A time differentiated dietary intervention effect on the biomarkers of exposure to pyrethroids and neonicotinoids pesticides.

Tailoring medical models to the right person or risk subgroups delivered at the right time is important in personalized medicine/prevention initiatives. The CIRCA-CHEM randomized 2x2 crossover pilot trial investigated whether the consumption of fruits/vegetables within a time-restricted daily window would affect urinary biomarkers of exposure to neonicotinoids (6-chloronicotinic acid, 6-CN) and pyrethroids (3-phenoxybenzoic acid, 3-PBA) pesticides, a biomarker of oxidative damage (4-hydroxynonenal, 4-HNE) and the associated urinary NMR metabolome. A statistically significant difference (p < 0.001) in both creatinine-adjusted 6-CN and 3-PBA levels was observed between the two-time dietary intervention windows (morning vs. evening). In the evening intervention period, pesticides biomarker levels were higher compared to the baseline, whereas in the morning period, pesticide levels remained unchanged. Positive associations were observed between pesticides and 4-HNE suggesting a diurnal chrono-window of pesticide toxicity. The discovery of a chronotoxicity window associated with chrono-disrupted metabolism of food contaminants may find use in personalized medicine initiatives.

The effect of an organic food intervention treatment on biomarkers of exposure to lead and cadmium in primary school children of Cyprus: A cluster-randomized crossover trial.

BACKGROUND: Food contaminants, such as, pesticides and metals are ubiquitous in the food chain. Studies routinely report on the metals content of organic and conventional food crops. However, comparative human studies on the body burden of metals associated with organic food consumption are currently lacking. OBJECTIVES: The objectives were to i) determine the effectiveness of an organic food intervention in reducing the body burden of urinary concentration of lead (Pb) and cadmium (Cd) and ii) evaluate the association between metal exposures and biomarkers of oxidative damage in primary school children in Cyprus. METHODS: This study was part of the ORGANIKO cluster-randomized crossover trial, a 40-day organic food treatment to 149 healthy children (10-12 years) in Cyprus. Urinary biomarkers of Pb and Cd were determined using inductively coupled plasma mass spectrometry. Linear mixed-effect regression models were used to account for the effect and duration of the organic food treatment. Multiple comparisons were handled using Benjamini-Hochberg correction. RESULTS: A time-dependent reduction for creatinine-adjusted Pb during the intervention period was observed (ß = -0.021; 95% CI: -0.034, -0.008; p-adjusted = 0.01). A similar trend was observed for creatinine-adjusted Cd, but it was not significant (ß = -0.013; 95% CI: -0.026, 0.000; p-adjusted = 0.15). The creatinine-adjusted oxidative damage biomarkers were significantly associated with both metal biomarkers; Pb (8-OHdG: ß = 0.388, 95% CI: 0.303, 0.472; p-adjusted<0.001; MDA: ß = 0.187, 95% CI: 0.109, 0.265; p-adjusted<0.001; 8-iso-PGF2a: ß = 0.320, 95% CI: 0.244, 0.397; p-adjusted<0.001), and Cd (8-OHdG: ß = 0.148, 95% CI: 0.063, 0.233; p-adjusted = 0.003; MDA: ß = 0.107, 95% CI: 0.030, 0.184; p-adjusted = 0.018; 8-iso-PGF2a: ß = 0.263, 95% CI: 0.186, 0.339; p-adjusted<0.001). DISCUSSION: A 40-day organic food treatment reduced primary school children's exposures to Pb over time. More human studies in settings with high food contaminant profiles across common crops are warranted.

Diurnal Nonlinear Recurrence Metrics of Skin Temperature and Their Association with Metabolic Hormones in Contrasting Climate Settings: A Randomized Cross-Over Trial.

