Increased adiposity, inflammation, metabolic disruption and dyslipidemia in adult male offspring of DOSS treated C57BL/6 dams

Temkin, Alexis M.; Bowers, Robert R.; Ulmer, Candice Z.; Penta, Kayla; Bowden, John A.; Nyland, Jennifer; Baatz, John E.; Spyropoulos, Demetri D.

doi:10.1038/s41598-018-38383-9

Increased adiposity, inflammation, metabolic disruption and dyslipidemia in adult male offspring of DOSS treated C57BL/6 dams

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Published: 06 February 2019

Volume 9, article number 1530, (2019)
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Scientific Reports

Increased adiposity, inflammation, metabolic disruption and dyslipidemia in adult male offspring of DOSS treated C57BL/6 dams

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Alexis M. Temkin¹,
Robert R. Bowers²,
Candice Z. Ulmer³,
Kayla Penta⁴,
John A. Bowden³,
Jennifer Nyland⁵,
John E. Baatz⁶ &
…
Demetri D. Spyropoulos^1,2

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Abstract

Evidence indicates that obesity can be promoted by chemical ‘obesogens’ that drive adiposity, hunger, inflammation and suppress metabolism. Dioctyl sodium sulfosuccinate (DOSS), a lipid emulsifier and candidate obesogen in vitro, is widely used in processed foods, cosmetics and as stool softener medicines commonly used during pregnancy. In vivo testing of DOSS was performed in a developmental origins of adult obesity model. Pregnant mice were orally administered vehicle control or DOSS at times and doses comparable to stool softener use during human pregnancy. All weaned offspring consumed only standard diet. Adult male but not female offspring of DOSS-treated dams showed significantly increased body mass, overall and visceral fat masses, and decreased bone area. They exhibited significant decreases in plasma adiponectin and increases in leptin, glucose intolerance and hyperinsulinemia. Inflammatory IL-6 was elevated, as was adipose Cox2 and Nox4 gene expressions, which may be associated with promoter DNA methylation changes. Multiple significant phospholipid/sterol lipid increases paralleled profiles from long-term high-fat diet induced obesity in males. Collectively, developmental DOSS exposure leads to increased adult adiposity, inflammation, metabolic disorder and dyslipidemia in offspring fed a standard diet, suggesting that pharmaceutical and other sources of DOSS taken during human pregnancy might contribute to long-term obesity-related health concerns in offspring.

