Exposure to environmental chemicals such as phthalates has been linked to numerous adverse pregnancy outcomes, potentially through an oxidative stress mediated mechanism. Most research examined ...urinary 8-iso-prostaglandin F2α (8-iso-PGF2α) as the oxidative stress biomarker. However, 8-iso-PGF2α also originates from enzymatic sources linked to inflammation. Therefore, associations between phthalates and 8-iso-PGF2α could have been misinterpreted. To clarify this, the 8-iso-PGF2α/prostaglandin F2α ratio approach was used to quantitatively distinguish between inflammation or oxidative stress derived 8-iso-PGF2α and estimate their associations with phthalate metabolites in a cohort of 758 pregnant women from The Infant Development and Environment Study (TIDES). Most urinary phthalate metabolites were associated with a significant increase in 8-iso-PGF2α. For example, a 22.4% higher 8-iso-PGF2α concentration (95% confidence interval = 14.4, 30.9) was observed with an interquartile range increase in mono-n-butyl phthalate. For most metabolites, associations were observed solely with oxidative stress derived 8-iso-PGF2α. In contrast, monocarboxy-isononyl phthalate and monoisononyl phthalate (MNP) were associated with both sources of 8-iso-PGF2α. Metabolites of the phthalate alternative 1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH), were only associated with inflammation-derived 8-iso-PGF2α, which is interesting because DINCH metabolites and MNP have structural similarities.In conclusion, phthalates metabolites are not exclusively associated with oxidative stress derived 8-iso-PGF2α. Depending on the metabolite structure, some are also associated with inflammation derived sources, which provides interesting insights in the toxicology of phthalates.
Glutathione (GSH) is a ubiquitous, redox-active, small molecule that is critical to cellular and organism health. In red blood cells (RBCs), the influence of the environment (e.g., diet and ...lifestyle) on GSH levels has been demonstrated in numerous studies. However, it remains unknown if levels of GSH are determined principally by environmental factors or if there is a genetic component, i.e., heritability. To investigate this we conducted a twin study. Twin studies are performed by comparing the similarity in phenotypes between mono- and dizygotic twin pairs. We determined the heritability of GSH, as well as its oxidation product glutathione disulfide (GSSG), the sum of GSH equivalents (tGSH), and the status of the GSSG/2GSH couple (marker of oxidation status, Eₕc) in RBCs. In our study population we found that the estimated heritability for the intracellular concentration of GSH in RBCs was 57 %; for GSSG it was 51 %, tGSH 63 %, and Eₕc 70 %. We conclude that a major portion of the phenotype of these traits is controlled genetically. We anticipate that these heritabilities will also be reflected in other cell types. The discovery that genetics plays a major role in the innate levels of redox-active species in RBCs is paradigm shifting and opens new avenues of research in the field of redox biology. Inherited RBC antioxidant levels may be important disease modifiers. By identifying the relative contributions of genes and the environment to antioxidant variation between individuals, new therapeutic strategies can be developed. Understanding the genetic determinants of these inherited traits may allow personalized approaches to relevant therapies.
Eicosanoids are a class of bioactive lipids produced from the oxygenation of polyunsaturated fatty acid precursors, including the primary omega-6 fatty acids (linoleic acid LA and arachidonic acid ...AA) and omega-3 fatty acids (docosahexaenoic acid DHA and eicosapentaenoic acid EPA) 12. Namely, 1 participant previously categorized as AGA was recategorized as SGA, and 2 participants previously categorized as LGA were recategorized as AGA. ...our final distribution of outcome groups was 31 SGA cases, 31 AGA controls, and 28 LGA cases. Eicosanoid quantification A panel of eicosanoids and fatty acids was measured in plasma samples by the Mass Spectrometry Research and Support Group at the National Institute of Environmental Health Sciences (Research Triangle, NC, US) in 2018. The eicosanoid pathway is defined by a fatty acid precursor—linoleic acid (LA), arachidonic acid (AA), docosahexaenoic acid (DHA), or eicosapentaenoic acid (EPA)—that is metabolized by an enzyme—cytochrome P450 (CYP), lipoxygenase (LOX), or cyclooxygenase (COX).