The urban overheating phenomenon in Mediterranean cities is a societal challenge with vast implications for the protection of public health. An additional analysis of the pilot TEMP randomized 2 × 2 cross-over trial was set up, using wearable sensor-based skin temperature measurements (n = 14). The study objectives were to: (i) assess the recurrence patterns of skin temperature measurements in individuals spending time in two climatologically contrasting settings (urban versus mountainous), and (ii) evaluate the association between the diurnal nonlinear recurrence quantification analysis (RQA) metrics and metabolic hormone levels. The intervention was a short-term stay (5-7 days) in a mountainous, climate-cooler setting (range 600-900 m altitude), which is about a 1 h drive from the main urban centres of Cyprus. The RQA analysis showed a blunting phenomenon on the nonlinear temporal dynamics of skin temperature time series observed in the urban setting. Compared with the mountainous setting, a more stable (and thus less adaptive) profile of skin temperature dynamics in the urban setting appeared, being less deterministic and with a smaller degree of complexity. No significant (p > 0.05) associations were observed between the leptin or cortisol and any of the skin temperature dynamical descriptors. However, there were marginal associations between the adiponectin and laminarity (beta = 0.24, 95%CI: -0.02, 0.50, p = 0.07) and with determinism (beta = 0.23, 95%CI: -0.037, 0.50, p = 0.09). We found dysregulations in skin temperature temporal dynamics of the study population while residing in the urban setting when compared with the cooler mountainous setting; these dysregulations took the form of reduced cycle duration and complexity, while skin temperature dynamics became less responsive to perturbations and less regular in magnitude. More research is needed to better understand heat stress temporal dynamics and their influence on human health. Trial registration: This trial is registered with ClinicalTrials.gov; number: NCT03625817.

Use of metabolomics in refining the effect of an organic food intervention on biomarkers of exposure to pesticides and biomarkers of oxidative damage in primary school children in Cyprus: A cluster-randomized cross-over trial.

BACKGROUND: Exposure to pesticides has been associated with oxidative stress in animals and humans. Previously, we showed that an organic food intervention reduced pesticide exposure and oxidative damage (OD) biomarkers over time; however associated metabolic changes are not fully understood yet. OBJECTIVES: We assessed perturbations of the urine metabolome in response to an organic food intervention for children and its association with pesticides biomarkers [3-phenoxybenzoic acid (3-PBA) and 6-chloronicotinic acid (6-CN)]. We also evaluated the molecular signatures of metabolites associated with biomarkers of OD (8-iso-PGF2a and 8-OHdG) and related biological pathways. METHODS: We used data from the ORGANIKO LIFE + trial (NCT02998203), a cluster-randomized cross-over trial conducted among primary school children in Cyprus. Participants (n = 149) were asked to follow an organic food intervention for 40 days and their usual food habits for another 40 days, providing up to six first morning urine samples (>850 samples in total). Untargeted GC-MS metabolomics analysis was performed. Metabolites with RSD ≤ 20% and D-ratio ≤ 50% were retained for analysis. Associations were examined using mixed-effect regression models and corrected for false-discovery rate of 0.05. Pathway analysis followed. RESULTS: Following strict quality checks, 156 features remained out of a total of 610. D-glucose was associated with the organic food intervention (ß = -0.23, 95% CI: -0.37,-0.10), aminomalonic acid showed a time-dependent increase during the intervention period (ßint = 0.012; 95% CI:0.002, 0.022) and was associated with the two OD biomarkers (ß = -0.27, 95% CI:-0.34,-0.20 for 8-iso-PGF2a and ß = 0.19, 95% CI:0.11,0.28 for 8-OHdG) and uric acid with 8-OHdG (ß = 0.19, 95% CI:0.11,0.26). Metabolites were involved in pathways such as the starch and sucrose metabolism and pentose and glucuronate interconversions. DISCUSSION: This is the first metabolomics study providing evidence of differential expression of metabolites by an organic food intervention, corroborating the reduction in biomarkers of OD. Further mechanistic evidence is warranted to better understand the biological plausibility of an organic food treatment on children's health outcomes.

