The increasing use of nanomaterials has raised concerns about their potential risks to human health. Recent studies have shown that nanoparticles can cross the placenta barrier in pregnant mice and cause neurotoxicity in their offspring, but a more detailed understanding of the effects of nanoparticles on pregnant animals remains elusive. Here, we show that silica and titanium dioxide nanoparticles with diameters of 70 nm and 35 nm, respectively, can cause pregnancy complications when injected intravenously into pregnant mice. The silica and titanium dioxide nanoparticles were found in the placenta, fetal liver and fetal brain. Mice treated with these nanoparticles had smaller uteri and smaller fetuses than untreated controls. Fullerene molecules and larger (300 and 1,000 nm) silica particles did not induce these complications. These detrimental effects are linked to structural and functional abnormalities in the placenta on the maternal side, and are abolished when the surfaces of the silica nanoparticles are modified with carboxyl and amine groups.

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We previously reported that well-dispersed amorphous nanosilicas with particle size 70 nm (nSP70) penetrate skin and produce systemic exposure after topical application. These findings underscore the need to examine biological effects after systemic exposure to nanosilicas. The present study was designed to examine the biological effects. BALB/c mice were intravenously injected with amorphous nanosilicas of sizes 70, 100, 300, 1000 nm and then assessed for survival, blood biochemistry, and coagulation. As a result, injection of nSP70 caused fatal toxicity, liver damage, and platelet depletion, suggesting that nSP70 caused consumptive coagulopathy. Additionally, nSP70 exerts procoagulant activity in vitro associated with an increase in specific surface area, which increases as diameter reduces. In contrast, nSP70-mediated procoagulant activity was absent in factor XII-deficient plasma. Collectively, we revealed that interaction between nSP70 and intrinsic coagulation factors such as factor XII, were deeply related to nSP70-induced harmful effects. In other words, it is suggested that if interaction between nSP70 and coagulation factors can be suppressed, nSP70-induced harmful effects may be avoided. These results would provide useful information for ensuring the safety of nanomaterials (NMs) and open new frontiers in biological fields by the use of NMs.

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The effects of defatted soybean and/or iodine-deficient diet feeding were investigated in female F344 rats. Rats were divided into four groups, each consisting of 10 animals, and fed basal AIN-93G diet in which the protein was exchanged for 20% gluten (Group 1), iodine-deficient gluten (Group 2), 20% defatted soybean (Group 3) and iodine-deficient defatted soybean (Group 4). At week 10, relative thyroid gland weights (mg/100 g body wt) were significantly (P < 0.01) higher in Groups 2 (15.5 +/- 1.3) and 4 (81.7 +/- 8.6) than in Group 1 (8.4 +/- 2.0) and pituitary gland weights (mg/100 g body wt) were significantly (P < 0.01) higher in Groups 3 (9.1 +/- 0. 6) and 4 (9.7 +/- 1.5) than in Group 1 (6.5 +/- 1.5). Serum biochemical assays revealed thyroxine to be significantly (P < 0.05) lower in Groups 2 and 4 than in Group 1. On the other hand, serum thyroid-stimulating hormone (TSH) was significantly (P < 0.01) higher in Groups 3 and 4 than in Group 1. This was particularly striking for TSH (ng/ml) at week 10 in Group 4 (126 +/- 11) as compared with Groups 1 (4.36 +/- 0.30), 2 (4.84 +/- 0.80) and 3 (5. 78 +/- 0.80). Histologically, marked diffuse follicular hyperplasia of the thyroid was evident in Group 4 rats. Proliferating cell nuclear antigen labeling indices (%) were significantly higher (P < 0.05) in Groups 2 (4.8 +/- 2.5) and 4 (13.2 +/- 1.1) than in Group 1 (0.4 +/- 0.5). Ultrastructurally, severe disorganization and disarrangement of mitochondria were apparent in thyroid follicular cells of Group 4. In the anterior pituitary, dilated rough surfaced endoplasmic reticulum and increased secretory granules were remarkable in this group. Our results thus strongly suggest that dietary defatted soybean synergistically stimulates the growth of rat thyroid with iodine deficiency, partly through a pituitary-dependent pathway.

In order to cast light on carcinogen-specific molecular mechanisms underlying experimental hepatocarcinogenesis in rats, in vivo mutagenicity and mutation spectra of known genotoxic rat hepatocarcinogens N-nitrosopyrrolidine (NPYR), and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), as well as the nongenotoxic hepatocarcinogen di(2-ethylhexyl)phthalate (DEHP) and the noncarcinogen acetaminophen (AAP), were investigated in guanine phosphoribosyltransferase (gpt) delta transgenic rats, a recently developed animal model for genotoxicity analysis. After 13-wk treatment, glutathione S-transferase placental form (GST-P)-positive liver cell foci were significantly increased in NPYR-treated and IQ-treated rats. In the DEHP-treated rats, marked hepatomegaly with centrilobular hypertrophy of hepatocytes occurred, although GST-P staining was consistently negative. Positive mutagenicity was detected in IQ- and NPYR-treated rats. Mutant frequencies (MFs) in the liver DNA were 188.0 x 10(-6) and 56.5 x 10(-6), approximately 35-fold and 10-fold higher, respectively, than that of nontreatment control rats (5.5 x 10(-6)). There were no increases in MFs in the DEHP- or AAP-treated rats as compared to the nontreatment control value. IQ induced mainly base substitutions leading to G:C to T:A transversions (56.9%) and deletions of G:C base pairs. In contrast, NPYR primarily caused specific A:T to G:C transitions (49.3%), which are very rare in the other groups. These data provided support for the conclusion that IQ and NPYR hepatocarcinogenesis depends on genotoxic processes and specific DNA adduct formation while DEHP exerts its influence via a nongenotoxic promotional pathway. Our data also indicate that analysis of specific in vivo mutational responses with transgenic animal models can provide crucial information for understanding the molecular mechanisms underlying chemical carcinogenesis.