Vicente Mustieles

Early-life exposure to plasticizer chemicals can affect child neurodevelopment. However, accurately characterizing exposure to these short-lived chemicals remains challenging. To address knowledge gaps, we examined the association between prenatal and infant exposure to a plasticizer mixture and child intelligence quotient (IQ) in a cohort with improved exposure assessment, informing the statistical analysis using the existing toxicological and epidemiological evidence. This work included 380 mother-infant pairs from the SEPAGES study, a French new-generation population-based birth cohort recruited between 2014 and 2018. Sixteen phenols and phthalate metabolites were quantified in pools of multiple urine samples collected at four time points during pregnancy and infancy (up to 21/week). Children’s IQ was assessed using the Wechsler Preschool and Primary Scale of Intelligence at age 3. A structured review of the toxicological and epidemiological evidence was conducted to prioritize the chemicals with the highest weight of evidence (WoE) to be analyzed as a mixture. Meta-analyses of the retrieved epidemiological studies were performed and used as priors in single-chemical Bayesian regression models. Of 1189 references screened, we retrieved data from 30 toxicological and 57 epidemiological studies supporting the prioritization of bisphenol A and S, diethylhexyl phthalate metabolites, monoethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), and mono-isobutyl phthalate (MiBP). Each quartile increase in maternal third-trimester concentrations of the high-WoE plasticizer mixture was associated with decreased full-scale (β: -2.86; 95% Credibility Interval, CrI: -5.05, -0.91), visual-spatial (-2.79; 95% CrI: -5.39, -0.82) and verbal (-1.95; 95% CrI: -3.84, 0.00) child IQ scores. Bayesian single-chemical models informed by meta-analysis-based priors also found that third-trimester concentrations of four of the six prioritized chemicals (bisphenol A, MEP, MnBP, and MiBP) were associated with reduced IQ scores. This novel evidence-based framework increased the biological plausibility and external validity of results, supporting that pregnancy exposure to a mixture of common plasticizers affects child IQ and represents a public health concern. The findings underscore the need to protect fetuses and children from plastic-associated chemicals and regulate them by class.

BackgroundChildren are exposed to acrylamide through diet, which may adversely impact cardiometabolic health. We investigated cross-sectional associations between urinary acrylamide metabolites and cardiometabolic health markers in children.MethodsParticipants from four HBM4EU Aligned Studies (n=1372, 6-12 years) with measured acrylamide metabolites in urine (N-acetyl-S-(2-carbamoylethyl)-L-cysteine [AAMA]), N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine [GAMA]), and cardiometabolic biomarkers (hormones, lipoproteins, lipids and liver enzymes, kisspeptin) in plasma. We used linear regression and meta-analysis to assess associations between acrylamide metabolites (AAMA and GAMA) standardised for creatinine, their sum (ΣAA) and ratio (GAMA:AAMA) and age- and sex-standardised BMI, blood pressure, waist circumference, and cardiometabolic biomarkers.ResultsEach interquartile range (IQR) increase in AAMA was associated with higher diastolic blood pressure z-score (β=0.08, 95% CI: -0.01, 0.17), larger waist circumference (β=0.07, 95% CI: -0.001, 0.13) and higher leptin z-score (β=0.12, 95% CI: 0.06, 0.17), similar for ΣAA. AAMA was not associated with BMI z-score or systolic blood pressure. GAMA was associated with 23% (95% CI: 6, 42%) higher odds of overweight/obesity, larger waist circumference (β=0.09, 95% CI: 0.01, 0.17), higher leptin (β=0.15, 95% CI: 0.09, 0.21) and triglycerides (β=0.14, 95% CI: 0.06, 0.22) z-scores. GAMA:AAMA ratio was associated with higher apolipoprotein B, total cholesterol, low-density lipoprotein cholesterol, triglycerides and phospholipids. Some sex differences were indicated.ConclusionThe results suggest a potential association between acrylamide exposure and cardiometabolic markers in children. Early-effect biomarkers provided a useful evaluation that complemented BMI and helped to identify acrylamide-related cardiometabolic associations. Longitudinal studies with long-term measures of acrylamide exposure could be useful.