Author Correction: Analysis of sequential hair segments reflects changes in the metabolome across the trimesters of pregnancy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cohort-friendly protocol for the determination of two urinary biomarkers of exposure to pyrethroids and neonicotinoids using gas chromatography-triple quadrupole mass spectrometry.

Neonicotinoids (NEOs) and synthetic pyrethroids (PYRs) are active ingredients of commercial pesticides and/or insecticides with extensive indoor and outdoor applications, worldwide. Improved exposure metrics are warranted for NEOs and PYRs, if we are to better understand their human health effects. A cohort-friendly protocol for determining non-specific biomarkers of exposure to NEOs and PYRs, e.g. 6-chloronicotinic acid (6-CN) and 3-phenoxybenzoic acid (3-PBA), respectively, in human urine voids was proposed. A series of optimization experiments were conducted to validate the bioanalytical protocol using gas chromatography coupled with triple quadrupole mass spectrometry (GC-QqQ-MS/MS) in MRM mode. The method reached low detection limits for both analytes (0.075 µg L-1 for 6-CN and 0.050 µg L-1 for 3-PBA) in a short preparation and analysis time. The method used small initial urine sample volume (2 mL), short extraction time (≈ 240 min for the batches of 32 samples) and instrumental analysis time (≈ 14 min) for both pesticide metabolites in a single run. This protocol could facilitate the assessment of population exposure metrics for these pesticides and their inclusion in health risk assessment. Graphical abstract.

Association between maternal exposure to phthalates and lower language ability in offspring derived from hair metabolome analysis.

The fetus undergoes a crucial period of neurodevelopment in utero. The maternal hair metabolome provides an integrated record of the metabolic state of the mother prior to, and during pregnancy. We investigated whether variation in the maternal hair metabolome was associated with neurodevelopmental differences across infants. Maternal hair samples and infant neurocognitive assessments (using the Bayley III Scales of Infant Development at 24 months) were obtained for 373 infant-mother dyads between 26-28 weeks' gestation from the Growing Up in Singapore Towards Healthy Outcomes cohort. The hair metabolome was analysed using gas chromatography-mass spectrometry. Intensity measurements were obtained for 276 compounds. After controlling for maternal education, ethnicity, and infant sex, associations between metabolites and expressive language skills were detected, but not for receptive language, cognitive or motor skills. The results confirm previous research associating higher levels of phthalates with lower language ability. In addition, scores were positively associated with a cluster of compounds, including adipic acid and medium-chain fatty acids. The data support associations between the maternal hair metabolome and neurodevelopmental processes of the fetus. The association between phthalates and lower language ability highlights a modifiable risk factor that warrants further investigation.

Analysis of sequential hair segments reflects changes in the metabolome across the trimesters of pregnancy.

The hair metabolome has been recognized as a valuable source of information in pregnancy research, as it provides stable metabolite information that could assist with studying biomarkers or metabolic mechanisms of pregnancy and its complications. We tested the hypothesis that hair segments could be used to reflect a metabolite profile containing information from both endogenous and exogenous compounds accumulated during the nine months of pregnancy. Segments of hair samples corresponding to the trimesters were collected from 175 pregnant women in New Zealand. The hair samples were analysed using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. In healthy pregnancies, 56 hair metabolites were significantly different between the first and second trimesters, while 62 metabolites were different between the first and third trimesters (p < 0.05). Additionally, three metabolites in the second trimester hair samples were significantly different between healthy controls and women who delivered small-for-gestational-age infants (p < 0.05), and ten metabolites in third trimester hair were significantly different between healthy controls and women with gestational diabetes mellitus (p < 0.01). The findings from this pilot study provide improved insight into the changes of the hair metabolome during pregnancy, as well as highlight the potential of the maternal hair metabolome to differentiate pregnancy complications from healthy pregnancies.

Metabolomics of Pregnancy Complications: Emerging Application of Maternal Hair.