The biological consequences upon exposure of cells in culture to a dose of xenobiotic are not only dependent on biological variables, but also the physical aspects of experiments e.g. cell number and ...media volume. Dependence on physical aspects is often overlooked due to the unrecognized ambiguity in the dominant metric used to express exposure, i.e. initial concentration of xenobiotic delivered to the culture medium over the cells. We hypothesize that for many xenobiotics, specifying dose as moles per cell will reduce this ambiguity. Dose as moles per cell can also provide additional information not easily obtainable with traditional dosing metrics.
Here, 1,4-benzoquinone and oligomycin A are used as model compounds to investigate moles per cell as an informative dosing metric. Mechanistic insight into reactions with intracellular molecules, differences between sequential and bolus addition of xenobiotic and the influence of cell volume and protein content on toxicity are also investigated.
When the dose of 1,4-benzoquinone or oligomycin A was specified as moles per cell, toxicity was independent of the physical conditions used (number of cells, volume of medium). When using moles per cell as a dose-metric, direct quantitative comparisons can be made between biochemical or biological endpoints and the dose of xenobiotic applied. For example, the toxicity of 1,4-benzoquinone correlated inversely with intracellular volume for all five cell lines exposed (C6, MDA-MB231, A549, MIA PaCa-2, and HepG2).
Moles per cell is a useful and informative dosing metric in cell culture. This dosing metric is a scalable parameter that: can reduce ambiguity between experiments having different physical conditions; provides additional mechanistic information; allows direct comparison between different cells; affords a more uniform platform for experimental design; addresses the important issue of repeatability of experimental results, and could increase the translatability of information gained from in vitro experiments.
Background
The degeneration of red blood cells (RBCs) during storage is a major issue in transfusion medicine. Family studies in the 1960s established the heritability of the RBC storage lesion based ...on poststorage adenosine triphosphate (ATP) concentrations. However, this critical discovery has not been further explored. In a classic twin study we confirmed the heritability of poststorage ATP concentrations and established the heritability of many other RBC metabolites.
Study Design and Methods
ATP concentrations and metabolomic profiles were analyzed in RBC samples from 18 twin pairs. On samples stored for 28 days, the heritability of poststorage ATP concentrations were 64 and 53% in CP2D‐ and AS‐3–stored RBCs, respectively.
Results
Metabolomic analyses identified 87 metabolites with an estimated heritability of 20% or greater. Thirty‐six metabolites were significantly correlated with ATP concentrations (p ≤ 0.05) and 16 correlated with borderline significance (0.05 ≤ p ≤ 0.10). Of the 52 metabolites that correlated significantly with ATP, 24 demonstrated 20% or more heritability. Pathways represented by heritable metabolites included glycolysis, membrane remodeling, redox homeostasis, and synthetic and degradation pathways.
Conclusion
We conclude that many RBC metabolite concentrations are genetically influenced during storage. Future studies of key metabolic pathways and genetic modifiers of RBC storage could lead to major advances in RBC storage and transfusion therapy.
Background
Prenatal psychological stress during pregnancy has been associated with adverse reproductive outcomes. A growing animal literature supports an association between psychological stress and ...oxidative stress. We assessed this relationship in pregnant women, hypothesising that psychological stress is associated with higher concentrations of oxidative stress biomarkers during pregnancy.
Methods
Psychosocial status and stressful life events (SLE) were self‐reported. 8‐iso‐prostaglandin F2α (8‐iso‐PGF2α) was measured as a biomarker of oxidative stress in urine samples at median 32 weeks’ gestation. We examined SLEs individually (ever vs never) and in summary (any vs none) and psychosocial status as measured by individual subscales and in summary (poor vs good). Linear models estimated associations between these parameters and urinary 8‐iso‐PGF2α concentrations after adjusting for covariates.
