment of sterologenesis in brain and liver.…”

Altered Hippocampal Lipid Profile Following Acute Postnatal Exposure to Di(2-Ethylhexyl) Phthalate in Rats

“…Altered lipid composition in the brain has also been reported following exposure to DEHP [ 24 , 25 ]. Lipids are biological molecules essential for normal neurodevelopment and are involved in a wide variety of cellular processes, including cellular signalling, protein and receptor trafficking, neurogenesis, and myelination [ 26 , 27 , 28 ].…”

“…Slight changes in the abundance of certain lipid species in the brain may drastically alter normal neurodevelopment via membrane stability, cell signalling, and cell survival. A reduction in squalene, C 27 and C 30 sterols, free cholesterol esters, and sphingomyelin (SM) were detected in fetal rat brains following in utero exposure to DEHP [ 24 , 25 ]. DEHP treatment also decreased the concentration of mono- and polyunsaturated fatty acids in fetal rat brains, and reduced the concentration of docosahexaenoic acid (DHA) in cholesterol esters, diacylglycerols, phosphatidylserines, lysophosphatidylcholines (LPC), and SM [ 25 ].…”

“…DEHP-induced changes in lipid composition have been more widely studied outside of the brain, particularly in the liver and gonadal organs [ 24 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. Phospholipid and free fatty acid content in the liver, as well as triglyceride (TG) content in the liver and kidneys, were reduced in adult male rats exposed to dietary DEHP [ 30 ].…”