In recent years, the study of metabolomics has begun to receive increasing international attention, especially as it pertains to medical research. This is due in part to the potential for discovery of new biomarkers in the metabolome and to a new understanding of the "exposome", which refers to the endogenous and exogenous compounds that reflect external exposures. Consequently, metabolomics research into pregnancy-related issues has increased. Biomarkers discovered through metabolomics may shed some light on the etiology of certain pregnancy-related complications and their adverse effects on future maternal health and infant development and improve current clinical management. The discoveries and methods used in these studies will be compiled and summarized within the following paper. A further focus of this paper is the use of hair as a biological sample, which is gaining increasing attention across diverse fields due to its noninvasive sampling method and the metabolome stability. Its significance in exposome studies will be considered in this review, as well as the potential to associate exposures with adverse pregnancy outcomes. Currently, hair has been used in only two metabolomics studies relating to fetal growth restriction (FGR) and gestational diabetes mellitus (GDM).

Triethylenetetramine Synergizes with Pharmacologic Ascorbic Acid in Hydrogen Peroxide Mediated Selective Toxicity to Breast Cancer Cell.

Breast cancer is characterized by overexpression of superoxide dismutase (SOD) and downregulation of catalase and more resistance to hydrogen peroxide (H2O2) than normal cells. Thus, relatively high H2O2 promotes breast cancer cell growth and proliferation. However, excessive intracellular H2O2 leads to death of breast cancer cells. In cancer cells, high level ascorbic acid (Asc) is able to be autoxidized and thus provides an electron to oxygen to generate H2O2. In the present study, we demonstrated that triethylenetetramine (TETA) enhances Asc autoxidation and thus elevates H2O2 production in MCF-7 cells. Furthermore, Asc/TETA combination significantly impaired cancer cell viability, while having much milder effects on normal cells, indicating Asc/TETA could be a promising therapy for breast cancer. Moreover, SOD1 and N-acetyl-L-cysteine failed to improve MCF-7 cells viability in the presence of Asc/TETA, while catalase significantly inhibited the cytotoxicity of Asc/TETA to breast cancer cells, strongly suggesting that the selective cytotoxicity of Asc/TETA to cancer cells is H2O2-dependent. In addition, Asc/TETA induces RAS/ERK downregulation in breast cancer cells. Animal studies confirmed that Asc/TETA effectively suppressed tumor growth in vivo. In conclusion, TETA synergizes pharmacologic Asc autoxidation and H2O2 overproduction in breast cancer cells, which suppresses RAS/ERK pathway and results in apoptosis.

Intravenous Administration of Lycopene, a Tomato Extract, Protects against Myocardial Ischemia-Reperfusion Injury.

BACKGROUND: Oral uptake of lycopene has been shown to be beneficial for preventing myocardial ischemia-reperfusion (I/R) injury. However, the strong first-pass metabolism of lycopene influences its bioavailability and impedes its clinic application. In this study, we determined an intravenous (IV) administration dose of lycopene protects against myocardial infarction (MI) in a mouse model, and investigated the effects of acute lycopene administration on reactive oxygen species (ROS) production and related signaling pathways during myocardial I/R. METHODS: In this study, we established both in vitro hypoxia/reoxygenation (H/R) cell model and in vivo regional myocardial I/R mouse model by ligating left anterior artery descending. TTC dual staining was used to assess I/R induced MI in the absence and presence of acute lycopene administration via tail vein injection. RESULTS: Lycopene treatment (1 µM) before reoxygenation significantly reduced cardiomyocyte death induced by H/R. Intravenous administration of lycopene to achieve 1 µM concentration in circulating blood significantly suppressed MI, ROS production, and JNK phosphorylation in the cardiac tissue of mice during in vivo regional I/R. CONCLUSION: Elevating circulating lycopene to 1 µM via IV injection protects against myocardial I/R injury through inhibition of ROS accumulation and consequent inflammation in mice.