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Introduction

Obesity and diabetes are chronic metabolic diseases affecting human populations worldwide. These metabolic disorders have increased to unprecedented levels over the past several decades. In the United States, nearly 40% of adults are obese and 7.7% are morbidly obese¹. Also, children and adolescents ages 2–19 are affected, with 18.5% obese and 5.6% morbidly obese¹. Body mass index (BMI) rose 2.3 kg/m² from 1988 to 2006^2,3. Rates of diabetes and metabolic syndrome have also increased and are often coupled with obesity^4,5. Caloric imbalance (greater intake/lower expenditure) and genetics are important drivers of obesity. Despite increased efforts in nutrition and fitness education, obesity rates fail to decline and are estimated to reach 51% of the US population by 2030⁶. However, increasing numbers of obesity cases cannot be attributed purely to genetics. GIANT consortium analyses indicate that only 2.7% of increases in BMI can be ascribed to genetics and that the total genetic contribution will only reach 20% once all such genes are identified^7,8. Such “missing heritability” cases have been attributed to gene-by-environment interactions^9,10. For example, familial heritability and obesity-discordant twins studies and complex trait analyses^11,12 indicate that combinations of polymorphisms can account for at most 30–37% of the variance associated with BMI^13,14. Environmental exposures, especially during development, have gained recognition as playing important roles in obesity and metabolic syndrome¹⁵. Developmental exposures that impact obesity include stress, diet, pollutants, pharmaceuticals and personal care products^16,17,18,19. Chemicals that promote obesity and metabolic syndrome have been termed ‘obesogens’^20,21. Obesogens can drive obesity by multiple molecular mechanisms. The most researched mechanism involves obesogens acting as agonists of the nuclear receptor PPARγ. Furthermore, hormone receptor assays are often utilized for the in vitro identification of potential obesogens, prior to in vivo validation¹⁰. Published work from our group identified the anionic surfactant, dioctyl sodium sulfosuccinate (DOSS), as a probable obesogen using in silico modeling, in vitro receptor ligand binding and transactivation assays and murine preadipocyte adipogenic differentiation²². DOSS (CAS #577-11-7) is also known as AOT, Aerosol OT, diethylhexyl sodium sulfosuccinate, Colace, Docusate sodium, and many other names. Structurally similar obesogens have been classified in literature as PPARγ agonists, including the anionic surfactants sodium dodecyl sulfate (SDS) and sodium dodecylbenzenesulfonate (SDBS), which suggest that surfactants/dispersants constitute a previously unidentified and unexplored class of obesogens²³. Epidemiological studies previously identified positive correlations between chemicals measured during pregnancy (e.g. phthalates and persistent organic pollutants) and childhood obesity^24,25,26. Exposures during development can profoundly impact epigenetic patterning that persistently impact later life health trajectories^27,28,29. As with the other surfactant PFOA, DOSS will be evaluated for its obesogenic potential in vivo during development³⁰. Pregnancy associated exposure may result from other possible sources of DOSS, including dietary emulsifying agents (e.g. colored/flavored powdered beverages) and personal care products^31,32,33,34. Approximately 11–38% of pregnant women experience constipation during pregnancy³⁵, and DOSS in the form of Colace/Docusate stool softener is the treatment of choice, being prescribed up to 500 mg/day^36,37. In addition, nearly 2 million gallons of COREXIT dispersants, containing DOSS as a principle component, were used to clean up the Deepwater Horizon oil spill.

In the current study, C57BL/6 mouse dams were exposed to DOSS following a dose and exposure scenario relevant to Colace/Docusate stool softener use by pregnant women. The C57BL/6 mouse line was chosen as it is commonly used for diet-induced obesity studies. The offspring of exposed dams were examined using markers of adiposity and metabolic syndrome and a combination of morphometrics (e.g. body composition, circulating adipokines and cytokines, tissue gene expression, glucose tolerance and epigenetic marks such as DNA methylation). This study followed the precedent set by other in vivo studies, which evaluated obesogens that act as ligands to activate PPARγ, including the phthalate metabolite MEHP^{Full size image}

The statistically significant reduction in normalized adiponectin levels observed in treated animals could be due to significant changes in white adipose tissue depots expressing AdipoQ, the gene encoding adiponectin (Supp. Table 1). Consistent with this, a statistically significant down regulation of AdipoQ expression (p = 0.015) was observed in F1 male offspring IWAT tissues from treated versus control dams (Fig. 3C). Although not statistically significant, decreased gene expression of AdipoQ was observed in male gonadal (EWAT) adipose tissue as well (data not shown). These data further support the hypothesis that DOSS exposure during pregnancy results in decreased adiponectin in adult male offspring at 16 weeks. A non-statistically significant trend for lower AdipoQ expression was observed in adult female offspring IWAT of treated dams (data not shown). These results suggest that no change in circulating adipokine levels in females would be observed, further supporting the association between DOSS exposure, adipokine levels and overweight phenotype in male, but not female animals.

Leptin, an adipokine that regulates satiety and appetite, has been shown to be positively correlated with adiposity and obesity⁴⁹. While other fat depots are capable of producing and secreting more leptin, models based on circulating leptin levels are likely more reliable than IWAT gene expression for whole body response to satiety and appetite. Therefore, this study provided circulating leptin levels. Significantly higher levels of circulating leptin (p = 0.033) were observed in adult F1 males from DOSS-treated dams compared to controls (Fig. 4A). A positive relationship between leptin and adiposity markers is well documented in both humans and mice^50,51. Our work demonstrates this same trend as circulating leptin levels were positively correlated with fat mass for DOSS treatment (Fig. 4B). Although some treatment F1 males displayed higher expression of the leptin gene in IWAT relative to controls, the differences were not statistically significant (Fig. 4C).

