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Oral intubation of styrene (1 ml/kg body weight daily) in adult male albino rats for 15 days produced a significant increase in serotonin and noradrenaline but no change in dopamine contents in brain. The brain of treated animals also showed a significant decrease in monoamine oxidase (MAO) but no change in acetyl cholinesterase (AChE) activity. The neurotoxic effects of styrene may be mediated through alterations in levels of these biogenic amines in the brain tissue.

Adult male rats were treated on 15 successive days with i.p. injection of manganese chloride at 10 or 15 mg/kg body weight. 24 h after the last dose, the binding of the dopaminergic antagonist [3H]spiroperidol to striatal membranes was elevated significantly. At the lower dose, no other high-affinity binding site measured was altered. However, at the 15 mg/kg body weight dose, cerebellar GABA, frontal cortical serotonin, and striatal muscarinic binding were all depressed. Neither dose level altered striatal levels of enkephalin, substance P, dopamine, serotonin, or dihydroxyphenylacetic acid (DOPAC). Receptor binding measurements may be a sensitive means of detecting disturbances of specific neural circuits.

Methyl methacrylate (MMA), a widely used monomer in the manufacture of acrylic polymers, has been reported to cause neurological deficits in industrial workers. The effect of MMA on regional brain biogenic amines and their correlation with behavioural responses were examined. Male Wistar rats received orally MMA (500 mg/kg body wt) for 21 consecutive days. Our results indicate that MMA markedly impaired locomotor activity and learning, while aggressive behaviour significantly increased. An overall enhancement of biogenic amine levels in pons-medulla and hippocampus was noted. In addition, for noradrenaline an increase in cerebral cortex and corpus striatum, for 5-hydroxytryptamine an increase in mid-brain and hypothalamus and for dopamine a slight decrease in corpus striatum were recorded. The changes in regional brain biogenic amine levels may be partly responsible for altered behaviour.

Evidence is presented for an enzyme-catalyzed conjugation of acrylamide (ACR) in rat erythrocytes. Daily exposure of rats to ACR for a period of 7, 14 and 21 days resulted in a time-dependent decrease in glutathione content. In vitro incubation of ACR with rat erythrocytes suspension caused a concentration-dependent decrease in glutathione levels. Red blood cell (RBC) enzyme-catalyzed conjugation of ACR with glutathione increased with protein concentration and was dependent on pH and time of incubation. Glutathione-S-transferase (GST) activity using acrylamide and 1-chloro 2,4-dinitrobenzene (CDNB) as substrates followed the order: liver greater than kidney greater than brain greater than erythrocytes. Glutathione peroxidase activity of RBC's was inhibited by the in vitro addition of ACR to erythrocytes. These results suggest that rat erythrocytes are equipped with the mechanism which can inactivate toxic electrophilic chemicals, such as acrylamide.

The effect of styrene (200 mg/kg, orally) on dopamine receptor binding using 3H-spiroperidol as a specific ligand was studied in developing rats. Gestational exposure caused no significant change in the binding of 3H-spiroperidol to striatal membranes of pups at 2 and 3 weeks of age. However, styrene exposure during lactation and the gestation-lactation period caused a significant increase in binding of 3H-spiroperidol. Scatchard analysis revealed that styrene exposure caused an increase in the number of receptor sites without affecting their affinity. Results of behavioral studies (amphetamine-induced locomotor activity and apomorphine-induced stereotypy) showed that styrene exposure during the gestation-lactation period caused a significant increase in motor activity and stereotypy of the rat pups. These behavioral and biochemical studies suggest that early postnatal exposure to styrene affects dopaminergic function.

Succinic dehydrogenase (SDH) and adenosine triphosphatase (ATPase) activity measured 21 days after 3 intraperitoneal injections of di-2-ethylhexyl phthalate (DEHP) was decreased in heart, lung and kidney while it remained unaltered in brain. Under in vitro conditions, only SDH was sensitive to DEHP, degree of inhibition being concentration-dependent. DEHP solubilized with Tween 80 inhibited the SDH activity significantly at small concentrations of 5 to 25 ppm. ATPase activity was not modified.

