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Background and Objectives: Diet plays critical roles in modulating maternal metabolic health in pregnancy, but is also a source of metabolic-disrupting phthalates and their replacements. We aimed to evaluate whether the effects of better diet quality on favorable maternal metabolic outcomes could be partially explained by lower exposure to phthalates/replacements., Methods: At 13 weeks gestation, 295 Illinois women (enrolled 2015-2018) completed a three-month food frequency questionnaire that we used to calculate the Alternative Healthy Eating Index (AHEI)-2010 to assess diet quality. We quantified 19 metabolites, reflecting exposure to 10 phthalates/replacements, in a pool of five first-morning urine samples collected monthly across pregnancy. We measured 15 metabolic biomarkers in fasting plasma samples collected at 17 weeks gestation, which we reduced to five uncorrelated principal components (PCs), representing adiposity, lipids, cholesterol, inflammation, and growth. We used linear regression to estimate associations of diet quality with [1] phthalates/replacements and [2] metabolic PCs, as well as [3] associations of phthalates/replacements with metabolic PCs. We estimated the proportion of associations between diet quality and metabolic outcomes explained by phthalates/replacements using a causal mediation framework., Results: Overall, every 10-point improvement in AHEI-2010 score was associated with -0.15 (95% CI: -0.27, -0.04) lower adiposity scores, reflecting lower glucose, insulin, C-peptide, leptin, C-reactive protein, but higher adiponectin biomarker levels. Every 10-point increase in diet quality was also associated with 18% (95%CI: 7%, 28%) lower sum of di-2-ethylhexyl terephthalate urinary metabolites (∑DEHTP). Correspondingly, each 18% increase in ∑DEHTP was associated with 0.03 point (95% CI: 0.01, 0.05) higher adiposity PC scores. In mediation analyses, 21% of the inverse relationship between diet quality and adiposity PC scores was explained by lower ∑DEHTP., Conclusions: The favorable impact of diet quality on maternal adiposity biomarkers may be partially attributed to lower metabolite concentrations of DEHTP, a plasticizer allowed to be used in food packaging materials., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Braun served as an expert witness in litigation related to perfluorooctanonic acid contamination in drinking water in New Hampshire. The other authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hairpin forming expanded CAG/CTG repeats pose significant challenges to DNA replication which can lead to replication fork collapse. Long CAG/CTG repeat tracts relocate to the nuclear pore complex to maintain their integrity. Forks impeded by DNA structures are known to activate the DNA damage checkpoint, thus we asked whether checkpoint proteins play a role in relocation of collapsed forks to the nuclear periphery in S. cerevisiae . We show that relocation of a (CAG/CTG) 130 tract is dependent on activation of the Mrc1/Rad53 replication checkpoint. Further, checkpoint-mediated phosphorylation of the kinetochore protein Cep3 is required for relocation, implicating detachment of the centromere from the spindle pole body. Activation of this pathway leads to DNA damage-induced microtubule recruitment to the repeat. These data suggest a role for the DNA replication checkpoint in facilitating movement of collapsed replication forks to the nuclear periphery by centromere release and microtubule-directed motion., Highlights: The DNA replication checkpoint initiates relocation of a structure-forming CAG repeat tract to the nuclear pore complex (NPC)The importance of Mrc1 (hClaspin) implicates fork uncoupling as the initial checkpoint signalPhosphorylation of the Cep3 kinetochore protein by Dun1 kinase allows for centromere release, which is critical for collapsed fork repositioningDamage-inducible nuclear microtubules (DIMs) colocalize with the repeat locus and are required for relocation to the NPCEstablishes a new role for the DNA replication and DNA damage checkpoint response to trigger repositioning of collapsed forks within the nucleus.

