Hexachlorophene and the central nervous system

Summary A study on hexachlorophene encephalopathy in mice and baboons is reported. By light microscopy, a severe spongiform lesion of the central nervous system (CNS) was localized in the white matter, without myelin breakdown or cellular reaction. By electron microscopy, the myelin alteration was characterized by wide intralamellar spaces or splitting developed in the intraperiod line of compact sheaths. The acute changes described were induced by administration of the drug by the digestive or cutancous routes at various dosage levels in an aqueous solution or in talcum powder. The toxic effects depended on the age of the animals, the survival times and the concentrations of hexachlorophene, i.e., 6%, 3%, and 0.5%. The findings are compared with previous reports on the neurotoxicity of hexachlorophene and other chemicals in humans and experimental animals. Hexachlorophene cannot be recommended for use in young infants because of its neurotoxicity in very low doses as demonstrated in the present report.     

Accumulation of aluminum by primary cultured astrocytes from aluminum amino acid complex and its apoptotic effect

Aluminum salts or doses that are unlikely in the human system have been employed in toxicity studies and much attention had been focused on the secondary target (neurons) of its toxicity rather than the primary target (astroglia). In order to address these issues, we have investigated the uptake and apoptotic effects of aluminum amino acid complex on primary cultured astrocytes because these are fundamental in understanding the mechanism of aluminum neurotoxicity. Aluminum solubilized by various amino acids was differentially internalized by astrocytes (glycine>serine>glutamine>glutamate), but aluminum was not internalized from citrate complex following 24 h of exposure. Inhibition of glutamine synthetase, by methionine sulfoximine (MSO), enhanced the uptake of aluminum from various amino acid complexes within 8 h except from glutamine complex. Blockade of selective GLT-1 (EAAT2) and GlyT1, as well as nonspecific transporters, did not inhibit or had no effect on uptake of aluminum in complex with the corresponding amino acids. Ouabain also failed to inhibit uptake of aluminum complexed with glycine. Pulse exposure to aluminum glycinate in the absence or presence of MSO caused apoptosis in over 25% of primary cultured astrocytes, and apoptotic features such as chromatin condensation and fragmentation became evident as early as 3 days of culture in normal medium. Lower doses (as low as 0.0125 mM) also caused apoptosis. The present findings demonstrate that aluminum solubilized by amino acids, particularly glycine, could serve as better candidate for neurotoxicity studies. Citrate may be a chelator of aluminum rather than a candidate for its cellular uptake. Amino acid transporters may not participate in the uptake of aluminum solubilized by their substrates. Another pathway of aluminum internalization may be implicated in addition to passive diffusion but may not require energy in form of Na+/K+-ATPase. Impaired astrocyes' metabolism can aggravate their accumulation of aluminum and aluminum can compromise astrocytes via apoptosis. Thus, loss of astrocytic regulatory and supportive roles in the central nervous system (CNS) may be responsible for neurodegeneration observed in Alzheimer's disease.     

Toluene disrupts synaptogenesis in cultured hippocampal neurons

Prenatal toluene exposure may lead to significant developmental neurotoxicity known as fetal solvent syndrome. Emerging evidence suggests that toluene embryopathy may arise from an elusive deviation of the neurogenesis process. One key event during neural development is synaptogenesis, which is essential for the progression of neuronal differentiation and the establishment of neuronal network. We therefore aim to test the hypothesis that toluene may interfere with synaptogenesis by applying toluene to cultured hippocampal neurons dissected from embryonic rat brains. In the presence of toluene, hippocampal neurons displayed a significant loss of the immunostaining of synapsin and densin-180 punctas. Notably, a dramatic reduction was also discerned for the colocalization of the two synaptic markers. Moreover, Western blotting analyses revealed that toluene exposure resulted in considerable down-regulation of the expression of synapse-specific proteins. None of the preceding observations can be attributed to toluene-induced cell death effects, since toluene treatments failed to affect the viability of hippocampal neurons. Overall, our data are consistent with the idea that toluene may alter the expression and localization of essential synaptic proteins, thereby leading to a disruption of synapse formation and maintenance.     

