Cadmium (Cd) is a heavy metal toxicant as a common pollutant derived from many agricultural and industrial sources. The absorption of Cd takes place primarily through Cd-contaminated food and water and, to a significant extent, via inhalation of Cd-contaminated air and cigarette smoking. Epidemiological data suggest that occupational or environmental exposure to Cd increases the health risk for osteoporosis and spontaneous fracture such as itai-itai disease. However, the direct effects and underlying mechanism(s) of Cd exposure on bone damage are largely unknown. We used primary bone marrow-derived mesenchymal stromal cells (BMMSCs) and found that Cd significantly induced BMMSC cellular senescence through over-activation of NF-κB signaling pathway. Increased cell senescence was determined by production of senescence-associated secretory phenotype (SASP), cell cycle arrest and upregulation of p21/p53/p16ᴵᴺᴷ⁴ᵃ protein expression. Additionally, Cd impaired osteogenic differentiation and increased adipogenesis of BMMSCs, and significantly induced cellular senescence-associated defects such as mitochondrial dysfunction and DNA damage. Sprague-Dawley (SD) rats were chronically exposed to Cd to verify that Cd significantly increased adipocyte number, and decreased mineralization tissues of bone marrow in vivo. Interestingly, we observed that Cd exposure remarkably retarded bone repair and regeneration after operation of skull defect. Notably, pretreatment of melatonin is able to partially prevent Cd-induced some senescence-associated defects of BMMSCs including mitochondrial dysfunction and DNA damage. Although Cd activated mammalian target of rapamycin (mTOR) pathway, rapamycin only partially ameliorated Cd-induced cell apoptosis rather than cellular senescence phenotypes of BMMSCs. In addition, a selective NF-κB inhibitor moderately alleviated Cd-caused the senescence-related defects of the BMMSCs. The study shed light on the action and mechanism of Cd on osteoporosis and bone ageing, and may provide a novel option to ameliorate the harmful effects of Cd exposure.

Polychlorinated biphenyls (PCBs) are notorious environmental pollutants. For their hydrophobic and lipophilic capability, they are wildly spread to environment to threat human health thus attracts more attention. In this study, we observed increasing numbers of CD163 positive (CD163⁺) macrophages in aortic valve of ApoE⁻/⁻ mice after 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ) treatment, the metabolite of polychlorinated biphenyl. In addition, in vitro studies identified that PCB29-pQ exposure significantly provoked the shifting of RAW264.7 macrophages and bone marrow derived monocytes (BMDMs) to CD163⁺ macrophages. Upon PCB29-pQ administration, CD163 and CD206 levels were enhanced in RAW264.7 cells as well as in BMDMs. However, the concentration of iron and total cholesterol (TC) were reduced due to the boosting of ferroportin (Fpn) and ATP binding cassette transporter, subfamily A, member 1 (ABCA1) which are efflux transporters of iron and cholesterol individually. Further investigation on mechanism indicated that PCB29-pQ exposure induced reactive oxygen species (ROS), which may result in activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a protein responsible for macrophage polarization. After that, we blocked Nrf2 through Nrf2 shRNA and ROS scavenger NAC, which significantly reversed the shifting of macrophage to CD163⁺ sub-population. These results confirmed the importance of Nrf2 in inducing macrophage polarization. In short, our study uncovered that PCB29-pQ could promote macrophage/monocyte polarization to CD163⁺ macrophage which would be a potential incentive to accelerate atherosclerosis through Nrf2 signaling pathway.

As alternatives to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide dimer acid (HFPO-DA) and hexafluoropropylene oxide trimer acid (HFPO-TA) have raised concerns of their potential health risks. Human bone marrow mesenchymal stem cell was employed as an in vitro model to investigate the molecular targets and the adverse effects of HFPOs in stem cells in concentrations range starting at human relevant levels. Unsupervised transcriptomic analysis identified 1794 and 1429 DEGs affected by HFPO-TA and HFPO-DA, respectively. Cell cycle-associated biological processes were commonly altered by both chemicals. 18 and 35 KEGG pathways were enriched in HFPO-TA and HFPO-DA treatment group, respectively, among which multiple pathways were related to cancer and pluripotency. Few genes in PPAR signalling pathway were disturbed by HFPOs suggesting the involvement of PPAR-independent toxic mechanism. HFPO-TA promoted cell proliferation with significance at 1 μM mRNA levels of CDK and MYC were down-regulated by HFPOs, suggesting the negative feedback regulation to the abnormal cell proliferation. Decreased expression of CD44 protein, and ENG and THY1 mRNA levels demonstrated HFPOs-caused changes of hBMSCs phenotype. The osteogenic differentiation was also inhibited by HFPOs with reduced formation of calcium deposition. Furthermore, gene and protein expression of core pluripotency regulators NANOG was enhanced by HFPO-TA. The present study provides human relevant mechanistic evidence for health risk assessment of HFPOs, prioritizing comprehensive carcinogenicity assessment of this type of PFOA alternatives.