Results
The geometric mean of 8‐iso‐PGF2α was significantly higher among pregnant women who were non‐White, smokers, had less than a college education, higher pre‐pregnancy BMI and were unmarried. Having ever had a death in the family (n = 39) during pregnancy was associated with a 22.9% increase in 8‐iso‐PGF2α in unadjusted models (95% confidence interval CI 1.50, 48.8). Poor psychosocial status was associated with a 13.1% (95% CI 2.43, 25.0) greater mean 8‐iso‐PGF2α in unadjusted analyses. Associations were attenuated, but remained suggestive, after covariate adjustment.
Conclusions
These data suggest that 8‐iso‐PGF2α is elevated in pregnant women with who are at a sociodemographic disadvantage and who have higher psychological stress in pregnancy. Previous studies have observed that 8‐iso‐PGF2α levels are associated with adverse birth outcomes, oxidative stress could be a mediator in these relationships.
BACKGROUND
The transfusion of red blood cells (RBCs) with maximum therapeutic efficacy is a major goal in transfusion medicine. One of the criteria used in determining stored RBC quality is ...end‐of‐storage hemolysis. Between donors, a wide range of hemolysis is observed under identical storage conditions. Here, a potential mechanism for this wide range is investigated. We hypothesize that the magnitude of hemolysis is a heritable trait. Also, we investigated correlations between hemolysis and RBC metabolites; this will establish pathways influencing hemolysis as future targets for genetic analysis.
STUDY DESIGN AND METHODS
Units of RBCs from identical and nonidentical twins were collected and stored under standard conditions for 56 days. Hemolysis, adenosine triphosphate (ATP), and total glutathione (tGSH) were measured throughout storage. Nontargeted metabolic analyses were performed on RBCs that had been stored for 28 days. Heritability was determined by comparing values between identical and nonidentical twins.
RESULTS
Hemolysis was found to be heritable (mean > 45%) throughout the storage period. Potential correlations were observed between hemolysis and metabolites from the purine metabolism, lysolipid, and glycolysis pathways. These also exhibited heritability (>20%). No correlation was found with ATP or tGSH.
CONCLUSION
The susceptibility of RBCs to lysis during storage is partly determined by inheritance. We have also uncovered several pathways that are candidate targets for future genomewide association studies. These findings will aid in the design of better storage solutions and the development of donor screening tools that minimize hemolysis during storage.
Systemic hyperuricemia (HyUA) in obesity/type 2 diabetes facilitated by elevated activity of xanthine oxidoreductase (XOR), which is the sole source of uric acid (UA) in mammals, has been proposed to ...contribute to the pathogenesis of insulin resistance/dyslipidemia in obesity. Here, the effects of hepatocyte-specific ablation of
, the gene encoding XOR (HXO), and whole-body pharmacologic inhibition of XOR (febuxostat) on obesity-induced insulin resistance/dyslipidemia were assessed. Deletion of hepatocyte
substantially lowered liver and plasma UA concentration. When exposed to an obesogenic diet, HXO and control floxed (FLX) mice became equally obese, but systemic HyUA was absent in HXO mice. Despite this, obese HXO mice became as insulin resistant and dyslipidemic as obese FLX mice. Similarly, febuxostat dramatically lowered plasma and tissue UA and XOR activity in obese wild-type mice without altering obesity-associated insulin resistance/dyslipidemia. These data demonstrate that hepatocyte XOR activity is a critical determinant of systemic UA homeostasis, that deletion of hepatocyte
is sufficient to prevent systemic HyUA of obesity, and that neither prevention nor correction of HyUA improves insulin resistance/dyslipidemia in obesity. Thus, systemic HyUA, although clearly a biomarker of the metabolic abnormalities of obesity, does not appear to be causative.
Purpose
Carotenoids may protect against chronic diseases including cancer and cardiometabolic disease by mitigating oxidative stress and/or inflammation. We cross-sectionally evaluated associations ...between carotenoids and biomarkers of oxidative stress or inflammation.