Sensitivity of central cholinergic (muscarinic) receptors was studied in rats after application of single and repeated (once daily for 7 days) electroconvulsive shocks (ECS). Oxotremorine-induced tremor was significantly enhanced after single as well as chronic exposure to ECS; [3H]QNB binding in frontal cortex was also significantly increased by chronic ECS. The results indicate that ECS develops supersensitivity in central muscarinic receptors.

Administration of parathion resulted in a greater inhibition of acetylcholinesterase (AChE) activity of plasma, erythrocytes, and brain in female rats than in male rats. No sex-related difference was observed in the antiacetylcholinesterase activity of paraoxon, an active metabolite of parathion. Gonadectomy increased the susceptibility of males but had no perceptible effect on females, resulting in comparable inhibition of AChE by parathion in both sexes. Administration of testosterone led to recovery from increased sensitivity to the antiacetylcholinesterase activity of parathion in castrated males and afforded partial protection to ovariectomized females. On the other hand, administration of estradiol further enhanced the enzyme inhibition by parathion in castrated males but had no significant effect on that in ovariectomized females. Alterations in the status of sex hormones did not affect the antiacetylcholinesterase activity of paraoxon in plasma and erythrocytes. However, inhibition of AChE activity by paraoxon was significantly higher in brains of gonadectomized rats than those of normal rats and the effect was reversible on administration of the respective sex hormones. The results indicate that testosterone plays an important role in determining parathion toxicity (as reflected by its antiacetylcholinesterase activity), probably by activating the oxidative cleavage of the insecticide into nontoxic metabolites.

Levles of DNA, RNA, DNase, RNase and manganese in different regions of rat brain were studied after daily administration of manganese chloride (8 mg MnCl2-4H2O/kg intraperitoneally) for a period of 120 days. DNA and RNA contents decreased significantly in cerebrum, cerebellum and rest of the brain regions after manganese treatment. A decrease in the DNase and an increase in the RNase activity was observed in the cerebellum and rest of brain region of the manganese treated animals. The manganese content increased significantly in all the regions of the brain, the maximum concentration being in the rest of brain portion. The presence of excess manganese in brain presumably leads to alterations in the functional activity of lysosomal enzymes. The decrease in the levels of nucleic acids is perhaps a consequence of the degenerating and dead neurones.

The involvement of testosterone in di(2-ethylhexyl)phthalate (DEHP) induced testicular injury has been examined by coadministration of testosterone (1 mg/kg) along with DEHP (2000 mg/kg) daily for 15 days. The coadministration of testosterone and DEHP appears to have prevented the testicular injury as judged by the biochemical and histopathological changes. The sperm count and the activity of the testicular enzymes, gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), sorbitol dehydrogenase (SDH), beta-glucuronidase and acid phosphatase, related with the maturation of sperm, which were significantly altered by DEHP treatment were found to be within normal levels after the combination treatment of DEHP and testosterone. The histopathological studies also showed more or less normal spermatogenic events. The results of this study have suggested the involvement of testosterone in DEHP induced testicular atrophy.

Adult male rats receiving styrene by gavage (200 or 400 mg kg-1, 6 days a week) for 100 days exhibited a significant dose-dependent increase in hepatic benzo[a]pyrene hydroxylase and aminopyrine-N-demethylase, a decrease in glutathione-S-transferase and no change in glucose-6-phosphatase. A decrease in the activity of mitochondrial succinic dehydrogenase and beta-glucuronidase was also observed. Activity of acid phosphatase was decreased only at the higher dose level. Levels of serum glutamic oxaloacetic transaminase and glutamic pyruvic transaminase were elevated only at the higher dose level. The absolute and relative weights of the liver of control and treated animals showed no significant difference. Histopathological studies of the liver tissue revealed tiny areas of focal necrosis, consisting of few degenerated hepatocytes and inflammatory cells at the higher dose level only.