Humans benefit from nuclear technologies but consequently experience nuclear disasters or side effects of iatrogenic radiation. Hematopoietic system injury first arises upon radiation exposure. As an intricate new layer of genetic control, the posttranscriptional m⁶A modification of RNA has recently come under investigation and has been demonstrated to play pivotal roles in multiple physiological and pathological processes. However, how the m⁶A methylome functions in the hematopoietic system after irradiation remains ambiguous. Here, we uncovered the time-varying epitranscriptome-wide m⁶A methylome and transcriptome alterations in γ-ray-exposed mouse bone marrow. 4 Gy γ-irradiation rapidly (5 min and 2 h) and severely impaired the mouse hematopoietic system, including spleen and thymus weight, blood components, tissue inflammation and malondialdehyde (MDA) levels. The m⁶A content and expression of m⁶A related enzymes were altered. Gamma-irradiation triggered dynamic and reversible m⁶A modification profiles and altered mRNA expression, where both m⁶A fold-enrichment and mRNA expression most followed the (5 min_up/2 h_down) pattern. The CDS enrichment region preferentially upregulated m⁶A peaks at 5 min. Moreover, the main GO and KEGG pathways were closely related to metabolism and the classical radiation response. Finally, m⁶A modifications correlated with transcriptional regulation of genes in multiple aspects. Blocking the expression of m⁶A demethylases FTO and ALKBH5 mitigated radiation hematopoietic toxicity. Together, our findings present the comprehensive landscape of mRNA m⁶A methylation in the mouse hematopoietic system in response to γ-irradiation, shedding light on the significance of m⁶A modifications in mammalian radiobiology. Regulation of the epitranscriptome may be exploited as a strategy against radiation damage.

Exposure to fine atmospheric Particulate Matter (PM) is one of the major environmental causes involved in the development of inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD) or asthma. When PM is penetrating in the pulmonary system, alveolar macrophages represent the first line of defense, in particular by triggering a pro-inflammatory response, and also by their ability to recruit infiltrating macrophages from the bone marrow. The aim of this in vitro study was to evaluate the gene expression and cytokine production involved in the toxicological and inflammatory responses of infiltrating macrophages, as well as the Extracellular Vesicles (EVs) production, after their exposure to PM. The ability of these EVs to convey information related to PM exposure from exposed macrophages to pulmonary epithelial cells was also evaluated.Infiltrating macrophages respond to fine particles exposure in a conventional manner, as their exposure to PM induced the expression of Xenobiotic Metabolizing Enzymes (XMEs) such as CYP1A1 and CYP1B1, the enzymes involved in oxidative stress SOD2, NQO1 and HMOX as well as pro-inflammatory cytokines in a dose-dependent manner. Exposure to PM also induced a greater release of EVs in a dose-dependent manner. In addition, the produced EVs were able to induce a pro-inflammatory phenotype on pulmonary epithelial cells, with the induction of the release of IL6 and TNFα proinflammatory cytokines. These results suggest that infiltrating macrophages participate in the pro-inflammatory response induced by PM exposure and that EVs could be involved in this mechanism.

Glyphosate-based herbicides (GBH) are the most widely used herbicide for treatment of crops in the world. The digestive tract is one of the first systems exposed to pesticides, and damage to this system can affect the general health of individuals. The aim of this study was to evaluate the effects of subchronic inhalation and oral exposure to GBH on the digestive tract in rats. Six groups of Wistar rats (male and female) were exposed to nebulization with three concentrations of GBH [3.71 × 10⁻³ grams of active ingredient per hectare (g.a.i./ha), 6.19 × 10⁻³ g.a.i./ha and 9.28 × 10⁻³ g.a.i./ha] administered orally or by inhalation for 75 days. Bone marrow cells, smears of the tongue and fragments of the tongue, oesophagus, stomach and intestine were collected for histopathological analysis. Congestion, inflammation, an increase in the number of mast cells and nucleoli-organizing regions were detected in the tongue in the groups exposed to GBH. Females had a higher number of mast cells in the tongue than males. Animals in the groups exposed to higher concentrations of GBH showed dysplasia in the oesophagus and small and large intestine regardless of sex. Gastric changes were not observed. Animals exposed to GBH showed increased micronucleus formation. Our data indicate that GBH causes oral allergies and dysplastic lesions in the oesophagus and small and large intestine and has genotoxic potential.

Recently, bio-nanofabrication becomes one of the widest methods for synthesizing nanoparticles (NPs); however, there is scanty literature exploring the toxicity of these green NPs against living organisms. This study aimed to evaluate the potential protective role of encapsulated cinnamon oil (ECO) against titanium oxide nanoparticle (TiO₂NP)–induced oxidative stress, DNA damage, chromosomal aberration, and reproductive disturbances in male mice. Sixty male Balb/c mice were distributed into six groups treated orally for 3 weeks and included control group, TiO₂NP-treated group (25 mg/kg b.w), ECO at low or high dose–treated groups (50 or 100 mg/kg b.w), and the groups that received TiO₂NPs plus ECO at a low or high dose. The results of GC-MS revealed the isolation of 21 compounds and the majority was cinnamaldehyde. The average size zeta potential of TiO₂NPs and ECO were 28.9 and 321 nm and −33.97 and −17.35 mV, respectively. TiO₂NP administration induced significant changes in liver and kidney function, decreased antioxidant capacity, and increased oxidative stress markers in liver and kidney, DNA damage in the hepatocytes, the number of chromosomal aberrations in the bone marrow and germ cells, and sperm abnormalities along with histological changes in the liver, kidney, and testis. Co-administration of TiO₂NPs and ECO could alleviate these disturbances in a dose-dependent manner. It could be concluded that ECO is a promising and safe candidate for the protection against the health hazards of TiO₂NPs.