DOSS treatment in dams produces a persistent inflammatory state in adult F1 male offspring

Obesity and type 2 diabetes (T2D) are often referred to as a chronic inflammatory diseases of adipose tissues, which are presumably driven by infiltration of adipose tissue with macrophages⁵². IL-6 is a proinflammatory cytokine secreted by immune cells. Circulating IL-6 levels were measured to determine if offspring of DOSS-treated animals showed indications of such an inflammatory state. Significantly higher circulating levels of IL-6 in treatment (48.12 pg/mL) versus control (13.70 pg/mL) adult F1 males were observed at p = 0.011 (Fig. 5A). Unlike adiponectin and leptin, a correlation between adipose tissue weight and circulating IL-6 levels was not observed in either treatment or control animals (Supp. Fig. 2A). IL-6 gene expression changes were also monitored in IWAT adipose tissue for potential associations with inflammation. No statistically significant differences in IL-6 gene expression were observed between treatment and control animals (Supp. Fig. 2B) despite increased circulating levels of IL-6 in treatment animals (Fig. 5A). This finding may suggest the contribution of other immune cell/fat depots to overall circulating IL-6 levels. Within adipose tissue, the stromal vascular fraction accounts for 90% of the IL-6 expression in adipose tissue even though it represents a small percentage of adipose tissue cells⁵³.

TNFα is another inflammatory cytokine secreted by immune cells and has been shown to be positively correlated with obesity and T2D. Therefore, mouse plasma were analyzed for levels of TNFα. The mean circulating TNFα was higher in treatment adult F1 males (8.44 pg/mL) compared to controls (7.54 pg/mL), although not statistically significant (Fig. 5B).

Other genes investigated included cyclooxygenase 2 (Cox2) and NADPH oxidase (Nox4; Supp. Table 1). Elevated expression of Cox2 and Nox4 are associated with the presence of reactive oxygen species and systemic chronic inflammation^54,55. Both Cox2 and Nox4 expressions were significantly increased in IWAT for DOSS-treatment versus control adult F1 males (Fig. 5C,D). Thus, the increased expression of multiple inflammatory markers in this work suggests that a state of chronic inflammation exists in offspring of DOSS-treated dams.

DOSS treatment in dams produce altered DNA promoter methylation of IL-6 and Cox2 genes in adult F1 male offspring

Increased levels of gene expression (Cox2 and Nox4) and circulating levels of IL-6, adipokines and cytokines were observed in 16 week-old F1 males of DOSS treated dams. These findings suggest alterations of promoter methylation at these loci in IWAT. Therefore, promoter methylation was investigated at these loci, as well as at previously identified gene promoters reported in the literature to be regulated by DNA methylation in response to high-fat diet, obesity or T2D (Leptin, Pparg, Glut4, Fasn, Irs1, Hmox1, Fabp4). A complete list of loci, bisulfite primers and references used in this work are presented in Supp. Table 2.

The promoter region of the IL-6 gene in IWAT tissue was investigated for changes in DNA methylation. Five previously identified CpG sites roughly 300 bp upstream of the IL-6 transcription start site were evaluated for methylation status⁵⁶. Results in Supp. Fig. 3A show DOSS treatment to be associated with significantly reduced methylation specifically at CpG site 2 by two-way ANOVA (p = 0.004) and by Sidak’s post hoc test (p = 0.045). Although there was no statistically significant correlation (p = 0.705) between IWAT gene expression and DNA methylation at CpG site 2 (Supp. Fig. 4A), there was a statistically significant inverse correlation (p = 0.011) between IL-6 CpG site 2 methylation and circulating IL-6 levels. (Supp. Fig. 3B). To the best of our knowledge this is the first significant finding of IL-6 CpG site 2 methylation status in adipose tissue as it relates to circulating IL-6 levels, though it’s biological importance remains to be determined. Although multiple tissue sources of IL-6 contribute to circulating levels, the potential of CpG site 2 to serve as a biomarker for the persistent effects in offspring of DOSS exposed mothers warrants further investigation.