Exposure to DBTL (20, 40 or 80 mg/kg body weight) caused a decrease in levels of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) at all treatment levels. Hypothalamus and frontal cortex appeared to be most affected, since levels of all the three amines examined showed changes in these areas. Maximum decrease of DA was found in corpus striatum, NA in pons medulla and of 5-HT in frontal cortex. These animals also showed a decrease in spontaneous locomotor activity and learning at all the doses. The data indicates involvement of hypothalamus and frontal cortical regions of the brain in the neurotoxicity of DBTL.

Male weanling Sprague-Dawley rats were fed a copper-deficient diet for 40 days. Copper-deficient rats weighed significantly (p less than 0.001) less (175 +/- 7 g) than copper-supplemented rats (230 +/- 6 g). Hematocrits were also significantly (p less than 0.001) decreased in deficient as compared to control animals from 43 +/- 0.6 to 30 +/- 2.7%. The binding of 3H-QNB to striatal and cerebellar membrane muscarinic receptors from control and deficient rats increased from 594 +/- 25 to 704 +/- 31 (p less than 0.02) and from 19 +/- 2 to 28 +/- 3 (p less than 0.01) pmol/g protein, respectively. Similarly, 3H-muscimol binding to GABA receptors (cerebellum) also increased from 39 +/- 5 to 58 +/- 3 (p less than 0.02) pmol/g protein. 3H-diazepam binding to benzodiazepine receptors in deficient versus control animal frontal cortex membranes decreased from 92 +/- 8 to 75 +/- 5 (p less than 0.02) pmol/g protein, respectively. These results may help explain CNS manifestations of copper deficiency.

Glutathione-S-transferase activity in the brain of male mammals (rat and mouse) was found to be relatively lower than in that of females. In contrast, the male aves (pigeon, kite, vulture, and crow) exhibited comparatively higher activity in brain glutathione-S-transferase than the corresponding females. Postnatal development of cytosolic glutathione-S-transferase activity in the rat brain was also investigated. The day-7 rats showed a low activity of 48 nmol/min/mg protein that gradually increased 3.2-fold over the age of 28 days. No striking differences in brain enzyme activities were observed between the 35- and 90-day-old rats. Discrete brain regions of immature rats were found to possess considerable but lower quantities of glutathione-S-transferase activity than those of the adults. The activity increased with the onset of development and attained a steady state after 21 days of age.

Neurotransmitter receptor binding was studied in the progeny of rats exposed to phenobarbital (80 mg/kg), phenytoin (80 mg/kg) or their combination daily from 5 to 20 days of gestation. At 22 days postnatally, female pups in all treated groups showed decreased binding of [3H]spiroperidol to striatal membranes. A decreased binding of [3H]diazepam to frontal cortical membranes was observed in the female pups of rats exposed to phenytoin or the combination. The Scatchard analysis of data from the affected groups revealed a decrease in the maximum number of dopamine and benzodiazepine receptor sites and no change in their affinities. The binding of [3H]spiroperidol or [3H]diazepam was not altered significantly in any of the drug-treated male pups. Also, no significant change in the binding of [3H]serotonin or [3H]quinuclidinyl benzilate to frontal cortical membranes was observed in any of the treated groups. At 60 days postnatally, no significant change in the binding of any of the above ligands was evident. The above prenatal drug exposures appear to cause transitory subsensitivity of dopamine and benzodiazepine receptors in rats.

Male albino rats were administered styrene in groundnut oil, PO at doses of 100 mg and 200 mg/kg body weight daily for 14 consecutive days. No neurological deficit was observed in any animal during the course of the experiment. Mean % avoidance response (learning) for each treated group, from day 1 to day 4 of conditioned avoidance response training, revealed a general increase. Styrene significantly increased the % avoidance response at both doses as compared to controls, although no definite dose-response relationship was evident. No significant difference was noted in the spontaneous locomotor activity and regional brain catecholamine levels, between controls and treated rats of either dose. Serotonin levels in hippocampus, hypothalamus, and mid-brain were significantly raised at the higher dose of styrene. Therefore, elevated serotonin levels in these brain regions may account for styrene-induced learning.