Triethyltin decreases maximal electroshock seizure severity in adult rats

Acute and subacute treatment of adult rats with triethyltin bromide (TET) caused dose-dependent and time-dependent decreases in maximal electroshock seizure (MES) severity. This decrease in excitability was characterized by both a decrease in the percentage of animals exhibiting a maximal seizure and a corresponding decrease in the extension durations and an increase in the flexion durations. Acutely treated rats received (ip) 0, 1, or 5 mg/kg TET while subacutely exposed (po) received 0, 1, 5, or 10 ppm TET in the drinking water for 10 days. Experiments were designed so that the total consumed dose of TET, on a milligram per kilogram basis, equaled that in the acute experiment. No alterations in body weight were observed in either experiment. Acutely, the onset of action of TET was detectable within 0.5 hr. For the 1 mg/kg group, the effect peaked between 4 and 24 hr and completely recovered by 72 to 96 hr. For the 5 mg/kg group, the marked effect peaked at 4 hr, however, no recovery was observed. Subacute exposure for 1 to 2 days produced marked decreases in MES severity which were still present in the 5- and 10-ppm groups 14 days after cessation of exposure. Comparison of the onset and recovery data in the acute and subacute experiments revealed a close correspondence in similarly dosed rats. Comparison with other MES data from our laboratory revealed that adult rats were more sensitive to TET than adult mice or developing rats. Additionally, the MES test was able to detect subtle functional alterations in the central nervous system at lower doses of TET than previously reported neurobehavioral evaluation procedures.     

The stamp of ancestry: roots of behavioral and neuronal impairment in adulthood

Exposure of pregnant animals to noxious conditions affects neuronal function in the offspring. However, exposure or treatment of the maternal animal during pregnancy affects both ancestor and offspring. In the present study, female CD-1 mice were repetitively treated with 3-nitropropionate (3-np), a selective inhibitor of succinic dehydrogenase, exclusively prior to mating. Clinically, mice appeared normal during treatment. Five days after cessation of treatment animals were mated with control male animals. At 4 months of age spatial learning, LTP, NADH autofluorescence, and hypoxic tolerance were alike in controls and the offspring of treated female ancestors. However, an additional metabolic challenge in the offspring unmasks impairment of spatial learning, diminution of long-term potentiation (LTP), an altered protein microenvironment of mitochondrial enzymes, and reduced hypoxic tolerance. We conclude that the exposure of maternal ancestors to subclinical repetitive impairment of oxidative phosphorylation fosters impairment of behavior and neuronal function in the adult offspring, becoming apparent only on additional challenge. This finding may ultimately help to understand the causes of neuronal impairment or even neuropsychiatric disease in old age.     

A brief review of cognitive assessment in neurotoxicology

Among commercial and industrial chemicals, cosmetics, food additives, pesticides, and medicinal drugs, there are more than 50,000 substances distributed. Neurotoxic insults to the brain can manifest in many different ways, especially involving cognition. Given many possible differences in the pathophysiology of neurotoxic exposure and related cognitive sequelae, a systematic method of cognitive assessment is important for appropriate management of neurotoxic exposure. In the context of Neurotoxicology, this article briefly reviews the contemporary literature and the utility of cognitive assessment tools that are used in neuropsychology.     

Neuropharmacology of drugs and alcohol in mother and fetus

Epidemiological evidence suggests that an adverse prenatal environment can have profound long-term health consequences throughout postnatal life. This chapter discusses the underlying mechanisms implicated in the consumption of mood-altering recreational drugs and teratogenicity in the fetus. The way metabolic parameters in pregnancy influence the pharmacokinetic characteristics of drugs and alcohol and the developmental stage of neurotoxicity are reviewed. The general underlying mechanisms that link multifaceted interactions between drug characteristics, gene polymorphisms, dietary deficiencies, changed endocrine indices and fetal programming are outlined, with specific examples throughout the text. As developmental injury is of significant social concern, the final section questions whether society provides adequate support for making appropriate and informed lifestyle choices to alleviate preventable transgenerational harm.     

The relationship between neurological damage and neurotoxic esterase inhibition in rats acutely exposed to tri-ortho-cresyl phosphate

A rodent model of organophosphorus-induced delayed neuropathy (OPIDN) has been developed using Long-Evans adult male rats exposed to tri-ortho-cresyl phosphate (TOCP). In the present study an attempt was made to relate neurochemical with neuropathological changes in rats exposed to single dosages of TOCP ranging from 145 to 3480 mg/kg. The degree of neurotoxic esterase (NTE) inhibition, measured at 20 and 44 hr and at 14 days postexposure was correlated with the appearance of spinal cord pathology 14 days postexposure in a separate group of similarly dosed rats. Those dosages that inhibited mean NTE activity in spinal cord greater than or equal to 72% and brain greater than or equal to 66% of control values within 44 hr postexposure produced marked spinal cord pathology 14 days postexposure in greater than or equal to 90% of similarly dosed animals. In contrast, dosages of TOCP which inhibited mean NTE activity in the spinal cord less than or equal to 65% and in the brain less than or equal to 57% produced spinal cord pathology in less than or equal to 15% of the animals. These data indicate that NTE inhibition may be used as a biochemical predictor for TOCP-induced neurological damage in rats.