A Transcriptomic Analysis of T98G Human Glioblastoma Cells after Exposure to Cadmium-Selenium Quantum Dots Mainly Reveals Alterations in Neuroinflammation Processes and Hypothalamus Regulation.

Quantum dots are nanoparticles with very promising biomedical applications. However, before these applications can be authorized, a complete toxicological assessment of quantum dots toxicity is needed. This work studied the effects of cadmium-selenium quantum dots on the transcriptome of T98G human glioblastoma cells. It was found that 72-h exposure to 40 µg/mL (a dose that reduces cell viability by less than 10%) alters the transcriptome of these cells in biological processes and molecular pathways, which address mainly neuroinflammation and hormonal control of hypothalamus via the gonadotropin-releasing hormone receptor. The biological significance of neuroinflammation alterations is still to be determined because, unlike studies performed with other nanomaterials, the expression of the genes encoding pro-inflammatory interleukins is down-regulated rather than up-regulated. The hormonal control alterations of the hypothalamus pose a new concern about a potential adverse effect of quantum dots on fertility. In any case, more studies are needed to clarify the biological relevance of these findings, and especially to assess the real risk of toxicity derived from quantum dots exposure appearing in physiologically relevant scenarios.

Titanium Dioxide, but Not Zinc Oxide, Nanoparticles Cause Severe Transcriptomic Alterations in T98G Human Glioblastoma Cells.

Titanium dioxide and zinc oxide are two of the most widely used nanomaterials. We assessed the effects of noncytotoxic doses of both nanomaterials on T98G human glioblastoma cells by omic approaches. Surprisingly, no effects on the transcriptome of T98G cells was detected after exposure to 5 µg/mL of zinc oxide nanoparticles during 72 h. Conversely, the transcriptome of the cells exposed to 20 µg/mL of titanium dioxide nanoparticles during 72 h revealed alterations in lots of biological processes and molecular pathways. Alterations to the transcriptome suggests that exposure to titanium dioxide nanoparticles might, potentially, compromise the integrity of the blood brain barrier integrity and cause neuroinflammation. The latter issue was further confirmed phenotypically with a proteomic analysis and by recording the release of interleukin 8. Titanium dioxide also caused autophagy, which was demonstrated through the increase in the expression of the autophagy-related 3 and microtubule associated protein 1 light chain 3 alpha genes. The proteomic analysis revealed that titanium dioxide nanoparticles might have anticancerigen properties by downregulating genes involved in the detoxication of anthracyclines. A risk assessment resulting from titanium dioxide exposure, focusing on the central nervous system as a potential target of toxicity, is necessary.

Effects of silver nanoparticles on T98G human glioblastoma cells.

Nanotechnology has been well developed in recent decades because it provides social progress and welfare. Consequently, exposure of population is increasing and further increases in the near future are forecasted. Therefore, assessing the safety of applications involving nanoparticles is strongly advisable. We assessed the effects of silver nanoparticles at a non-cytotoxic concentration on the performance of T98G human glioblastoma cells mainly by an omic approach. We found that silver nanoparticles are able to alter several molecular pathways related to inflammation. Cellular repair and regeneration were also affected by alterations to the fibroblast growth factor pathways operating mainly via mitogen-activated protein kinase cascades. It was concluded that, given the relevant role of glia on central nervous system maintenance homeostasis, exposure to silver nanoparticles could eventually lead to severe toxicity in the central nervous system, although current exposure levels do not pose a significant risk.

Effects of mipafox, paraoxon, chlorpyrifos and its metabolite chlorpyrifos-oxon on the expression of biomarker genes of differentiation in D3 mouse embryonic stem cells.

Chlorpyrifos (CPS) is an organophosphorus compound (OP) capable of causing well-known cholinergic and delayed syndromes through the inhibition of acetylcholinesterase and Neuropathy Target Esterase (NTE), respectively. CPS is also able to induce neurodevelopmental toxicity in animals. NTE is codified by the Pnpla6 gene and plays a central role in differentiation and neurodifferentiation. We tested, in D3 mouse embryonic stem cells under differentiation, the effects of the NTE inhibition by the OPs mipafox, CPS and its main active metabolite chlorpyrifos-oxon (CPO) on the expression of genes Vegfa, Bcl2, Amot, Nes and Jun, previously reported to be under- or overexpressed after Pnpla6 silencing in this same cellular model. Mipafox did not significantly alter the expression of such genes at concentrations that significantly inhibited NTE. However, CPS and CPO at concentrations that caused NTE inhibition at similar levels to mipafox statistically and significantly altered the expression of most of these genes. Paraoxon (another OP with capability to inhibit esterases but not NTE) caused similar effects to CPS and CPO. These findings suggest that the molecular mechanism for the neurodevelopmental toxicity induced by CPS is not based on NTE inhibition, and that other unknown esterases might be potential targets of neurodevelopmental toxicity.

Organophosphorus pesticide chlorpyrifos and its metabolites alter the expression of biomarker genes of differentiation in D3 mouse embryonic stem cells in a comparable way to other model neurodevelopmental toxicants.

There are discrepancies about whether chlorpyrifos is able to induce neurodevelopmental toxicity or not. We previously reported alterations in the pattern of expression of biomarker genes of differentiation in D3 mouse embryonic stem cells caused by chlorpyrifos and its metabolites chlorpyrifos-oxon and 3,5,6-trichloro-2-pyridinol. Now, we reanalyze these data comparing the effects on these genes with those caused in the same genes by retinoic acid, valproic acid, and penicillin-G (model compounds considered as strong, weak, and non-neurodevelopmental toxicants, respectively). We also compare the effects of chlorpyrifos and its metabolites on the cell viability of D3 cells and 3T3 mouse fibroblasts with the effects caused in the same cells by the three model compounds. We conclude that chlorpyrifos and its metabolites act, regarding these end-points, as the weak neurodevelopmental toxicant valproic acid, and consequently, a principle of caution should be applied avoiding occupational exposures in pregnant women. A second independent experiment run with different cellular batches coming from the same clone obtained the same result as the first one.

Polµ deficiency increases resistance to oxidative damage and delays liver aging.

Polµ is an error-prone PolX polymerase that contributes to classical NHEJ DNA repair. Mice lacking Polµ (Polµ(-/-)) show altered hematopoiesis homeostasis and DSB repair and a more pronounced nucleolytic resection of some V(D)J junctions. We previously showed that Polµ(-/-) mice have increased learning capacity at old ages, suggesting delayed brain aging. Here we investigated the effect of Polµ(-/-) deficiency on liver aging. We found that old Polµ(-/-) mice (>20 month) have greater liver regenerative capacity compared with wt animals. Old Polµ(-/-) liver showed reduced genomic instability and increased apoptosis resistance. However, Polµ(-/-) mice did not show an extended life span and other organs (e.g., heart) aged normally. Our results suggest that Polµ deficiency activates transcriptional networks that reduce constitutive apoptosis, leading to enhanced liver repair at old age.