Effect of Di(2-ethylhexyl) phthalate (DEHP), was investigated on chemical constituents and activity of certain enzymes of rat liver. A significant increase in liver weight; total and relative to body weight; decrease in total, free and esterified cholesterol; and no change in dry weight, moisture; RNA, DNA, total lipids, phospholipids, pyruvic acid and lactic acid contents was observed in liver of DEHP-treated rats as compared to controls. Activity of 3 mitochondrial enzymes, malic dehydrogenase, cytochrome-c-oxidase and diaphorase were significantly decreased while that of NADH-cytochrome c reductase, RNAase and DNAase remained unaltered upon treatment. The results suggest that DEHP exerts its hepatotoxic effects by interfering with bioenergetics of the cell.

Acrylamide, a reactive electrophile, caused a concentration-dependent inhibition of alcohol dehydrogenase (ADH) activity (purified) which was reversed by prior addition of glutathione. Reaction of thiol groups of this enzyme with orthophthalaldehyde (OPT), a fluorescent reagent, exhibited characteristic fluorescence maxima at 330 nm excitation and 420 nm emission. Addition of acrylamide to the enzyme resulted in a concentration-dependent (acrylamide and protein) quenching of fluorescence of thiol groups when compared with fluorescence quenching caused by N-ethylmaleimide (NEM), a known thiol ligand. The results demonstrate that acrylamide-induced inhibition of purified ADH activity is mediated through its specific interaction with -SH groups in the enzyme molecule.

A population of rhesus monkeys (Macaca mulatta) at the ancient site of Tughlaqabad on the southern outskirts of New Delhi, India, showed moderate growth throughout the 1960s and 1970s and very rapid growth in the last 4 years. Between July 1980 and July 1983, the population increased 79%, from two groups of 160 monkeys to five groups of 286 monkeys, an average annual increase of 21.4%. The natality of the population has been high, averaging 82.4% over three birth seasons. Mortality and disappearance rates, especially of juveniles and adults, have been remarkably low with total annual mortality averaging only 3.7% from 1980 to 1983. We believe the striking record of population growth in this population can be attributed to total protection, abundant food, good cover, a lack of predators, a generally improving habitat, and low disease. With the right combination of ecological and behavioral factors, rhesus populations can double in four years. The Tughlaqabad population provides important guidelines for the restoration and conservation of primate populations., (Copyright © 1984 Wiley-Liss, Inc., A Wiley Company.)

Daily oral administration of acrylonitrile (10 mg/kg body weight) to mice for a period of 60 days caused a significant decrease in the activity of testicular sorbitol dehydrogenase and acid phosphatase, and an increase in that of lactate dehydrogenase and beta-glucuronidase. Histopathological studies revealed degeneration of the seminiferous tubules. A decrease in the sperm counts of the epididymal spermatozoa was also observed in the animals of the acrylonitrile-exposed group. These observations suggest that acrylonitrile may affect the male reproductive function by causing testicular injury.

Di(2-ethylhexyl) phthalate (DEHP), a commonly used plasticizer and microchemical environmental pollutant, produces subtle changes in hepatic function as judged by increase in liver weight and morphological and biochemical alterations. It can modify the biological response of drugs and other xenobiotics. Such interactions appear to occur at the pharmacokinetic phase, as DEHP was found to alter the activity of microsomal drug-metabolizing enzymes and ethanol metabolism. DEHP produced a time- and route-dependent effect on the hepatic cytochrome P-450 contents and activity of aminopyrine N-demethylase, aniline hydroxylase, alcohol dehydrogenase and high and low Km aldehyde dehydrogenases when given orally or intraperitoneally. Under in vitro conditions, DEHP produced no effect on the activity of aminopyrine N-demethylase or aniline hydroxylase, while mono(2-ethylhexyl) phthalate (MEHP) and 2-ethylhexanol (2-EH) significantly inhibited their activity at concentrations ranging from 2.5 to 15.0 mM. Activity of aminopyrine N-demethylase and aniline hydroxylase was also inhibited by dimethyl phthalate (DMP) and dibutyl phthalate (DBP) after a single oral administration. In view of the possibility of the human exposure to phthalates and other xenobiotics simultaneously, these observations are of great significance.

