4-Nitrophenol at environmentally relevant concentrations mediates reproductive toxicity in Caenorhabditis elegans via metabolic disorders-induced estrogen signaling pathway.

4-Nitrophenol (4-NP), as a toxic and refractory pollutant, has generated significant concern due to its adverse effects. However, the potential toxic effects and mechanism remained unclear. In this study, the reproduction, development, locomotion and reactive oxygen species (ROS) production of Caenorhabditis elegans were investigated to evaluate the 4-NP toxicity. We used metabolomics to assess the potential damage mechanisms. The role of metabolites in mediating the relationship between 4-NP and phenotypes was examined by correlation and mediation analysis. 4-NP (8 ng/L and 8 µg/L) caused significant reduction of brood size, ovulation rate, total germ cells numbers, head thrashes and body bends, and an increase in ROS. However, the oosperm numbers in uterus, body length and body width were decreased in 8 µg/L. Moreover, 36 differential metabolites were enriched in the significant metabolic pathways, including lysine biosynthesis, ß-alanine metabolism, tryptophan metabolism, pentose phosphate pathway, pentose and glucuronate interconversions, amino sugar and nucleotide sugar metabolism, starch and sucrose metabolism, galactose metabolism, propanoate metabolism, glycerolipid metabolism, and estrogen signaling pathway. The mechanism of 4-NP toxicity was that oxidative stress caused by the perturbation of amino acid, which had effects on energy metabolism through disturbing carbohydrate and lipid metabolism, and finally affected the estrogen signaling pathway to exert toxic effects. Moreover, correlation and mediation analysis showed glycerol-3P, glucosamine-6P, glucosamine-1P, UDP-galactose, L-aspartic acid, and uracil were potential markers for the reproduction and glucose-1,6P2 for developmental toxicity. The results provided insight into the pathways involved in the toxic effects caused by 4-NP and developed potential biomarkers to evaluate 4-NP toxicity.

Testosterone Mediates Reproductive Toxicity in Caenorhabditis elegans by Affecting Sex Determination in Germ Cells through nhr-69/mpk-1/fog-1/3.

Testosterone (T), an environmental androgen, significantly disrupts endocrine systems in wildlife and ecosystems. Despite growing concern over its high levels in aquatic environments, the reproductive toxicity of testosterone and its mechanisms are not well understood. In this study, we investigated the reproductive toxicity and mechanisms of testosterone using Caenorhabditis elegans (C. elegans) and assessed its ecological toxicity through the benchmark dose (BMD) method. Our results indicate that T concentrations exceeding 0.01 µg/L significantly reduce the brood size, decrease germ cell counts, and prolong the generation time in C. elegans as T concentrations increase. Furthermore, to elucidate the specific mechanisms, we analyzed the expression of nhr-69, mpk-1, and other genes involved in sex determination. These findings suggest that the nhr-69-mediated reproductive toxicity of T primarily affects sperm formation and the offspring number by influencing its downstream targets, mpk-1 and fog-1/3, which are critical in the germ cell sex-determining pathway. Additionally, this study determined that the 10% lower boundary of the baseline dose (BMDL10) is 1.160 ng/L, offering a more protective reference dose for the ecological risk assessment of T. The present study suggests that nhr-69 mediates the reproductive toxicity of T by influencing mpk-1 and fog-1/3, critical genes at the end of the germ cell sex-determining pathway, thereby providing a basis for establishing reproductive toxicity thresholds for T.

Associations of Urinary Heavy Metal Mixtures with High Remnant Cholesterol among US Adults: Evidence from the National Health and Nutrition Examination Survey (1998-2018).

The main objective of our study is to explore the associations between combined exposure to urinary heavy metals and high remnant cholesterol (HRC), a known cardiovascular risk factor. Utilizing data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018, we conducted a cross-sectional analysis of 5690 participants, assessing urinary concentrations of ten heavy metals. Ten heavy metals in urine were measured by inductively coupled plasma mass spectrometry (ICP-MS). Fasting residual cholesterol ≥0.8 mmol/L was defined as HRC (using blood samples). Statistical analyses included weighted multivariable logistic regression, weighted quantile sum (WQS) regression, quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR) to evaluate the associations of heavy metal exposure with HRC. Stratified analyses based on individual characteristics were also conducted. Multivariable logistic regression found that the four metals (OR Q4 vs. Q1: 1.33, 95% CI: 1.01-1.75 for barium (Ba); OR Q4 vs. Q1: 1.50, 95% CI: 1.16-1.94 for cadmium (Cd); OR Q4 vs. Q1: 1.52, 95% CI: 1.15-2.01 for mercury (Hg); OR Q4 vs. Q1: 1.35, 95% CI: 1.06-1.73 for lead (Pb)) were positively correlated with the elevated risk of HRC after adjusting for covariates. In addition, all three mixed models, including WQS (OR: 1.25; 95% CI: 1.07-1.46), qgcomp (OR: 1.17; 95% CI: 1.03-1.34), and BKMR, consistently showed a significant positive correlation between co-exposure to heavy metal mixtures and HRC, with Ba and Cd being the main contributors within the mixture. These associations were more pronounced in younger adults (20 to 59 years), males, and those with a higher body mass index status (≥25 kg/m2). Our findings reveal a significant relationship between exposure to the mixture of heavy metals and HRC among US adults, with Ba and Cd being the major contributors to the mixture's overall effect. Public health efforts aimed at reducing heavy metal exposure can help prevent HRC and, in turn, cardiovascular disease.