Background: Per- and polyfluoroalkyl substances (PFAS) can disrupt metabolism. Early-to-mid pregnancy is characterized by amplified metabolic processes and inflammation to support maternal adaptations and fetal growth. Thus, we cross-sectionally evaluated whether PFAS are individually and jointly associated with these processes in early-to-mid pregnancy., Methods: Pregnant Illinois women (n = 452) provided fasted blood samples at median 17 weeks gestation. We quantified serum perfluorononanoic (PFNA), perfluorooctane sulfonic (PFOS), perfluorooctanoic (PFOA), methyl-perfluorooctane sulfonamide acetic acid (Me-PFOSA-AcOH), perfluorohexanesulfonic (PFHxS), perfluorodecanoic (PFDeA), and perfluoroundecanoic (PFUdA) acid. Key outcomes were plasma glucose, insulin, C-peptide, insulin-like growth factor 1 (IGF-1), adiponectin, leptin, triglycerides, free fatty acids, total cholesterol, high-density lipoprotein (HDL) cholesterol, C-reactive protein, tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and interleukin 6. We calculated homeostatic model assessment for insulin resistance (HOMA-IR), low-density lipoprotein (LDL) cholesterol, and very low-density lipoprotein (VLDL). We evaluated associations of PFAS with each metabolic/inflammatory biomarker individually using covariate-adjusted linear regression and jointly using quantile-based g-computation., Results: In linear regression, all PFAS (except Me-PFOSA-AcOH) were negatively associated with insulin, HOMA-IR, and leptin, whereas all PFAS were positively associated with HDL cholesterol. We also observed negative associations of some PFAS with TNF-α and MCP-1; positive associations with adiponectin and total cholesterol also emerged. Additionally, PFOS was positively, whereas Me-PFOSA-AcOH was negatively, associated with triglycerides and VLDL. Each 25% increase in the PFAS mixture was associated with -31.3% lower insulin (95%CI: -45.8, -12.9), -31.9% lower HOMA-IR (95%CI: -46.4, -13.4), and -9.4% lower leptin (95%CI: -17.3, -0.8), but 7.4% higher HDL cholesterol (95%CI: 4.6, 10.3). For most outcomes, the major contributors to the PFAS mixture often differed compared to single-PFAS analyses., Implications: Individual and joint PFAS exposures were associated with markers of maternal metabolism and inflammation in pregnancy. Further investigation is needed to elucidate possible mechanisms and consequences of these findings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/aims: Pregnant women are exposed to persistent environmental contaminants, including per- and polyfluoroalkyl substances (PFAS) that disrupt thyroid function. However, it is unclear if PFAS alter maternal sex-steroid hormone levels, which support pregnancy health and fetal development., Methods: In Illinois women with relatively high socioeconomic status (n = 460), we quantified perfluorononanoic (PFNA), perfluorooctane sulfonic (PFOS), perfluorooctanoic (PFOA), methyl-perfluorooctane sulfonamide acetic acid, perfluorohexanesulphonic (PFHxS), perfluorodecanoic (PFDeA), and perfluoroundecanoic (PFUdA) acid concentrations in fasting serum samples at median 17 weeks gestation, along with plasma progesterone, testosterone, and estradiol. We evaluated covariate-adjusted associations of ln-transformed hormones with each ln-transformed PFAS individually using linear regression and with the PFAS mixture using quantile-based g-computation (QGComp)., Results: Interquartile range (IQR) increases in PFOS were associated with higher progesterone (%Δ 3.0; 95%CI: -0.6, 6.6) and estradiol (%Δ: 8.1; 95%CI: 2.2, 14.4) levels. Additionally, PFHxS was positively associated with testosterone (%Δ: 10.2; 95%CI: 4.0, 16.7), whereas both PFDeA and PFUdA were inversely associated with testosterone (%Δ: -5.7; 95%CI: -10.3, -0.8, and %Δ: -4.1; 95%CI: -7.6, -0.4, respectively). The IQR-standardized PFAS mixture was not associated with progesterone (%Δ: 1.6; 95%CI: -5.8, 9.2), due equal partial positive (%Δ: 9.2; driven by PFOA) and negative (%Δ: -7.4; driven by PFOS) mixture associations. Similarly, the mixture was not associated with testosterone (%Δ: 5.3; 95%CI: -9.0, 20.1), due to similar partial positive (%Δ: 23.6; driven by PFHxS) and negative (%Δ: -17.4; driven by PFDeA) mixture associations. However, we observed a slightly stronger partial positive (%Δ: 25.6; driven by PFOS and PFUdA) than negative (%Δ: -16.3; driven by PFOA) association resulting in an overall non-significant positive trend between the mixture and estradiol (%Δ: 8.5; 95%CI: -3.7, 20.9)., Conclusion: PFAS mixture modeled using QGComp was not associated with maternal sex-steroid hormones due to potential opposing effects of certain PFAS. Additional prospective studies could corroborate these findings., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Activated phosphoinositide 3-kinase delta syndrome (APDS) is an ultra-rare primary