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Additional file 1: Study population. Each year, the ENVIRONAGE birth cohort [29] recruits around 150 singleton births, making it the largest birth cohort with a prospective follow-up in Belgium. Mothers without planned caesarean section and able to fill out a Dutch language questionnaire are eligible for the cohort. We collect biological samples (e.g. placental tissue, cord blood, maternal blood) and have access to all medical records during and after pregnancy, including anthropometric and foetal ultrasound data in addition to lifestyle factors derived from questionnaires filled out after delivery. After birth, we follow these children throughout different stages of life, with a first follow-up visit at the age of 4 – 6 years. During follow-up, we collect biological tissues, lifestyle and medical data, and perform clinical and neurological measurements of both the child and the mother. Measurement of mitochondrial DNA content. DNA was isolated from cord blood buffy coat, containing leukocytes, using the QIAamp DNA mini kit (Qiagen). The relative amount of mtDNA was measured by determining the ratio of two mitochondrial gene copy numbers (MTF3212/R3319 and MT-ND1) to a single-copy nuclear control gene (RPLP0) using a real-time quantitative polymerase chain reaction (qPCR). qPCR reactions were carried out in triplicate on a 384-well plate on the 7900HT Fast Real-Time PCR System (Applied Biosystems) in a 10 μl volume containing: 5 μl Fast SYBR Green (Applied Biosystems) mastermix, 0.3 μl of forward and reverse primers (300 nM) and 1.9 μl RNAse-free water and 6 ng DNA diluted in 2.5 μl RNAse-free water. Primer sequences for mitochondrial genes are reported elsewhere [16]. Six interrun calibrators and no-template controls were included in each qPCR run. The thermal cycling profile for the three targets was 10 min at 95 °C for activation of the polymerase enzyme and initial denaturation, followed by 40 cycles of 15 s at 94 °C for denaturation and 70 s at 58 °C for annealing and extension. After thermal cycling, the raw data were collected and processed using SDS 2.3 software (Applied Biosystems). The cycle quantification (Cq) values were normalized relatively to the RPLP0 gene using qBase + software (Biogazelle) taking into account the run-to-run differences [69]. Supplementary Table S1. Sex- and age-specific BMI cut-offs according to the International Obesity Task Force (IOTF) [30]. Supplementary Table S2. The trimester-specific association between prenatal PM2.5 exposure and childhood overweight (n = 368). Models were adjusted for gestational age, sex, ethnicity, maternal age, socioeconomic status, pre-pregnancy BMI, parity, smoking during pregnancy, and child’s age at follow-up. Trimester-specific estimates of change are given as odds ratio per 5 µg/m³ increment in PM2.5. Childhood overweight was defined based on WHO’s SD BMI scores: > sex- and age-specific BMI cut-offs according to the International Obesity Task Force (IOTF) [30]. Supplementary Table S3. Difference in childhood overweight in association with week-specific prenatal exposure to PM2.5 (n = 368). Models were adjusted for gestational age, sex, ethnicity, maternal age, socioeconomic status, pre-pregnancy BMI, parity, smoking during pregnancy, and child’s age at follow-up. Week-specific estimates of change are given as odds ratio per 5 µg/m³ increment in PM2.5. Supplementary Table S4. The trimester-specific association between prenatal PM2.5 exposure and cord blood MT-ND4L10550A>G heteroplasmy (n = 386). Models were adjusted for gestational age, sex, ethnicity, maternal age, SES, pre-pregnancy BMI, parity, season of delivery, smoking during pregnancy, cord blood mtDNA content, and maternal MT-ND4L10550A>G. Trimester-specific estimates are given as odds ratio per 5 µg/m³ increment in PM2.5. Supplementary Table S5. Difference in cord blood MT-ND4L10550A>G heteroplasmy in association with week-specific prenatal exposure to PM2.5 (n = 386). Models were adjusted for gestational age, sex, ethnicity, maternal age, socioeconomic status, pre-pregnancy BMI, parity, season of delivery, smoking during pregnancy, cord blood mtDNA content, and maternal MT-ND4L10550A>G. Week-specific estimates are given as odds ratio per 5 µg/m³ increment in PM2.5. Supplementary Table S6. Difference in cord blood MT-ND4L10550A>G in association with week-specific prenatal exposure to PM2.5 without mothers who smoked during pregnancy (n = 345). Models were adjusted for gestational age, sex, ethnicity, maternal age, socioeconomic status, pre-pregnancy BMI, parity, season of delivery, cord blood mtDNA content, and maternal MT-ND4L10550A>G. Week-specific estimates are given as odds ratio per 5 µg/m³ increment in PM2.5. Supplementary Figure S1. Flowchart study population selection. The ENVIRONAGE birth cohort included 1993 mother-child pairs until March 2021. The study population (n = 400) was recruited between February 2010 and December 2015. The association between prenatal PM2.5 exposure and cord blood MT-ND4L10550A>G was analyzed for 386 mother-newborn pairs. The association between prenatal PM2.5 exposure or cord blood MT-ND4L10550A>G and childhood overweight was analyzed for 368 mother-newborn pairs. The mediation analysis was performed on 355 mother-child pairs. Supplementary Figure S2. Variation in cord blood MT-ND4L10550A>G heteroplasmy level (n = 400), ordered by study ID.

