Ferroptosis Is Involved in Sex-Specific Small Intestinal Toxicity in the Offspring of Adult Mice Exposed to Polystyrene Nanoplastics during Pregnancy

Abstract

Nanoplastics are common contaminants in the living environment. Thus far, no investigations have focused on small intestinal injury in the offspring of adult mice that were exposed to nanoplastics through the respiratory system during pregnancy. Here, we evaluated potential intestinal injury in the offspring of adult mice that were subjected to maternal 80 nm polystyrene nanoparticle (PS-NP) exposure during gestation. PS-NP exposure significantly reduced the birth weight of female mice compared with male mice. However, the adult body weights of the female and male offspring were substantially greater in the PS-NP-exposed groups. Additionally, we found that exposure to PS-NPs during pregnancy caused histological changes in the small intestines of both female and male offspring. Mechanistic analysis revealed upregulation of reactive oxygen species in the small intestines, as indicated by changes in the levels of superoxide dismutase (SOD) and malondialdehyde (MDA). Furthermore, exposure to PS-NPs led to downregulation of GPx4, FTH1, and FTL protein levels, indicating initiation of ferroptosis. Notably, the changes in mRNA expression levels of GPx4, FTH1, and FTL differed between female and male offspring. Although all phenotypes failed to demonstrate classic dose-dependent effects, the data imply that small intestinal toxicity is greater in female offspring than in male offspring. Our results suggest that PS-NP exposure during pregnancy causes sex-specific small intestinal toxicity, which might contribute to reactive oxygen species activation and subsequent ferroptosis. Overall, this study showed toxic effects in offspring after PS-NP exposure during pregnancy.

Surface-Charge-Driven Ferroptosis and Mitochondrial Dysfunction Is Involved in Toxicity Diversity in the Marine Bivalve Exposed to Nanoplastics

“…24,28,59 These variations are all significant indicators of mitochondrial dysfunction, often linked to ferroptosis. 27,40,59 This conclusion aligns with the tran- scriptome and proteome analyses, which revealed a significant enrichment of ferroptosis pathways (Figures 2f and 4c).…”

“…This implies that NPs may interact with and interfere with the metabolism and transport of iron within the bivalves. Iron, being an essential transition metal, can unbalance the redox equilibrium, leading to an increase in reactive oxygen species (ROS) and lipid peroxidation (LPO), triggering ferroptosis. ,, Compared to the control group, a marked ROS increase was detected in the bivalve’s viscera (a mixture of all tissues except for the shells), especially in the p-NP groups (Figure i and Figure S2d–f). Additionally, the levels of malondialdehyde (MDA), a marker of LPO, , were considerably higher in clams treated with p-NPs or the high dose of n-NPs than in the control (Figure j).…”

“…Conversely, proteins related to purine metabolism (important for cell signaling) and ECM–receptor interaction (known regulators of autophagy) are implicated in clams’ ability to cope with n-NP stress. , Furthermore, our proteomic analysis unveiled that the p-NPs enhanced ferroptosis, marked by iron-dependent lipid peroxidation (Figure d). This form of cell death is associated with inflammation-related processes and may result from mitochondrial dysfunction. , While ferroptosis and mitochondrial dysfunction are not directly correlated, mitochondrial dysfunction can lead to cellular conditions that favor ferroptosis. , The proteomics-based protein–protein interaction (PPI) network highlighted glycogen phosphorylase protein as critical in the metabolic processes induced by p-NPs (Figure f). In the n-NP group, proteins with the highest centrality were the upstream in-frame stop codon and glyceraldehyde-3-phosphate dehydrogenase, indicating their pivotal role in maintaining system balance in n-NP-treated bivalves (Figure g and Figure S6c, and Data Set S6).…”

“…27,36 While ferroptosis and mitochondrial dysfunction are not directly correlated, mitochondrial dysfunction can lead to cellular conditions that favor ferroptosis. 25,27 The proteomics-based protein−protein interaction (PPI) network highlighted glycogen phosphorylase protein as critical in the metabolic processes induced by p-NPs (Figure 3f). In the n-NP group, proteins with the highest centrality were the upstream in-frame stop codon and glyceraldehyde-3-phosphate dehydrogenase, indicating their pivotal role in maintaining system balance in n-NP- treated bivalves (Figure 3g and Figure S6c, and Data Set S6).…”

“…Generally, a decrease in the GSH/GSSG ratio and an increase in Fe 2+ indicate ferroptosis. 25,27,56 Lipid peroxidation (LPO), known to harm cell membranes, lipoproteins, and other lipid-containing structures, is a direct consequence of the overaccumulation of ROS (Figure 5f and Figure S7d), and the core feature of ferroptosis. 57,58 In cells exposed to p-NPs (especially ≥5.4 × 10 10 particles/mL), there was a noticeable increase in the number of lipid droplets (Figure 5g and Figure S7e).…”