Nanoparticles exposure induced brain pathology and behavioral dysfunction depends on age

Recent epidemiological studies show profound incidences of major depression (MD) in our military deployment that is more prevalent in young women (18-25 age group) than their male counterparts of similar ages. Since the military personals are often exposed to various nanoparticles (NPs) e.g., SiO2 in desert environment or carbon NPs (CNPs) due to missile explosion or blast injuries a possibility exists that these NPs may also affect their MD. However, whether age or size of the NPs may also affect MD among the military is still unclear. To answer these questions, we used repeated forced swimming (FS) as an animal model of MD in rats and examined the effects of age e.g., (10-12 and 25 to 28 weeks) in a group of female or male rats on brain pathology and behavioral dysfunction following saline or CNPs or SiO2 NPs (20-30 nm or 50-60 nm sizes) exposure (50 mg/kg, i.p. daily for 7 days). Rats were subjected to 10 min FS daily for 1 week in a pool of water (30 cm height, at 30±1° C) in a glass jar (diameter 8 cm²). On the 8^th day these animals were subjected to behavioral tests e.g. Rota Rod (16 rpm), walking on mesh grid or standing on an inclined plane angle. The brain pathology was examined using alterations in the blood-brain barrier (BBB) function to Evans blue albumin (EBA) and radioiodine as well as increase in brain water content. Histological analyses were done using Nissl staining to study neuronal changes. Our result showed that young females exhibited the most profound alterations in behavioral dysfunctions and regional BBB leakage to EBA and radioiodine (+60 to 234 % from controls) in 14 brain areas. Significant increase in brain water was also seen in 8 regions (+ 1.05 to 1.16 % from controls) containing several damaged neurons (80 to 190). On the other hand, the age matched male rats showed much less behavioral dysfunction, BBB damage (+40 to 110 %), brain edema (0.78 to 0.96 %) and neuronal injuries (40 to 80) after identical FS. Interestingly, the adult male or female rats showed only mild but significant changes in behavioral dysfunction and brain pathologies. When young rats were subjected to FS after NPs intoxication, the behavioral disturbances and brain pathologies were much more exacerbated. This effect was most marked in females  (+3 to 4-fold increase) than male rats (+1.5 to 2-fold). The smaller sizes of the NPs have the most adverse effects and SiO2 induces greater damage than CNPs. Whereas, NPs exposure in adult male or female rats following FS showed only mild exacerbation of brain pathology. These observations are the first to show that young females are the most vulnerable to MD and their symptoms are further exacerbated following NPs exposer, depending on their size and the type used.