The adverse health effects of benzene occupational and circumstance pollution exposure are an increasing concern. It leads to damage to various human tissues including bone marrow and ovarian tissues and many vital physiological processes. Previous studies showed that kefir is a rich probiotic, having protective effect, thanks to its antioxidant, anti-inflammatory, and immunomodulatory capacity. The purpose of this study was to evaluate the potential efficacy of kefir to remediate benzene toxicity in rat. Thirty-two female rats were randomly allocated and administered orally with benzene and/or kefir during a period of 21 consecutive days. At the end of the experiment, hematological and bone marrow cell changes were estimated. The animals exposed to benzene exhibited anemia and a significant decrease in the levels of white blood cell. Moreover, benzene led to the activation of gene expression of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6), a myelotoxicity in bone marrow cells. Our data showed that kefir treatment alleviated benzene-associated weight loss and increased the number of whole blood cells in peripheral blood and nucleated cells in the bone marrow. Furthermore, these physiological results were observed with animals showing high concentrations of lactic acid bacteria (LAB) determined from fecal samples, which are considered an indicator of kefir-associated microorganisms. Our study suggests that kefir is a potential nutritional supplement target to attenuate hematotoxicity induced by benzene.

Exposure to lead (Pb) is a major risk factor in reproductive toxicity, somatic, and germ cell genotoxicity. Exposure via deteriorating Pb paints and contaminated air, soil, and water had been the primary routes. However, with increasing reports of Pb accumulation in mushrooms and other food items may increase the etiology of Pb poisoning. The study herein investigated somatic genotoxicity and reproductive abnormalities in mice fed extracts of Pb-contaminated Pleurotus ostreatus. Male mice were fed aqueous extracts of P. ostreatus cultivated in 0, 10, 20, 100, 200, 500, and 1000 mg/L of Pb-contaminated rice straw for 35 days. Testes were analyzed for Pb accumulation, histopathology and relative weight gain, caudal epididymis for abnormal sperm morphology, and bone marrow for micronucleus test. Concentration-related significant increase in Pb accumulation was observed in P. ostreatus and testes of exposed mice. Decrease testicular weight, congestion of blood vessels, necrosis, and disorganization of the seminiferous tubules were observed in treated mice. In addition, fold increase of 2.78, 3.39, 6.67, 7.21, 9.63, and 9.70 in abnormal sperm morphology in accordance with the Pb concentrations respectively, confirmed reproductive toxicity. Significant increase in micronucleated polychromatic (PCE) and normochromatic (NCE) erythrocytes and concentration-related decrease PCE-NCE ratio in the bone marrow of treated mice suggest genome instability. Pb-contaminated P. ostreatus increased somatic and germ cell genotoxicity in mice. This may predispose the mice to genetic related syndromes and reproductive syndromes. It further suggests caution in the consumption of metal laden wild mushrooms and crop plants.

Exposure to ionizing radiation emitted from natural sources induces many health hazards. The response to ionizing radiation involves a number of mediators including inflammatory cytokines and free radicals which mediate immunosuppression. The present study aimed to monitor the impact of exposure to natural radioactive rocks from the Egyptian eastern desert on the primary immune organs. Therefore, three experimental groups (15 rats per group) were used: group I included the control non-irradiated rats; group II included rats that were exposed for 28 consecutive days to natural radioactive rocks from the Egyptian eastern desert (IR/R group); and group III (positive control group) included rats that were exposed to high dose of γ-rays (4 Gy/14 days for 28 days) (IR/γR group). We found that rats of both the IR/R and IR/γR groups exhibited pathological alterations in the architecture of the primary immune organs (bone marrow and thymus). Additionally, the levels of C-reactive protein (CRP), proinflammatory cytokines (IL-1β, IL-6 and TNF-α), and reactive oxygen species (ROS) were significantly increased in the IR/R and IR/γR groups compared to the control group. Furthermore, rats from the IR/R and IR/γR groups exhibited significant increase in the activity of caspase-3 and caspase-9 and subsequently exhibited a significant increase in the apoptosis of PBMCs compared with the control group. Most importantly, apoptosis induction in the PBMCs was associated with increased expression of cyclin B1 and decreased expression of cyclin D1 and survivin compared with the control non-irradiated group. Taken together, our data demonstrated that consecutive exposure to natural radioactive rocks from the Egyptian eastern desert could dampen the immune response through damaging the architectures of the immune system and mediating serious health problems to the population inhabiting this region.