Associations of Combined Exposure to Metabolic and Inflammatory Indicators with Thyroid Nodules in Adults: A Nested Case-Control Study.

Objective: To explore associations of combined exposure to metabolic/inflammatory indicators with thyroid nodules. Methods: We reviewed personal data for health screenings from 2020 to 2021. A propensity score matching method was used to match 931 adults recently diagnosed with thyroid nodules in a 1 : 4 ratio based on age and gender. Conditional logistic regression and Bayesian kernel machine regression (BKMR) were used to explore the associations of single metabolic/inflammatory indicators and the mixture with thyroid nodules, respectively. Results: In the adjusted models, five indicators (ORQ4 vs. Q1: 1.30, 95% CI: 1.07-1.58 for fasting blood glucose; ORQ4 vs. Q1: 1.30, 95% CI: 1.08-1.57 for systolic blood pressure; ORQ4 vs. Q1: 1.26, 95% CI: 1.04-1.53 for diastolic blood pressure; ORQ4 vs. Q1: 1.23, 95% CI: 1.02-1.48 for white blood cell; ORQ4 vs. Q1: 1.28, 95% CI: 1.07-1.55 for neutrophil) were positively associated with the risk of thyroid nodules, while high-density lipoproteins (ORQ3 vs. Q1: 0.75, 95% CI: 0.61-0.91) were negatively associated with the risk of thyroid nodules. Univariate exposure-response functions from BKMR models showed similar results. Moreover, the metabolic and inflammatory mixture exhibited a significant positive association with thyroid nodules in a dose-response pattern, with systolic blood pressure being the greatest contributor within the mixture (conditional posterior inclusion probability of 0.82). No interaction effects were found among the five indicators. These associations were more prominent in males, participants with higher age (≥40 years old), and individuals with abnormal body mass index status. Conclusions: Levels of the metabolic and inflammatory mixture have a linear dose-response relationship with the risk of developing thyroid nodules, with systolic blood pressure levels being the most important contributor.

Gender-and age-specific associations of sleep duration and quality with cognitive impairment in community-dwelling older adults in Anhui Province, China.

Objective: To examine associations of sleep duration and quality with cognitive impairment in older adults and the moderating role of gender and age in these associations. Methods: This community-based cross-sectional study included 4,837 participants aged 60 years and above. Cognitive function was assessed using the Chinese version of the Mini-Mental State Examination (MMSE), and the participants were grouped based on the presence of cognitive impairment. The duration and quality of sleep were assessed using the Pittsburgh Sleep Quality Index (PSQI). Multivariate logistic regression models were used to analyze associations of sleep duration and quality with cognitive impairment. The role of age and gender in these associations have also been explored. Results: The age (mean ± SD) of the participants was 71.13 ± 5.50 years. Of all older adults, 1,811 (37.44%) were detected as cognitive impairment, and 1755 (36.8%) had poor sleep quality. Among those with cognitive impairment, 51.09% were female. The proportion of the participants with cognitive impairment is significantly higher in those with symptoms of depression (49.73%, 273/549) (χ2 = 41.275, p < 0.001) than in those without depressive symptoms. After adjustment for multiple confounding factors and the crucial covariate (depressive symptoms), the odds ratios (OR) (95% confidence interval [CI]) of cognitive impairment (with 7-7.9 h regarded as the reference group) for individuals with a sleep duration of <6, 6-6.9, 8-8.9, and ≥ 9 h were 1.280 (1.053-1.557), 1.425 (1.175-1.728), 1.294 (1.068-1.566), and 1.360 (1.109-1.668), respectively. Subgroup analysis showed a V-shaped association between night sleep duration and cognitive impairment in males (p ≤ 0.05), and the association was stronger for individuals aged 60-80 years. With regard to sleep quality, the fully adjusted OR (95%CI) of cognitive impairment were 1.263 (1.108-1.440). According to scores of subscales in the PSQI, daytime dysfunction was associated with an increased risk of cognitive impairment (OR: 1.128, 95%CI: 1.055-1.207). Subgroup analysis also revealed a statistically significant correlation between poor sleep quality (including daytime dysfunction) and cognitive impairment in different gender and age groups, with the association being stronger in females (OR: 1.287, 95%CI: 1.080-1.534) and those aged 81-97 years (OR: 2.128, 95%CI: 1.152-3.934). For cognitive impairment, the group aged 81-97 years with daytime dysfunction was associated with a higher odds ratio than other age groups. Conclusion: The present study showed that inadequate or excessive sleep was associated with cognitive impairment, especially in males, who exhibited a V-shaped association. Cognitive impairment was also associated with poor sleep quality as well as daytime dysfunction, with females and individuals aged 81-97 years exhibiting the strongest association.