Additional file 1: Table S1. Maternal and neonate characteristics of 1) the original population of 794 mother-neonate pairs who were enrolled in the ENVIRONAGE birth cohort between March 1st, 2013 and April 1st, 2017; 2) The randomly selected population (n = 498) for which we had placental iodine concentrations; and 3) the final study population (n = 471) after exclusion of preterm births, pre-eclamptic pregnancies, and mothers with thyroid problems.

Planarians, such as Schmidtea mediterranea, are flatworms that are capable of regenerating any missing body region. They show an extensive regenerative ability and are able to circumvent tumor formation. Even under strong carcinogenic conditions, tumors were never observed. Regeneration in S. mediterranea is due to undifferentiated pluripotent stem cells. It is likely that these adult stem cells have a role in the evasion of tumor formation. The process of regeneration is mediated by neoblasts, which is a proliferative cell population that contains pluripotent stem cells. We hypothesized that during carcinogenic exposure in S. mediterranea, pluripotent stem cells activate specific damage responses to provoke the circumvention of carcinogenesis. Focusing on differentiation processes and DNA repair, it could be that stem cells with high potency have better DNA repair mechanisms, explaining the effective response to carcinogens. To address this hypothesis, in vivo experiments were performed to define whether the differentiation process is altered after carcinogen exposure and whether DNA repair mechanisms play a role in this alteration. Since stem cells possibly play an important role in the circumvention of cancer and to support this in vivo approach, cell culture conditions were optimized.

Additional file 2: Table S2. Maternal and neonate characteristics of the current study group (n = 471) compared with a reference population of births in Flanders, Belgium (born 2002 until 2011; n = 606,877).

Additional file 2: Table S2. Maternal and neonate characteristics of the current study group (n = 471) compared with a reference population of births in Flanders, Belgium (born 2002 until 2011; n = 606,877).

Background Mitochondria play an important role in the energy metabolism and are susceptible to environmental pollution. Prenatal air pollution exposure has been linked with childhood obesity. Placental mtDNA mutations have been associated with prenatal particulate matter exposure and MT-ND4L10550A>G heteroplasmy has been associated with BMI in adults. Therefore, we hypothesized that in utero PM2.5 exposure is associated with cord blood MT-ND4L10550A>G heteroplasmy and early life growth. In addition, the role of cord blood MT-ND4L10550A>G heteroplasmy in overweight during early childhood is investigated. Methods This study included 386 mother-newborn pairs. Outdoor PM2.5 concentrations were determined at the maternal residential address. Cord blood MT-ND4L10550A>G heteroplasmy was determined using Droplet Digital PCR. Associations were explored using logistic regression models and distributed lag linear models. Mediation analysis was performed to quantify the effects of prenatal PM2.5 exposure on childhood overweight mediated by cord blood MT-ND4L10550A>G heteroplasmy. Results Prenatal PM2.5 exposure was positively associated with childhood overweight during the whole pregnancy (OR = 2.33; 95% CI: 1.20 to 4.51; p = 0.01), which was mainly driven by the second trimester. In addition, prenatal PM2.5 exposure was associated with cord blood MT-ND4L10550A>G heteroplasmy from gestational week 9 – 13. The largest effect was observed in week 10, where a 5 µg/m3 increment in PM2.5 was linked with cord blood MT-ND4L10550A>G heteroplasmy (OR = 0.93; 95% CI: 0.87 to 0.99). Cord blood MT-ND4L10550A>G heteroplasmy was also linked with childhood overweight (OR = 3.04; 95% CI: 1.15 to 7.50; p = 0.02). The effect of prenatal PM2.5 exposure on childhood overweight was mainly direct (total effect OR = 1.18; 95% CI: 0.99 to 1.36; natural direct effect OR = 1.20; 95% CI: 1.01 to 1.36)) and was not mediated by cord blood MT-ND4L10550A>G heteroplasmy. Conclusions Cord blood MT-ND4L10550A>G heteroplasmy was linked with childhood overweight. In addition, in utero exposure to PM2.5 during the first trimester of pregnancy was associated with cord blood MT-ND4L10550A>G heteroplasmy in newborns. Our analysis did not reveal any mediation of cord blood MT-ND4L10550A>G heteroplasmy in the association between PM2.5 exposure and childhood overweight.