Changes in Cox2 promoter hypermethylation upon exposure have been linked to Cox2 gene expression in other studies⁵⁷. Therefore, fourteen CpG sites approximately 500 bp upstream of the Cox2 transcription start site were evaluated for methylation status. Results demonstrate that although DOSS treatment was not significantly associated (p = 0.128) with Cox2 promoter methylation in this region (Supp. Fig. 3C), average DNA methylation at CpG site 1 was significantly reduced (p = 0.005) in treatment males (Supp. Fig. 3D). However, there was only a modest correlation (p = 0.280) between CpG site 1 methylation and Cox2 gene expression (Supp. Fig. 4B).

Bisulfite sequencing for six CpG sites in the adiponectin promoter were targeted (i.e. four adiponectin region 2 sites, associated with high-fat diet induced gene expression, and two nearby adiponectin region 1 sites having no previously documented associations with gene expression). Statistically significant hypomethylation was observed in region 1, particularly at CpG site 1 (Supp. Fig. 4C) in tissues from treatment males. There was no statistically significant difference in region 2 promoter methylation between treatment and controls. Decreased levels of circulating adiponectin and gene expression in IWAT tissue suggest the possible hypermethylation of the adiponectin promoter at each CpG site in region 2, resulting in repression of gene expression upon DOSS treatment (Supp. Fig. 4D). Region 2 CpG site 3 showed that 58% of DOSS treatment animals had over 80% methylation compared to 29% of controls with over 80% methylation (Supp. Fig. 4E). However, no statistically significant correlations were observed between region 2 CpG site 3 methylation and gene expression (Supp. Fig. 4E). Furthermore, no statistically significant differences in promoter methylation were observed for Leptin, Fasn, Pparg, Glut4, Irs1, Fabp4, or Hmox1 (Supp. Table 3).

DOSS treatment in dams induces glucose intolerance in adult F1 male offspring

Glucose tolerance tests are used clinically to assess metabolic function in humans at risk for diabetes and experimentally in obesity and diabetic mouse models. To determine the effect of maternal DOSS treatment during development on glucose tolerance in adult offspring, oral glucose tolerance tests were performed at 12 weeks of age on offspring of control and DOSS-treated dams. Results demonstrate that only male offspring of DOSS treated dams exhibit marked glucose intolerance (Fig. 6). Specifically, Fig. 6A shows statistically significant higher blood glucose levels at 30 minutes in male offspring of DOSS treated vs. control dams. Similarly, these DOSS treatment F1 males show a significantly higher overall glucose tolerance impairment (p = 0.010), as indicated by the area under the curve (AUC) for the entire time course (Fig. 6B). No specific time points or AUC differences were observed amongst the female offspring (Fig. 6C,D). Male-specific results are commonly observed in C57BL/6 mouse models for high-fat diet induced obesity^58,59.

C-reactive peptide (C-peptide), a more stable marker for insulin due to its longer half-life, is released in a 1:1 ratio to insulin, making it more conducive for plasma studies with variable storage times and conditions. Therefore, circulating C-peptide levels were measured as a stable surrogate for insulin secretion in male offspring (n = 10/group) to determine whether glucose intolerance in DOSS treatment F1 males resulted from insulin desensitization marked by hyperinsulinemia. Significantly higher levels of fasting C-peptide (p = 0.040) was measured in male offspring of DOSS-treated dams (718 pM) relative to controls (563 pM; Fig. 6E). Furthermore, upon glucose stimulation, a statistically significant increase (p = 0.020) in C-peptide levels was observed only in control animals (Fig. 6E). These results suggest that adult male offspring of DOSS-treated dams demonstrate hyperinsulinemia and blunted insulin responsiveness to glucose stimulation. Primarily glucose intolerance and adiponectin, but also obesity and adiponectin have been described to have an inverse relationship⁶⁰, while positive correlations between circulating adiponectin and adipose fat mass have been observed^61,62. Consistent with these results, raw adiponectin level and glucose intolerance are positively correlated with adipose tissue mass in our animals (Fig. 6F,G), and adiponectin levels are negatively correlated with glucose intolerance (Fig. 6H).

