The genotype-dependent influence of functionalized multiwalled carbon nanotubes on fetal development

Abstract

In many cases cancer is caused by gene deficiency that is being passed along from generation to generation. Soluble carbon nanotubes (CNTs) have shown promising applications in the diagnosis and therapy of cancer, however, the potential relationship between cancer-prone individuals and response to CNT exposure as a prerequisite for development of personalized nanomedicine, is still poorly understood. Here we report that intravenous injections of multi-walled carbon nanotubes into p53 (a well-known cancer susceptible gene) heterozygous pregnant mice can induce p53- dependent responses in fetal development. Larger sized multi-walled carbon nanotubes moved across the blood-placenta barrier (BPB), restricted the development of fetuses, and induced brain deformity, whereas single-walled and smaller sized multi-walled carbon nanotubes showed no or less fetotoxicity. A molecular mechanism study found that multi-walled carbon nanotubes directly triggered p53-dependent apoptosis and cell cycle arrest in response to DNA damage. Based on the molecular mechanism, we also incorporated N-acetylcysteine (NAC), a FDA approved antioxidant, to prevent CNTs induced nuclear DNA damage and reduce brain development abnormalities. Our findings suggest that CNTs might have genetic background-dependent toxic effect on the normal development of the embryo, and provide new insights into protection against nanoparticle-induced toxicity in potential clinical applications.

A perspective on the developmental toxicity of inhaled nanoparticles

“…Interestingly, even at very high doses (0.8 mg/mouse), at which other NPs induce severe fetal effects, fullerenes were non-toxic [62]. In comparison, SWCNT and MWCNT interfere with placental and embryonic morphogenesis in a size, concentration and functionalization dependent manner [61,76,157,158]. Intravenously injected short SWCNT have been shown to induce a wide range of morphological alterations to embryos at concentrations as low as 100 ng/mouse.…”

In Vivo Induction of Primary DNA Lesions upon Subchronic Oral Exposure to Multi-walled Carbon Nanotubes

“…which are involved in inflammatory as well as carcinogen signal transmission (28). Apart from attributes of the nanotubes, if the p53 gene is intact, it protects cells from malignant transformation by activating an inflammatory response (29), as well as preventing foetotoxicity (30). Indeed, p53 gene expression level corresponds to specific gene (Ha-ras, c-myc) expression patterns involved in early steps of carcinogenesis (30,31,32).…”

“…Apart from attributes of the nanotubes, if the p53 gene is intact, it protects cells from malignant transformation by activating an inflammatory response (29), as well as preventing foetotoxicity (30). Indeed, p53 gene expression level corresponds to specific gene (Ha-ras, c-myc) expression patterns involved in early steps of carcinogenesis (30,31,32). On the other hand, specific lipoxygenase and cyclooxygenase enzyme families not only take part in inflammatory pathways mediated by arachidonic acid metabolism but also overlap with carcinogenesis (33).…”

“…are capable of ameliorating deleterious effects of specific environmental carcinogens (e.g. dimethylbenz[α]anthracene) while reducing inflammatory response gene expression (33), and N-acetylcysteine (NAC) as antioxidant prevented CNTinduced nuclear DNA damage, as well as foetotoxicity (30).…”

Toxicity assessment of nanoparticles in various systems and organs

“…Mostly, the teratogenicity of NPs on the fetus is of great concern [115,117]. Also, the survival, growth, development, and reproduction of the offspring need to be mainly assessed upon prenatal exposure [101,113,118].…”