Female rats present higher oxidative damage and inflammation during goitrogenesis.

Thyroid disorders affect more women than men, but the underlying mechanisms contributing to this disparity remain incompletely understood. Thyrotropin (TSH), the primary regulator of thyroid oxidative hormonogenesis, has been implicated as a risk factor for proliferative thyroid diseases and a predictor of malignancy. In this study, we aimed to evaluate the impact of sustained elevated TSH levels on thyroid redox homeostasis, inflammatory markers, and DNA damage response in both male and female rats. Rats were treated with methimazole for 7 or 21 days, and hormonal measurements were conducted. H2O2 levels were evaluated in thyroid membrane fractions, while enzymatic activities were assessed in total thyroid homogenates. Sex-specific differences emerged, with females displaying higher reactive oxygen species levels - increased transiently NOX and sustained DUOX activities. Lipid peroxidation marker 4-hydroxynonenal (4-HNE) was elevated in females at both time points, contrasting with males just at 21 days. Sexual dimorphism was observed in DNA damage response, with females showing higher γH2AX levels at 21 days. Elevated IL-1ß, TNF-α, CD11b mRNA, and phospho-NF-κB levels at 7 days indicated a distinct inflammatory profile in females. Notably, both sexes exhibited upregulated antioxidant enzymes. Our data suggest that females are more susceptible to oxidative damage and inflammation in our goiter model, which may be associated with higher ROS production and a less-efficient antioxidant defense system. These findings provide insights into the sex-specific mechanisms underlying thyroid dysfunction and highlight the importance of considering sex disparities in thyroid disorder research.

Hypothyroidism induces oxidative stress and DNA damage in breast.

Breast cancer and thyroid dysfunctions have been associated for decades. Although many studies suggest a biological correlation, the mechanisms linking these two pathologies have not been elucidated. Reactive oxygen species (ROS) can oxidize lipids, proteins, and DNA molecules and may promote tumor initiation. Hence, we aimed at evaluating the mammary redox balance and genomic instability in a model of experimental hypothyroidism. Female Wistar rats were treated with 0.03% methimazole for 7 or 21 days to evaluate ROS generation, antioxidant enzyme activities, and oxidative stress biomarkers, as well as genomic instability. After 7 days, lower catalase, GPX, and DUOX activities were detected in the breast of hypothyroid group compared to the control while the levels of 4-hydroxynonenal (HNE) were higher. In addition, hypothyroid group showed an increase in γH2Ax/H2Ax ratio. Twenty-one days hypothyroid group had increased catalase and SOD activities, without significant differences between groups in the levels of oxidative stress biomarkers and DNA damage. TSH-treated MCF10A cells showed a higher extracellular, intracellular, and mitochondrial ROS production. Additionally, greater DNA damage was observed in these cells, demonstrated by a higher comet tail DNA percentage and increased 53BP1 foci. Finally, we found that TSH treatment was not able to alter cell viability. The Genome Cancer Atlas (TGCA) data showed that high TSHR expression is associated with more invasive breast cancer types. In conclusion, we demonstrate that oxidative stress and DNA damage in breast are early events of experimental hypothyroidism. Moreover, high TSH levels induce oxidative stress and genomic instability in mammary cells.

The Effects of Combined Physical Exercise on Serum Redox Biomarkers and Leukocyte DNA Damage of Obese Women.