DOSS treatment in dams produces adult F1 male offspring with elevated circulating phospholipid patterns commonly observed in long-term high-fat diet induced obesity and diabetes

Due to recent advancements in mass spectrometry (MS) and ultra-high performance liquid chromatography (UHPLC) untargeted lipidomic applications have broadened to investigate lipid profiles associated with obesity and diabetes^63,64,65. Biomarkers identified using this approach have the potential to elucidate cellular mechanisms associated with disease progression. Therefore, an untargeted lipidomics workflow was incorporated to identify significant and persistent changes in plasma lipid profiles as a result of DOSS exposure during development. Overall, 664 features were identified in positive MS scan mode and 171 features identified in negative MS scan mode. Various phospholipids (e.g. phosphatidyl choline (PC) and phosphatidylethanolamine (PE)) and sterol lipid (e.g. cholesterol ester (CE)) species were increased in 16 week-old F1 male offspring of DOSS-treated dams. As shown in Fig. 7A–H, the following lipid species demonstrated statistically significant or near significant increases in relative peak areas: PC(34:3) (p = 0.043), PC(36:1) (p = 0.005), PC(38:4) (p = 0.012), PC(18:0_20:1) (p = 0.018), PC(18:0_20:3) (p = 0.038), PE(18:0_20:1) (p = 0.015), PE(18:0_20:3) (p = 0.044), and CE(20:3) (p = 0.058). Several of the lipid species annotated in this work have also been highlighted in literature⁶⁶ as putative biomarkers for high-fat diet induced obesity in C57BL/6 mice, including PC(36:1), PC(38:3), PC(38:4) and CE(20:3). Lysophosphatidylcholine (LPC) lipid species have been shown to be reduced in response to high-fat diet, obesity and diabetes⁶⁷. Reductions in several novel LPCs were observed in response to DOSS exposure during development, including LPC 15:0, 17:0, 19:0, 20:0, 22:0, 22:1 and 24:1. These results suggest that developmental exposure to DOSS followed by a normal ad lib diet promotes persistent dyslipidemia akin to long-term high fat-diet induced obesity in adult mice.

Discussion

This work provides evidence in support of the hypothesis that DOSS acts as an obesogen in vivo via metabolic disruption. Exposure to DOSS during development resulted in impaired glucose tolerance, insulin desensitization, increases in adiposity, and altered gene expression, circulating levels of adipokines, cytokines and phospholipids. These changes, observed only in the male mice studied, are consistent with obese, diabetic and metabolic syndrome phenotypes demonstrated in literature. Previous studies have shown C57BL/6 mice to demonstrate sexually dimorphic metabolic and obesogenic effects. For instance, female mice fed a high-fat diet for 14 weeks were protected from metabolic syndrome, unlike the male counterpart^68,69. In a prenatal exposure model for MEHP in C57BL/6 mice, markers of obesity were observed in male offspring but not in female offspring^{1). Data are expressed as a fold change in treated animals compared with control animals.}

Oral glucose tolerance test

At 12 weeks of age, F1 offspring of treated and control dams were assessed for glucose tolerance using an oral glucose tolerance test (oGTT). Before administering the test, animals were fasted for 5–6 hours in cages containing Alpha-Dri bedding with only access to water. At T0, animals were weighed and a baseline blood glucose measurement and plasma sample were taken after making a 0.5–1 mm cut at the tip of the tail with a razor blade. A glucose bolus (2 mg/g body weight) was administered via oral gavage followed with tail tip blood glucose measurements at 15, 30, 60, 90 and 120 minutes. TRUEBalance glucose meter and strips were used for all measurements. If a “HI” error was obtained, the measurement was taken again using a new test strip, and if “HI” was obtained again the value was assigned as 600 (mg/dL), the maximum output of the detector.