Background/Objectives: Digestive cancers are among the leading causes of death worldwide. Although their etiology is not fully understood, diet is an important modifiable risk factor. This scoping review aimed to explore the existing evidence on the association between adherence to various plant-based dietary (PBD) patterns and the risk of major digestive cancers. Methods: The scoping review followed the Arksey and O’Malley framework and Joanna Briggs Institute recommendations, and results were reported according to PRISMA-ScR guidelines. A systematic search was performed in PubMed/MEDLINE, Scopus, EMBASE, and Web of Science between January 2020 and May 2025. Original observational studies and clinical trials in English or Spanish examining the association between PBD patterns and digestive cancers were included. Results: A total of 24 studies were identified, including 16 prospective cohort studies and 8 hospital-based case–control studies, conducted mainly in Europe (n = 10), North America (n = 8), and Asia (n = 6). Most studies used food frequency questionnaires and predefined PBD indices, particularly the plant-based diet index (PDI), healthful (hPDI), and unhealthful (uPDI) (n = 13), while others assessed pro-vegetarian (n = 2) or EAT-Lancet dietary patterns (n = 3). Most studies reported protective associations with all digestive cancer localizations examined, particularly in relation to healthful PBD patterns: colorectal (13/15), pancreatic (6/7), liver (4/4), esophageal (4/5), stomach (3/4) and oropharyngeal (2/2) cancers. On the contrary, unhealthful PBD patterns were linked to a higher risk. Conclusions: Overall, the findings of this review highlight that the quality of PBD patterns is crucial for digestive cancer risk. PBD patterns emphasizing whole and minimally processed plant foods were protective, while those characterized by refined or ultra-processed plant products were deleterious. A future standardization of PBD indices would help to improve comparability among studies.

Trihalomethanes (THMs), the leading species of disinfection byproducts in chlorinated tap water, have demonstrated cardiovascular toxicity. However, the association between THM exposure and blood pressure (BP) among pregnant women remains unclear. This study included 1456 women from a Chinese prospective birth cohort. We determined blood THM concentrations [chloroform (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and bromoform (TBM)] across pregnancy trimesters (n = 3642) and repeatedly measured BP throughout pregnancy (n = 5816) and during postpartum (n = 1062). Blood concentrations of TCM and chlorinated THMs (Cl-THMs; the sum of TCM, BDCM, and DBCM) in the second, but not first, trimester were positively associated with gestational diastolic BP and mean arterial pressure (MAP). Additionally, women with higher second-trimester blood concentrations of brominated THMs (the sum of BDCM, DBCM, and TBM) and total THMs (TTHM; the sum of 4 THM) had an increased risk of experiencing a sharply rising MAP throughout pregnancy. Second-trimester blood concentrations of TCM, Cl-THMs, and TTHMs were positively associated with the risk of hypertension during pregnancy, particularly among women carrying male fetuses. However, blood concentrations of THMs were unrelated to postpartum BP. In summary, THM exposure in the second trimester may be associated with elevated BP and a greater risk of hypertension during pregnancy.

