Physicochemical Properties of Engineered Nanomaterials that Influence Their Nervous System Distribution and Effects

This critical review examines in vitro and in vivo evidence for the influence of engineered nanomaterial (ENM) physicochemical properties on their distribution into, and effects on, the nervous system. Nervous system applications of ENMs; exposure routes and potential for uptake; the nervous system and its barriers to ENM uptake; and the mechanisms of uptake into the nervous system and overcoming those barriers are summarized. The findings of English-language publications of studies that included at least two variations of an ENM physicochemical property and reported results of their pharmacokinetic and/or pharmacodynamic interaction with the nervous system that differed as a function of ENM physicochemical property(ies) are summarized in Supplementary Materials. A summary conclusion is drawn for each of the physicochemical properties on the strength of the evidence that it influences ENM-nervous system interaction

Hair as an Indicator of Excessive Aluminum Exposure

To determine if excessive systemic exposure to aluminum would be reflected in increased aluminum concentration in hair, rabbits were given a series of aluminum lactate injections. Hair was collected before the aluminum lactate administration from the site of injections and twice after the injections from this site as well as from an area adjoining the injection site. Aluminum was determined by flameless atomic absorption analysis of acid-digested samples. The concentration of aluminum in the hair increased after the injections in samples taken at both times from both sites. Considerable variability in hair aluminum was found before excessive exposure, as has been reported in humans, and in response to the exposure. The increase in hair aluminum did not correlate with the amount of hair produced. Nevertheless, because some subjects exposed to excessive aluminum showed a very large increase in hair aluminum, hair may be a useful indicator of aluminum body burden in such aluminum-induced conditions as dialysis encephalopathy

Manganese Flux across the Blood-Brain Barrier

Manganese (Mn) is essential for brain growth and metabolism, but in excess can be a neurotoxicant. The chemical form (species) of Mn influences its kinetics and toxicity. Significant Mn species entering the brain are the Mn2+ ion and Mn citrate which, along with Mn transferrin, enter the brain by carrier-mediated processes. Although the divalent metal transporter (DMT-1) was suggested to be a candidate for brain Mn uptake, brain Mn influx was not different in Belgrade rats, which do not express functional DMT-1, compared to controls. Brain Mn influx was not sodium dependent or dependent on ATP hydrolysis, but was reduced by mitochondrial energy inhibitors. Mn and Fe do not appear to compete for brain uptake. Brain Mn uptake appears to be mediated by a Ca uptake mechanism, thought to not be a p-type ATPase, but a store-operated calcium channel. Efflux of Mn from the brain was found to be slower than markers used as membrane impermeable reference compounds, suggesting diffusion mediates brain Mn efflux. Owing to carrier-mediated brain Mn influx and diffusion-mediated efflux, slow brain Mn clearance and brain Mn accumulation with repeated excess exposure would be predicted, and have been reported. This may render the brain susceptible to Mn-induced neurotoxicity from excessive Mn exposure

The Toxicology of Aluminum in the Brain: A Review

Aluminum is environmentally ubiquitous, providing human exposure. Usual human exposure is primarily dietary. The potential for significant Al absorption from the nasal cavity and direct distribution into the brain should be further investigated. Decreased renal function increases human risk of Al-induced accumulation and toxicity. Brain Al entry from blood may involve transferrin-receptor mediated endocytosis and a more rapid process transporting small molecular weight Al species. There appears to be Al efflux from the brain, probably as Al citrate. There is prolonged retention of a fraction of Al that enters the brain, suggesting the potential for accumulation with repeated exposure. Al is a neurotoxicant in animals and humans. It has been implicated in the etiology of sporadic Alzheimer\u27s disease (AD) and other neurodegenerative disorders, although this is highly controversial. This controversy has not been resolved by epidemiological studies, as only some found a small association between increased incidence of dementia and drinking water Al concentration. Studies of brain Al in AD have not produced consistent findings and have not resolved the controversy. Injections of Al to animals produce behavioral, neuropathological and neurochemical changes that partially model AD. Aluminum has the ability to produce neurotoxicity by many mechanisms. Excess, insoluble amyloid beta protein (A beta) contributes to AD. Aluminum promotes formation and accumulation of insoluble A beta and hyperphosphorylated tau. To some extent, Al mimics the deficit of cortical cholinergic neurotransmission seen in AD. Al increases Fe-induced oxidative injury. The toxicity of Al to plants, aquatic life and humans may share common mechanisms, including disruption of the inositol phosphate system and Ca regulation. Facilitation of Fe-induced oxidative injury and disruption of basic cell processes may mediate primary molecular mechanisms of Al-induced neurotoxicity. Avoidance of Al exposure, when practical, seems prudent

Aluminum Reproductive Toxicity: A Summary and Interpretation of Scientific Reports

Publications addressing aluminum (Al)-induced reproductive toxicity were reviewed. Key details were compiled in summary tables. Approximate systemic Al exposure, a measure of bioavailability, was calculated for each exposure, based on the Al percentage in the dosed Al species, Al bioavailability, and absorption time course reports for the exposure route. This was limited to laboratory animal studies because no controlled-exposure human studies were found. Intended Al exposure was compared to unintended dietary Al exposure. The considerable and variable Al content of laboratory animal diets creates uncertainty about reproductive function in the absence of Al. Aluminum-induced reproductive toxicity in female mice and rats was evident after exposure to ≥ 25-fold the amount of Al consumed in the diet. Generally, the additional daily Al systemic exposure of studies that reported statistically significant results was greater than 100-fold above the typical human daily Al dietary consumption equivalent. Male reproductive endpoints were significantly affected after exposure to lower levels of Al than females. Increased Al intake increased fetus, placenta, and testes Al concentrations, to a greater extent in the placenta than fetus, and, in some cases, more in the testes than placenta. An adverse outcome pathway (AOP) was constructed for males based on the results of the reviewed studies. The proposed AOP includes oxidative stress as the molecular initiating event and increased malondialdehyde, DNA and spermatozoal damage, and decreased blood testosterone and sperm count as subsequent key events. Recommendations for the design of future studies of reproductive outcomes following exposure to Al are provided

Nanoparticle Brain Delivery: A Guide to Verification Methods

Many reports conclude nanoparticle (NP) brain entry based on bulk brain analysis. Bulk brain includes blood, cerebrospinal fluid and blood vessels within the brain contributing to the blood-brain and blood-cerebrospinal fluid barriers. Considering the brain as neurons, glia and their extracellular space (brain parenchyma), most studies did not show brain parenchymal NP entry. Blood-brain and blood-cerebrospinal fluid barriers anatomy and function are reviewed. Methods demonstrating brain parenchymal NP entry are presented. Results demonstrating bulk brain versus brain parenchymal entry are classified. Studies are reviewed, critiqued and classified to illustrate results demonstrating bulk brain versus parenchymal entry. Brain, blood and peripheral organ NP timecourses are compared and related to brain parenchymal entry evidence suggesting brain NP timecourse informs about brain parenchymal entry