Methods
From 2003 to 2009, the Sister Study enrolled 50,884 breast cancer-free US women aged 35–74. Post-menopausal participants (
n
= 512) were randomly sampled to measure carotenoids and biomarkers of oxidative stress. Dietary carotenoid consumption was assessed using a validated 110-item Block 1998 food frequency questionnaire; use of β-carotene-containing supplements was also assessed. Plasma carotenoids were quantified, adjusting for batch. Urinary markers of lipid peroxidation, 8-iso-prostaglandin F
2α
(8-iso-PGF
2α
) and its metabolite (8-iso-PGF
2α
-M) were also measured. Since the biomarker 8-iso-PGF
2α
can reflect both oxidative stress and inflammation, we used a modeled 8-iso-PGF
2α
to prostaglandin F
2α
ratio approach to distinguish effects reflecting oxidative stress versus inflammation. Multivariable linear regression was used to assess the associations of dietary and plasma carotenoids with the estimated biomarker concentrations.
Results
Total plasma carotenoids were inversely associated with 8-iso-PGF
2α
-M concentrations (
P
for trend across quartiles = 0.009). Inverse trends associations were also seen for α-carotene and β-carotene. In contrast, lutein/zeaxanthin showed associations with both 8-iso-PGF
2α
and 8-iso-PGF
2α
-M concentrations. The inverse association for total carotenoids appeared to be specific for oxidative stress (chemical 8-iso-PGF
2α
;
P
highest vs. lowest quartile
= 0.04 and
P
for trend across quartiles = 0.02). The pattern was similar for α-carotene. However, lutein/zeaxanthin tended to have a stronger association with enzymatic 8-iso-PGF
2α
, suggesting an additional anti-inflammatory effect. Supplemental β-carotene was inversely associated with both 8-iso-PGF
2α
and 8-iso-PGF
2α
-M concentrations, as well as with both chemical and enzymatic 8-iso-PGF
2α
. Dietary carotenoids were not associated with either biomarker.
Conclusion
Plasma carotenoids and supplemental β-carotene were associated with lower concentrations of 8-iso-PGF
2α
metabolite. Plasma carotenoids associations may reflect antioxidant effects.
Oxidative stress is a biological imbalance in reactive oxygen species and antioxidants. Increased oxidative stress during pregnancy has been associated with adverse birth outcomes. Omega-3 fatty acid ...(n-3 FA) supplementation may decrease oxidative stress; however, this relationship is seldom examined during pregnancy. This study assessed the association between n-3 FA supplement use during pregnancy and urinary oxidative stress biomarker concentrations. Data came from The Infant Development and the Environment Study (TIDES), a prospective cohort study that recruited pregnant women in 4 US cities between 2010-2012. Third trimester n-3 FA intake was self-reported. Third trimester urinary 8-iso-prostaglandin F2α (8-iso-PGF2α) was measured as an oxidative stress biomarker. Additionally, we measured the major metabolite of 8-iso-PGF2α and Prostaglandin F2α (PGF2α) and utilized the 8-iso-PGF2α to PGF2α ratio to calculate the change in 8-iso-PGF2α reflecting oxidative stress versus inflammation. Adjusted linear models were used to determine associations with control for confounding. Of 725 women, 165 reported n-3 FA supplement use in the third trimester. In adjusted linear models, n-3 FA use was associated with 10.2% lower levels of 8-iso-PGF2α (95% Confidence Interval CI: -19.6, 0.25) and 10.3% lower levels of the metabolite (95% CI: -17.1, -2.91). No associations were observed with PGF2α. The lower levels of 8-iso-PGF2α appeared to reflect a decrease in oxidative stress (percent change with supplement use: -18.7, 95% CI: -30.1, -5.32) rather than inflammation. Overall, third trimester n-3 FA intake was associated with lower concentrations of 8-iso-PGF2α and its metabolite, suggesting a decrease in maternal oxidative stress during pregnancy.
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