Brain-derived neurotrophic factor (BDNF) and its isoforms (pro- and mBDNF) are promising neurobiomarkers. While total serum BDNF levels have been previously validated, the newer isoforms have not. We aimed to identify the most common serum pro- and mBDNF assays through a literature search (MEDLINE/PubMed, until March 2024), and to compare their methodological performance in 23 human serum samples [total BDNF: R&D Systems, #DBNT00; both isoforms: R&DSystems (#DY3175, #DBD00); Aviscera-Bioscience (#SK00752-09, #SK00752-01); FineTest (#EH4255, #EH0043)]. Western-blot and cross-reactivity assays were used to confirm whether the kits tested for the declared isoforms. The total BDNF (#DBNT00) and pro-BDNF (#DY3175) ELISA kits from R&D Systems, and the pro-BDNF ELISA kits from FineTest (#EH4255) and Aviscera-Bioscience (#SK00752-01) showed high specificity, sensitivity, accuracy, and reproducibility. None of the commercial brands tested for mBDNF quantification showed optimal specificity, although R&D Systems (#DBD00) showed an acceptable result. Additionally, comparison of serum mBDNF levels by direct measurement and estimation (total minus pro-BDNF) using the three R&D Systems kits in the 23 serum samples showed acceptable variation (± 15%). This work indicated that there is a need to continue improving the specificity of some ELISA kits, mainly those measuring mBDNF. Total, pro- and m-BDNF serum levels can be quantified using the R&D Systems kits, whereas pro-BDNF serum levels could, in principle, be measured using any of the three brands evaluated.

Based on toxicological evidence, children’s exposure to phthalates may contribute to altered neurodevelopment and abnormal regulation of brain-derived neurotrophic factor (BDNF). We analyzed data from five aligned studies of the Human Biomonitoring for Europe (HBM4EU) project. Ten phthalate metabolites and protein BDNF levels were measured in the urine samples of 1148 children aged 6–12 years from Italy (NACII-IT cohort), Slovakia (PCB-SK cohort), Hungary (InAirQ-HU cohort) and Norway (NEBII-NO). Serum BDNF was also available in 124 Slovenian children (CRP-SLO cohort). Children’s total, externalizing and internalizing behavioral problems were assessed using the Child Behavior Checklist at 7 years of age (only available in the NACII-IT cohort). Adjusted linear and negative binomial regression models were fitted, together with weighted quantile sum (WQS) regression models to assess phthalate mixture associations. Results showed that, in boys but not girls of the NACII-IT cohort, each natural-log-unit increase in mono-n-butyl phthalate (MnBP) and Mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) was cross-sectionally associated with higher externalizing problems [incidence rate ratio (IRR): 1.20; 95% CI: 1.02, 1.42 and 1.26; 95% CI: 1.03, 1.55, respectively]. A suggestive mixture association with externalizing problems was also observed per each tertile mixture increase in the whole population (WQS—IRR = 1.15; 95% CI: 0.97, 1.36) and boys (IRR = 1.20; 95% CI: 0.96, 1.49). In NACII-IT, PCB-SK, InAirQ-HU and NEBII-NO cohorts together, urinary phthalate metabolites were strongly associated with higher urinary BDNF levels, with WQS regression confirming a mixture association in the whole population (percent change (PC) = 25.9%; 95% CI: 17.6, 34.7), in girls (PC = 18.6%; 95% CI: 7.92, 30.5) and mainly among boys (PC = 36.0%; 95% CI: 24.3, 48.9). Among CRP-SLO boys, each natural-log-unit increase in ∑DINCH concentration was associated with lower serum BDNF levels (PC: −8.8%; 95% CI: −16.7, −0.3). In the NACII-IT cohort, each natural-log-unit increase in urinary BDNF levels predicted worse internalizing scores among all children (IRR: 1.15; 95% CI: 1.00, 1.32). Results suggest that (1) children’s exposure to di-n-butyl phthalate (DnBP) and di(2-ethylhexyl) phthalate (DEHP) metabolites is associated with more externalizing problems in boys, (2) higher exposure to DINCH may associate with lower systemic BDNF levels in boys, (3) higher phthalate exposure is associated with higher urinary BDNF concentrations (although caution is needed since the possibility of a “urine concentration bias” that could also explain these associations in noncausal terms was identified) and (4) higher urinary BDNF concentrations may predict internalizing problems. Given this is the first study to examine the relationship between phthalate metabolite exposure and BDNF biomarkers, future studies are needed to validate the observed associations.