Obesity is usually linked to oxidative stress, which can lead to damage to biomolecules. The combination of aerobic and strength exercises seems to induce health benefits in obese individuals, but little is known about the effects of combined physical exercise on redox homeostasis and DNA damage in this population. Thus, the aim of the current study was to determine the effects of 16 weeks of combined physical exercise on biomarkers of oxidative stress and DNA damage in obese women. 17 obese women underwent 16 weeks of a combined physical training program, 3 times per week. Anthropometric and biochemical parameters, serum superoxide dismutase (SOD) and glutathione peroxidase activity, plasma 8-isoprostane levels, and DNA and chromosomal damage were evaluated before and after physical training. Combined physical exercise training decreased body weight (83.2 ± 9.6 vs. 80.2 ± 9.6 kg), body mass index (33.8 ± 3.6 vs. 32.6 ± 3.7 kg·m-2), body fat (40.2 ± 2.6 vs. 39.0 ± 3.2%), and waist circumference (99.3 ± 9.4 vs. 94.1 ± 8.8 cm), while the fat-free mass was augmented (59.9 ± 2.9 vs. 60.7 ± 3.1 kg). Moreover, blood glucose reduced (113.5 ± 29.6 vs. 107.3 ± 28.9 mg/dL) along with high-density lipoprotein (54.6 ± 18.1 vs. 59.0 ± 18.8 mg/dL), TSH (2.1 ± 1.1 vs. 2.6 ± 1.2 mIU/mL), and free T4 (0.9 ± 0.1 vs. 1.12 ± 0.2 ng/dL) increase after physical exercise training. Plasma 8-isoprostane levels (17.24 ± 7.9 vs. 29.11 ± 17.44 pg/mL) and DNA damage (34.16 ± 7.1 vs. 45.96 ± 5.8% DNA in tail) were also higher after physical training. No changes were observed in chromosomal damage levels. These results suggest that 16 weeks of combined exercise training 3 times per week is effective in reducing body fat but also increases oxidative stress and DNA damage in obese women.

Acute cylindrospermopsin exposure: Pulmonary and liver harm and mitigation by dexamethasone.

Cylindrospermopsin (CYN) is a cyanotoxin of increasing worldwide environmental importance as it can harm human beings. Dexamethasone is a steroidal anti-inflammatory agent. Thus, we aimed at evaluating the pulmonary outcomes of acute CYN intoxication and their putative mitigation by dexamethasone. Male BALB/c mice received intratracheally a single dose of saline or CYN (140 µg/kg). Eighteen hours after exposure, mice instilled with either saline solution (Ctrl) or CYN were intramuscularly treated with saline (Tox) or 2 mg/kg dexamethasone (Tox + dexa) every 6 h for 48 h. Pulmonary mechanics was evaluated 66 h after instillation using the forced oscillation technique (flexiVent) to determine airway resistance (RN), tissue viscance (G) and elastance (H). After euthanasia, the lungs were removed and separated for quantification of CYN, myeloperoxidase activity and IL-6 and IL-17 levels plus histological analysis. CYN was also measured in the liver. CYN increased G and H, alveolar collapse, PMN cells infiltration, elastic and collagen fibers, activated macrophages, peroxidase activity in lung and hepatic tissues, as well as IL-6 and IL-17 levels in the lung. Tox + Dexa mice presented total or partial reversion of the aforementioned alterations. Briefly, CYN impaired pulmonary and hepatic characteristics that were mitigated by dexamethasone.

Oxidative stress, mutagenic effects, and cell death induced by retene.

Retene (RET) is the most abundant polycyclic aromatic hydrocarbon (PAH) released upon burning of cellulose, although it is not considered as one of the priority PAHs and is not included for risk assessments by the US Environmental Protection Agency (US-EPA). There are only a few studies concerning the toxic effects of RET. To the best of our knowledge, this study is the first one to examine whether RET, in an environmental concentration, plays a crucial role in the induction of oxidative stress in A549 lung cell line, and its consequence as such as mutagenicity and cell death. Our results revealed that RET was able to significantly decrease cell viability only at 72 h of exposure, increase oxidative stress, mitochondrial membrane potential and mitochondrial contents, leading an increased reactive oxygen species (ROS) production. Mutagenic activity was not detected in Salmonella strains, suggesting that RET does not induce base-pair substitution (TA100), frameshift (TA98 and TA97a) and transition/transversion (TA102) mutations. However, exposure to RET led to a significant increase in micronuclei (MN), nucleoplasmic bridges (NPBs), and nuclear buds (NBUDs) frequency, as well as cell death, mainly due to necrosis. Taken together, the results of our study provide new evidence suggesting that RET promotes oxidative stress, contributes to the processes of genomic instability, and favors necrosis. Thus, we highlight the importance of including RET in routine environmental analyses in the future as a potential risk factor involved in complex diseases and carcinogenesis.