immunodeficiency, with only 256 cases reported globally. This study aimed to explore the disease burden of APDS from the perspective of individuals with APDS and their caregivers., Methods: Qualitative interviews were conducted with healthcare providers (HCPs), individuals with APDS and caregivers, to explore the symptoms and health-related quality of life (HRQoL) impact of APDS. Some individuals and caregivers also completed a narrative account exercise. All interviews were audio recorded and transcribed. Data were analysed using thematic analysis and saturation was recorded., Results: Semi-structured qualitative interviews were conducted with healthcare providers (HCPs), individuals with APDS and caregivers. Individuals and caregivers had the option of completing a narrative account exercise. Six HCPs participated in an interview. Seven participants completed the narrative account exercise (N = 5 caregivers and N = 2 individuals with APDS) and 12 took part in an interview (N = 4 caregivers and N = 8 individuals with APDS). Themes identified from HCPs interviews included symptoms, clinical manifestations, HRQoL impacts and treatments/management of APDS. The narrative account exercise identified similar themes, but with the addition to the journey to diagnosis. These themes were explored during the individual/caregiver interviews. Reported clinical manifestations and symptoms of APDS included susceptibility to infections, lymphoproliferation, gastrointestinal (GI) disorders, fatigue, bodily pain, and breathing difficulties. HRQoL impacts of living with APDS included negative impacts to daily activities, including work, education and social and leisure activities, physical functioning, as well as emotional well-being, such as concern for the future, and interpersonal relationships. Impacts to caregiver HRQoL included negative impacts to physical health, work, emotional well-being, interpersonal relationships and family life and holidays. The management of APDS included the use of healthcare services and medications including immunoglobulin replacement therapy (IRT), rapamycin, prophylactic antibiotics, leniolisib, as well as medical procedures due to complications., Conclusions: APDS has a high disease burden and there is an unmet need for licensed, more targeted treatments which modify disease progression. This study was the first to describe the day-to-day experience and HRQoL impact of APDS from the perspective of individuals living with the condition, caregivers and treating physicians., (© 2024. The Author(s).)

Background/objectives: Pregnant women are exposed to numerous endocrine disrupting chemicals (EDCs) that can affect hormonal pathways regulating pregnancy outcomes and fetal development. Thus, we evaluated overall and fetal sex-specific associations of phthalate/replacement, paraben, and phenol biomarkers with sex-steroid and thyroid hormones., Methods: Illinois women (n = 302) provided plasma for progesterone, estradiol, testosterone, free T4 (FT4), total T4 (TT4), and thyroid stimulating hormone (TSH) at median 17 weeks gestation. Women also provided up-to-five first-morning urine samples monthly across pregnancy (8-40 weeks), which we pooled to measure 19 phthalate/replacement metabolites (reflecting ten parent compounds), three parabens, and six phenols. We used linear regression to evaluate overall and fetal sex-specific associations of biomarkers with hormones, as well as weighted quantile sum and Bayesian kernel machine regression (BKMR) to assess cumulative associations, non-linearities, and chemical interactions., Results: In women of relatively high socioeconomic status, several EDC biomarkers were associated with select hormones, without cumulative or non-linear associations with progesterone, FT4, or TT4. The biomarker mixture was negatively associated with estradiol (only at higher biomarker concentrations using BKMR), testosterone, and TSH, where each 10% mixture increase was associated with -5.65% (95% CI: -9.79, -1.28) lower testosterone and -0.09 μIU/mL (95% CI: -0.20, 0.00) lower TSH. Associations with progesterone, testosterone, and FT4 did not differ by fetal sex. However, in women carrying females, we identified an inverted u-shaped relationship of the mixture with estradiol. Additionally, in women carrying females, each 10% increase in the mixture was associated with 1.50% (95% CI: -0.15, 3.18) higher TT4, whereas in women carrying males, the mixture was associated with -1.77% (95% CI: -4.08, 0.58) lower TT4 and -0.18 μIU/mL (95% CI: -0.33, -0.03) lower TSH. We also identified select chemical interactions., Conclusion: Some biomarkers were associated with early-to-mid pregnancy hormones. There were some sex-specific and non-linear associations. Future studies could consider how these findings relate to pregnancy/birth outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)