Serum levels of albumin, triglycerides, total protein and glucose in rats are altered after oral treatment with low doses of 13-cis-retinoic acid or all-trans-retinoic acid.

Currently used to treat severe acne, 13-cis-retinoic acid (13-cis-RA) is under investigation for its anticancer effects as is the isomer, all-trans-retinoic acid (all-trans-RA). Here, the effects of oral 13-cis-RA or all-trans-RA treatment on serum chemistry, leptin and adiponectin levels were evaluated. Adult Sprague-Dawley rats were gavaged once daily for 7 consecutive days with 13-cis-RA (7.5 or 15 mg kg(-1)), all-trans-RA (10 or 15 mg kg(-1)) (n=24/sex/dose), or soy oil (n=16/sex) and blood was sampled 30-480 min after the last gavage. The body weight was unaffected; however, the liver/body weight ratios were increased by both doses of all-trans-RA. Sex differences were noted for levels of cholesterol, creatine, triglycerides, albumin, alanine aminotransferase and total protein. Both doses of all-trans-RA reduced albumin levels to approximately 90% of the control and total protein levels to approximately 93% of the control while substantially elevating triglyceride levels to approximately 66%-99% above the control. Additionally, triglyceride levels of the 15 mg kg(-1) 13-cis RA group were approximately 62% higher than the controls and total protein levels were approximately 5% less. Glucose levels were affected by sex and RA treatment in that males treated with 15 mg kg(-1) of 13-cis-RA or 10 mg kg(-1) all-trans-RA had lower (13%-19%) levels than the same-sex controls; however, females were not similarly affected. Neither 13-cis-RA nor all-trans-RA treatment had significant effects on the levels of blood urea nitrogen, aspartate amino transferase, leptin or adiponectin. On a mg kg(-1) basis, all-trans-RA was more potent than 13-cis-RA. These results replicate previous findings of RA-induced increased triglyceride levels. Additionally, several new findings indicate there may be sex-specific effects of RA treatment. Finally, neither treatment appeared to alter the typical diurnal cycles of these endpoints.

Correlation of blood cholinesterase levels with toxicity of sarin in rats.

The dose-mortality response curve for sarin when administered to pregnant rats is extremely steep. The pregnant animal either died during the treatment or survived with no observable fetal toxicity. Animals that died displayed many symptoms characteristic of anticholinesterase toxicity. The present study was conducted to determine whether the maternal deaths, clinical observations, and/or weight loss could be correlated with baseline blood cholinesterase levels in individual animals. Cholinesterase levels (plasma and erythrocyte) were obtained prior to, during, and following treatment of nonpregnant rats by gavage with 380 microg/kg/d sarin for 10 d. After the first dose, there was a drop in the plasma cholinesterase levels, which then remained low throughout the dosing period. There was a statistically significant correlation between body weight loss and plasma cholinesterase levels of the sarin dosed animals. The surviving animals also had lower plasma cholinesterase levels and lower body weights, both of which recovered on the cessation of dosing. The erythrocyte cholinesterase levels were not different between treated and nontreated rats. Neither plasma or erythrocyte baseline cholinesterase levels nor relative or absolute cholinesterase decline values could be used as predictors of mortality from sarin administration in rats.

Neurochemical effects of prenatal haloperidol exposure.

The neurochemical effects of prenatal exposure to dopamine receptor antagonists are as yet poorly characterized. To further examine this problem, pregnant rats were given daily subcutaneous injections of vehicle, 2.5 or 5.0 mg/kg haloperidol over gestational days 6 through 20. Membrane binding of [3H]SCH-23390 (D1-specific) and [3H]spiroperidol (D2-specific in most brain areas) was measured in four regions of the cerebral dopamine system at postnatal day (PND) 30. Dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels were measured in caudate on PND 30 following a d-amphetamine challenge. Prenatal haloperidol exposure reduced [3H]SCH-23390 and [3H]spiroperidol binding in caudate in a dose-dependent manner. [3H]Spiroperidol binding was similarly reduced in nucleus accumbens, but only the low dose (2.5 mg/kg) group showed decreased [3H]SCH-23390 binding in this region. Binding of neither compound was significantly altered in amygdala or frontal cortex. Basal or drug-stimulated levels of caudate DA and DOPAC were unaltered. It is concluded that prenatal haloperidol exposure reduces D1 and D2 binding in some, but not all regions of the forebrain dopamine system.

Chronic prenatal haloperidol exposure: lack of effect on presynaptic dopamine autoreceptors.

Prenatal haloperidol exposure in rats is known to reduce striatal D2 receptor binding in postnatal day (PND) 30 offspring. The effects of prenatal haloperidol exposure on presynaptic dopamine (DA) autoreceptor function are not well described. Pregnant albino rats were given daily injections of haloperidol (2.5 or 5.0 mg/kg, sc) or vehicle over gestational days 6-20. Presynaptic DA autoreceptor function was assessed using the DOPA decarboxylase inhibitor NSD-1015 and gamma-butyrolactone in the caudate, nucleus accumbens and olfactory tubercles of male offspring sacrificed on PND 97. There appeared to be no impairment of autoreceptor function in any region studied. The data indicate that prenatal haloperidol exposure does not result in permanent alterations in presynaptic DA autoreceptor function.

A rapid procedure to efficiently clean blenders repeatedly used to prepare dosed feed for bioassays.

An effective and economical procedure is described to clean blending equipment repeatedly used to prepare dosed feed for animal bioassays. The cleanup procedure was evaluated with 2 types of blenders against 10 test chemicals with a broad spectrum of polarities by separately spiking the agents into feed at various levels. Analytical data illustrating the level of contamination at each interval of the multi-step cleanup procedure are presented for each test chemical. Analytical chemical methods and efficiencies of the cleaning steps with the feed admixtures are discussed. The procedure was tested and adopted for use at the National Center for Toxicological Research (NCTR).

Metabolism of diethylstilbestrol in the C3H mouse: chromatographic systems for the quantitative analysis of DES metabolic products.

Initial excretion studies with orally administered [monoethyl-1-3H] DES demonstrated the feces to be the principal mode of elimination of DES in the C3H mouse. Metabolic studies with tritiated DES and/or [UL-14C] DES were performed with orally dosed C3H high (MTV+) and low (MTV-) titer MMTV female mice. Extraction and partitioning of the fecal radioactivity demonstrated 77 to 86% (n = 4) to be benzene soluble and the remainder H2O soluble. The principal product in the organic phase following Sephadex LH-20 and HPLC purification was DES. The aqueous phase was resolved by LH-20 into two conjugate fractions that were partially hydrolyzed by beta-glucuronidase. The principal aglycone was chromatographically identical with authentic DES. The urinary conjugates were resolved into six fractions. The four major fractions were 80% hydrolyzable with beta-glucuronidase. Two of these fractions had trans-DES as the principal aglycone, whereas the other two had a major peak similar to but not chromatographically coincident with cis-DES. In certain experiments mice were sequentially dosed with tritium (24 hr) followed by a 14C dose (24 hr). Two mice (MTV+) were also previously fed 1000 ppb DES prior to these experiments. The tritated and 14C products were combined and analyzed simultaneously. This experiment did not reveal significant differences in the metabolism due to the modes of radioactive labeling, MMTV titer, or the prior feeding of DES. The developed methodology was judged to purify quantitatively 90% or more of the DES radioactive products.