Plasma lipidomic profiling

Lipids were extracted from blood plasma samples using a Bligh-Dyer extraction¹¹². Thirty microliters of plasma were spiked with lipid internal standards (36μL), and 4 mL of 1:1 (v:v) chloroform:methanol, followed by the addition of 1.8 mL water. Samples were then incubated on ice for 30 min, vortexed for 20 sec, and centrifuged at 2000 rpm for 10 min to separate organic and aqueous layers. The organic layer was collected and the aqueous layer was re-extracted with 1 mL 1:1 chloroform:methanol. The organic layers were combined, transferred to a new tube, then dried down under nitrogen, and reconstituted in 50 μL of isopropanol.

All lipid extracts were analyzed by ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS). Individuals performing extractions and running samples were blinded to sample conditions. Mass spectra were acquired on a Thermo Scientific Orbitrap Fusion Lumos Tribrid mass spectrometer equipped with a heated electrospray ionization (HESI II) probe in positive and negative ion mode. HESI and mass spectrometric parameters for lipid extracts were as follows in positive/negative ion mode, respectively: spray voltage: 3.5/2.5 kV, sheath gas: 40/35 AU; auxiliary nitrogen pressure: 15 AU; sweep gas: 1/0 AU; ion transfer tube and vaporizer temperatures: 325 and 300/275 °C, respectfully; and RF lens level: 30. Full scan, data-dependent MS/MS (top10-ddMS2), and data-independent acquisition mode data were collected at m/z 150–2000, corresponding to the mass range of most expected cellular lipids. External calibration was applied before each run to allow for LC-HRMS analysis at 120,000 resolution (at m/z 200).

A Thermo Scientific Vanquish UHPLC system (Thermo Scientific, San Jose, CA) was coupled to the Orbitrap Fusion Lumos Tribrid for the chromatographic separation of lipids. The autosampler temperature was maintained at 4 °C for all experiments. Solvent extraction blanks and quality control samples were jointly analyzed over the course of a batch (10–15 samples). A Waters Acquity™ C18 BEH column (2.1 × 100 mm, 1.7 μm particle size, Waters, Milford, MA) maintained at 60 °C was used for all lipidomic studies. The injection volume was 5 μL in positive and negative ion mode with a mobile phase flow rate of 450 μL/min. The gradient program consisted of mobile phase C [60:40 (v:v) acetonitrile/water] and mobile phase D [90:8:2 (v:v:v) isopropanol/ acetonitrile/water], each containing 10 mM ammonium formate and 0.1% formic acid. The gradient included 32% D at 0 min, 40% D at 1 min, a hold at 40% D until 1.5 min, 45% D at 4 min, 50% D at 5 min, 60% D at 8 min, 70% D at 11 min, 80% D at 14 min, 100% D at 16 min, and a hold at 100% D until 17 min. The total run time was 22 min, including a 5 min equilibration.

Full scan raw data files acquired from Xcalibur™ (Thermo Fisher Scientific), centroided and converted to a useable format (mzXML) using MSConvert. Data processing and peak area integration were performed using MZmine, resulting in a feature intensity table. The resulting feature table was filtered using extraction blank samples in FRAMe (Feature Reduction Assistant for Metabolomics v1.0). Only features with a signal/noise ratio greater than 10 times that of the blank were included. LipidSearch™ (Thermo Scientific) and LipidMatch⁶⁴ were used to identify features. Peak areas were normalized to plasma weight for each sample.

Statistical analysis

We estimated that 12 animals per group would be more than sufficient for this study. This is a conservative number, considering that the Mouse Phenome Database has developed a wealth of phenotypic data, including high-fat diet studies on 43 inbred strains using 7–10 mice per group^113,114. A sample size of 12 mice per group for comparisons between treatment and control groups provides 80% power to detect a small effect size of 0.44 in obesity outcomes of between treatment groups for a two-sided test at significance level α = 0.004 using a two-sided test and assuming moderate correlation between measures within each mouse (ρ = 0.5). The significance level is Bonferroni adjusted for up to 4 pair-wise comparisons.

For oGTT data, area under the curve (AUC) was calculated for each individual in GraphPad Prism. Means for AUC from treated and control groups were then compared using unpaired student’s t-test. Additionally, means for blood glucose were compared at each time point between treated and control groups using two-way ANOVA.