Sex differences in subcutaneous adipose tissue redox homeostasis and inflammation markers in control and high-fat diet fed rats.

The development of obesity-related metabolic disorders is more evident in male in comparison with female subjects, but the mechanisms are unknown. Several studies have shown that oxidative stress is involved in the pathophysiology of obesity, but the majority of these studies were performed with male animals. The aim of this study was to evaluate the sex-related differences in subcutaneous adipose tissue redox homeostasis and inflammation of rats chronically fed a high-fat diet. NADPH oxidase (NOX), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase activities were evaluated in the subcutaneous adipose tissue (SC) of adult male and female rats fed either a standard chow (SCD) or a high-fat diet (HFD) for 11 weeks. NOX2 and NOX4 messenger RNA (mRNA) levels, total reduced thiols, interleukin (IL)-1ß, tumor necrosis factor α (TNF-α), and IL-6 were also determined. Higher antioxidant enzyme activities and total reduced thiol levels were detected in SC of control male compared with female rats. Chronic HFD administration increased NOX activity and NOX2 and NOX4 mRNA levels and decreased SOD and GPx activities only in male animals. IL-1ß, TNF-α, and IL-6 levels, as well as Adgre1, CD11b, and CD68 mRNA levels, were also higher in SC of males after HFD feeding. In SC of females, catalase activity was higher after HFD feeding. Taken together, our results show that redox homeostasis and inflammation of SC is sexually dimorphic. Furthermore, males show higher oxidative stress in SC after 11 weeks of HFD feeding owing to both increased reactive oxygen species (ROS) production through NOX2 and NOX4 and decreased ROS detoxification.

Biomass burning in the Amazon region causes DNA damage and cell death in human lung cells.

Most of the studies on air pollution focus on emissions from fossil fuel burning in urban centers. However, approximately half of the world's population is exposed to air pollution caused by biomass burning emissions. In the Brazilian Amazon population, over 10 million people are directly exposed to high levels of pollutants resulting from deforestation and agricultural fires. This work is the first study to present an integrated view of the effects of inhalable particles present in emissions of biomass burning. Exposing human lung cells to particulate matter smaller than 10 µm (PM10), significantly increased the level of reactive oxygen species (ROS), inflammatory cytokines, autophagy, and DNA damage. Continued PM10 exposure activated apoptosis and necrosis. Interestingly, retene, a polycyclic aromatic hydrocarbon present in PM10, is a potential compound for the effects of PM10, causing DNA damage and cell death. The PM10 concentrations observed during Amazon biomass burning were sufficient to induce severe adverse effects in human lung cells. Our study provides new data that will help elucidate the mechanism of PM10-mediated lung cancer development. In addition, the results of this study support the establishment of new guidelines for human health protection in regions strongly impacted by biomass burning.

Cell death pathways of particulate matter toxicity.

Humans are exposed to various complex mixtures of particulate matter (PM) from different sources. Long-term exposure to high levels of these particulates has been linked to a diverse range of respiratory and cardiovascular diseases that have resulted in hospital admission. The evaluation of the effects of PM exposure on the mechanisms related to cell death has been a challenge for many researchers. Therefore, in this review, we have discussed the effects of airborne PM exposure on mechanisms related to cell death. For this purpose, we have compiled literature data on PM sources, the effects of exposure, and the assays and models used for evaluation, in order to establish comparisons between various studies. The analysis of this collected data suggested divergent responses to PM exposure that resulted in different cell death types (apoptosis, autophagy, and necrosis). In addition, PM induced oxidative stress within cells, which appeared to be an important factor in the determination of cell fate. When the levels of reactive oxygen species were overpowering, the cellular fate was directed toward cell death. This may be the underlying mechanism of the development or exacerbation of respiratory diseases, such as emphysema and chronic obstructive pulmonary diseases. In addition, PM was shown to cause DNA damage and the resulting mutations increased the risk of cancer. Furthermore, several conditions should be considered in the assessment of cell death in PM-exposed models, including the cell culture line, PM composition, and the interaction of the different cells types in in vivo models.