The influence of endosulfan, a chlorinated hydrocarbon insecticide, on rat hepatic drug metabolizing enzymes and lipid peroxidation has been explored in the present study. Total liver weight was significantly increased after endosulfan administration at both dose levels (2.5 and 5.0 mg/kg body weight) without affecting body weight or 9000 x g supernatant protein content. There was a marked increase in the activity of aminopyrine-N-demethylase, aniline hydroxylase, tyrosine amino-transferase and spontaneous lipid peroxidation. In all cases the increase was dose dependent.

Repeated administration of 0.5 mg/kg endosulfan (for 5 days a week) for 3 and 5 weeks of age, produced no significant alteration either in the binding of 3H-5HT to frontal cortical membranes or in foot-shock induced fighting behavior. However, administration of 1 mg/kg endosulfan for 5 weeks caused a significant increase in 3H-5HT binding as well as in foot shock induced aggressive behavior. The endosulfan-induced increase in aggressive behavior and increased binding of 3H-5HT were detectable even 8 days after the cessation of endosulfan treatment. Scatchard analysis revealed that exposure to endosulfan altered the affinity (KD) of the receptors without causing any significant change in maximum number of high affinity binding sites (Bmax). The endosulfan-induced fighting behavior was blocked by the pretreatment of animals with methysergide, a 5-HT blocker. These results suggest an involvement of serotonergic systems in the neonatal neurotoxicity of endosulfan.

Effect of di-2-ethylhexyl phthalate (DEHP) on glycogen contents and certain enzymes of carbohydrate metabolism of rat liver was investigated. A significant decrease in glycogen content of unfasted and an increase in fasted animals was observed. Blood glucose tolerance was reduced and the rate of both glycogenesis and glycogenolysis, as judged by measuring glycogen contents after feeding labelled and unlabelled glucose, was also decreased. Activities of glucose-6-phosphate dehydrogenase, phosphorylase and glucose-6-phosphatase were significantly decreased while activities of fructose-1-6-diphosphatase and aldolase remained unaltered. The present results suggest that DEHP affects both glycogenesis and glycogenolysis in rat liver.

Procarbazine, a non-benzodiazepine tranquilizer and anti-convulsant, significantly decreased the binding of [3H]diazepam to mouse cerebellar membranes. The drug treatment reduced both the affinity and density of the receptor. The effect, however, was more pronounced on the number of binding sites suggesting occupation of the receptor by procarbazine. The results suggest that benzodiazepine receptors may also be involved in the pharmacological action of non-benzodiazepine drugs.

The effects of modifiers of the microsomal mixed-function oxidase system on acrylamide-induced hind-limb paralysis were investigated in rats. Pretreatment of rats with phenobarbital, trans-stilbene oxide or dichloro diphenyl trichloroethane (DDT) resulted in an earlier onset and subsequent development of acrylamide-induced hind-limb paralysis than that observed in animals treated only with acrylamide. Cobalt chloride pretreatment of rats caused a significant delay in the onset and development of hind-limb paralysis. Our results suggest that an intermediate formed by the cytochrome P-450 system may be responsible for acrylamide neurotoxicity.

The covalent binding of benzo[a]pyrene (BP) to calf thymus DNA by brain microsomes isolated from control and 3-methylcholanthrene (3-MC) treated rats was investigated. The influence of incubation time, pH, and concentrations of protein, BP and NADPH on covalent binding was investigated to obtain optimum conditions for the in vitro binding of [3H]BP to DNA. Treatment of rats to 3-MC resulted in a 1.53-fold increase in the brain microsomal mediated covalent binding of [3H]BP to DNA. Inhibitors of monooxygenase enzyme activity such as alpha-naphthoflavone, metyrapone, 1-benzylimidazole and ellagic acid significantly inhibited the binding of [3H]BP to DNA from control and 3-MC stimulated brain microsomes. Our results indicate that inhibitors and inducers of monooxygenases may modulate brain enzyme-mediated binding of polycyclic aromatic hydrocarbons (PAHs) to DNA.