Normality and equal variances were assessed by Shapiro-Wilks test and Brown-Forsythe or F test respectively, before proceeding with mean comparisons using Student’s t-test. Data were log transformed if they did not pass the assumptions and to increase normality and Welch’s correction was used to account for differences in variance. Results are discussed in each section and statistical tests are specified in Figure legends. For DNA methylation analysis, average methylation results are determined for each CpG site in an amplicon. Two-way ANOVA was used to assess overall treatment effect and differences observed at specific CpG sites. A p-value of less than 0.05 was considered significant.

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Acknowledgements

This study was supported in part by the “Gulf of Mexico Research Initiative” grant GoMR12012-11-344. The identification of equipment and materials does not imply recommendation or endorsement by the National Institute of Standards and Technology.

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Molecular and Cellular Biology and Pathobiology Program, Medical University of South Carolina, Charleston, SC, USA
Alexis M. Temkin & Demetri D. Spyropoulos
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA
Robert R. Bowers & Demetri D. Spyropoulos
National Institute of Standards and Technology, Chemical Sciences Division, Hollings Marine Laboratory, Charleston, SC, USA
Candice Z. Ulmer & John A. Bowden
Department of Biological Sciences, University of South Carolina, Columbia, SC, USA
Kayla Penta
Department of Biological Sciences, Salisbury University, Salisbury, MD, USA
Jennifer Nyland
Department of Pediatrics and Neonatology, Medical University of South Carolina, Charleston, SC, USA
John E. Baatz

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A.M.T., R.R.B. and D.D.S. were responsible for the design and execution of all experimental procedures described and not attributed to other authors. C.Z.U. and J.A.B. were responsible for the design and execution of the untargeted lipidomic experiments. K.P. and J. N. were responsible for the design and execution of the DXA scan experiments. J.E.B. was responsible for the review and, if needed, modification of all experimental designs and review of all experimental results. A.M.T., R.R.B. and D.D.S. wrote the main manuscript text and prepared all figures and figure legends and all other authors edited these materials prior to submission. All authors contributed to responses to reviewers.

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Temkin, A.M., Bowers, R.R., Ulmer, C.Z. et al. Increased adiposity, inflammation, metabolic disruption and dyslipidemia in adult male offspring of DOSS treated C57BL/6 dams. Sci Rep 9, 1530 (2019). https://doi.org/10.1038/s41598-018-38383-9

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Received: 23 September 2018
Accepted: 16 December 2018
Published: 06 February 2019
DOI: https://doi.org/10.1038/s41598-018-38383-9
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Increased adiposity, inflammation, metabolic disruption and dyslipidemia in adult male offspring of DOSS treated C57BL/6 dams

Abstract

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Introduction

DOSS treatment in dams produces a persistent inflammatory state in adult F1 male offspring

DOSS treatment in dams produce altered DNA promoter methylation of IL-6 and Cox2 genes in adult F1 male offspring

DOSS treatment in dams induces glucose intolerance in adult F1 male offspring

DOSS treatment in dams produces adult F1 male offspring with elevated circulating phospholipid patterns commonly observed in long-term high-fat diet induced obesity and diabetes

Discussion

Oral glucose tolerance test

Plasma lipidomic profiling

Statistical analysis

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Increased adiposity, inflammation, metabolic disruption and dyslipidemia in adult male offspring of DOSS treated C57BL/6 dams

Abstract

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Introduction

DOSS treatment in dams produces a persistent inflammatory state in adult F1 male offspring

DOSS treatment in dams produce altered DNA promoter methylation of IL-6 and Cox2 genes in adult F1 male offspring

DOSS treatment in dams induces glucose intolerance in adult F1 male offspring

DOSS treatment in dams produces adult F1 male offspring with elevated circulating phospholipid patterns commonly observed in long-term high-fat diet induced obesity and diabetes

Discussion

Oral glucose tolerance test

Plasma lipidomic profiling

Statistical analysis

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