Background The micronutrient iodine is essential for a healthy intrauterine environment and is required for optimal fetal growth and neurodevelopment. Evidence linking urinary iodine concentrations, which mainly reflects short-term iodine intake, to gestational diabetes mellitus (GDM) is inconclusive. Although the placental concentrations would better reflect the long-term gestational iodine status, no studies to date have investigated the association between the placental iodine load and the risk at GDM. Moreover, evidence is lacking whether placental iodine could play a role in biomarkers of insulin resistance and β-cell activity. Methods We assessed the incidence of GDM between weeks 24 and 28 of gestation for 471 mother-neonate pairs from the ENVIRONAGE birth cohort. In placentas, we determined the iodine concentrations. In maternal and cord blood, we measured the insulin concentrations, the Homeostasis Model Assessment (HOMA) for insulin resistance (IR) index, and β-cell activity. Logistic regression was used to estimate the odds ratios (OR) of GDM, and the population attributable factor (PAF) was calculated. Generalized linear models estimated the changes in insulin, HOMA-IR, and β-cell activity for a 5 μg/kg increase in placental iodine. Results Higher placental iodine concentrations decreased the risk at GDM (OR = 0.82; 95%CI 0.72 to 0.93; p = 0.003). According to the PAF, 54.2% (95%CI 11.4 to 82.3%; p = 0.0006) of the GDM cases could be prevented if the mothers of the lowest tertile of placental iodine would have placental iodine levels as those belonging to the highest tertile. In cord blood, the plasma insulin concentration was inversely associated with the placental iodine load (β = − 4.8%; 95%CI − 8.9 to − 0.6%; p = 0.026). Conclusions Higher concentrations of placental iodine are linked with a lower incidence of GDM. Moreover, a lower placental iodine load is associated with an altered plasma insulin concentration, HOMA-IR index, and β-cell activity. These findings postulate that a mild-to-moderate iodine deficiency could be linked with subclinical and early-onset alterations in the normal insulin homeostasis in healthy pregnant women. Nevertheless, the functional link between gestational iodine status and GDM warrants further research.

Background/Aim: Glyphosate, a broad-spectrum herbicide, and its main metabolite aminomethylphosphonic acid (AMPA) are persistent in the environment. Studies showed associations between glyphosate or AMPA exposure and several adverse cellular processes, including metabolic alterations and oxidative stress.& nbsp;Objective: To determine the association between glyphosate and AMPA exposure and biomarkers of biological aging.& nbsp;Methods: We examined glyphosate and AMPA exposure, mtDNA content and leukocyte telomere length in 181 adults, included in the third cycle of the Flemish Environment and Health Study (FLEHSIII). DNA was isolated from leukocytes and the relative mtDNA content and telomere length were determined using qPCR. Urinary glyphosate and AMPA concentrations were measured by Gas Chromatography-Tandem Mass Spectrometry (GC-MS-MS). We used multiple linear regression models to associate mtDNA content and leukocyte telomere length with glyphosate or AMPA exposure while adjusting for confounding variables.& nbsp;Results: A doubling in urinary AMPA concentration was associated with 5.19% (95% CI: 0.49 to 10.11; p = 0.03) longer leukocyte telomere length, while no association was observed with urinary glyphosate concentration. No association between mtDNA content and urinary glyphosate nor AMPA levels was observed.& nbsp;Conclusions: This study showed that AMPA exposure may be associated with telomere biology in adults.

Simple Summary Multiple myeloma (MM), characterized by the expansion of plasma cells in the bone marrow, is the second most common hematological malignancy. This incurable cancer is consistently preceded by non-malignant asymptomatic precursor conditions known as monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). These pre-stages are relatively frequent, but only a select percentage of them will progress to MM. However, it is still not possible to individually predict when and which patients will develop MM. Therefore, this study aimed to investigate the mutational profile in the progression in serial bone marrow samples with a custom targeted sequencing panel, designed to detect variants in myeloma-related genes. Remarkably, almost all variants identified in the MM samples were also already present in the pre-stages, sometimes even many years before the progression. These results provide new important insights into the molecular mechanisms of the precursor conditions and progression to MM. Multiple myeloma (MM), or Kahler's disease, is an incurable plasma cell (PC) cancer in the bone marrow (BM). This malignancy is preceded by one or more asymptomatic precursor conditions, monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). The molecular mechanisms and exact cause of this progression are still not completely understood. In this study, the mutational profile underlying the progression from low-intermediate risk myeloma precursor conditions to MM was studied in serial BM smears. A custom capture-based sequencing platform was developed, including 81 myeloma-related genes. The clonal evolution of single nucleotide variants and short insertions and deletions was studied in serial BM smears from 21 progressed precursor patients with a median time of progression of six years. From the 21 patients, four patients had no variation in one of the 81 studied genes. Interestingly, in 16 of the 17 other patients, at least one variant present in MM was also detected in its precursor BM, even years before progression. Here, the variants were present in the pre-stage at a median of 62 months before progression to MM. Studying these paired BM samples contributes to the knowledge of the evolutionary genetic landscape and provides additional insight into the mutational behavior of mutant clones over time throughout progression. The authors thank all members of the University Biobank Limburg, Clinical Biobank and Laboratory for Molecular Diagnostics (Jessa Hospital, Hasselt, Belgium) fortheir assistance