Per- and polyfluoroalkyl substances, polychlorinated biphenyls, organochlorine pesticides, and polybrominated diphenyl ethers and dysregulation of MicroRNA expression in humans and animals-A systematic review.

BACKGROUND: Persistent organic pollutants (POPs) are chemicals characterized by their environmental persistence. Evidence suggests that exposure to POPs, which is ubiquitous, is associated with microRNA (miRNA) dysregulation. miRNA are key regulators in many physiological processes. It is thus of public health concern to understand the relationships between POPs and miRNA as related to health outcomes. OBJECTIVES: This systematic review evaluated the relationship between widely recognized, intentionally manufactured, POPs, including per- and polyfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and organochlorine pesticides (dichlorodiphenyltrichloroethane [DDT], dichlorodiphenyldichloroethylene [DDE], hexachlorobenzene [HCB]), with miRNA expression in both human and animal studies. METHODS: We used PubMed and Embase to systematically search the literature up to September 29th, 2023. Search results for human and animal studies were included if they incorporated at least one POP of interest in relation to at least one miRNA. Data were synthesized to determine the direction and significance of associations between POPs and miRNA. We utilized ingenuity pathway analysis to review disease pathways for miRNA that were associated with POPs. RESULTS: Our search identified 38 eligible studies: 9 in humans and 29 in model organisms. PFAS were associated with decreased expression of miR-19, miR-193b, and miR-92b, as well as increased expression of miR-128, miR-199a-3p, and miR-26b across species. PCBs were associated with increased expression of miR-15a, miR-1537, miR-21, miR-22-3p, miR-223, miR-30b, and miR-34a, as well as decreased expression of miR-130a and let-7b in both humans and animals. Pathway analysis for POP-associated miRNA identified pathways related to carcinogenesis. DISCUSSION: This is the first systematic review of the association of POPs with miRNA in humans and model organisms. Large-scale prospective human studies are warranted to examine the role of miRNA as mediators between POPs and health outcomes.

Exposure to perfluoroalkyl substances and longitudinal changes in bone mineral density in adolescents and young adults: A multi-cohort study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) may impair bone development in adolescence, which impacts life-long bone health. No previous studies have examined prospective associations of individual PFAS and their mixture with bone mineral density (BMD) changes in Hispanic young persons, a population at high risk of osteoporosis in adulthood. OBJECTIVES: To examine associations of individual PFAS and PFAS mixtures with longitudinal changes in BMD in an adolescent Hispanic cohort and examine generalizability of findings in a mixed-ethnicity young adult cohort (58.4% Hispanic). METHODS: Overweight/obese adolescents from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR; n = 304; mean follow-up = 1.4 years) and young adults from the Southern California Children's Health Study (CHS; n = 137; mean follow-up = 4.1 years) were included in this study. Plasma PFAS were measured at baseline and dual x-ray absorptiometry scans were performed at baseline and follow-up to measure BMD. We estimated longitudinal associations between BMD and five PFAS via separate covariate-adjusted linear mixed effects models, and between BMD and the PFAS mixture via quantile g-computation. RESULTS: In SOLAR adolescents, baseline plasma perfluorooctanesulfonic acid (PFOS) was associated with longitudinal changes in BMD. Each doubling of PFOS was associated with an average -0.003 g/cm2 difference in change in trunk BMD per year over follow-up (95% CI: -0.005, -0.0002). Associations with PFOS persisted in CHS young adults, where each doubling of plasma PFOS was associated with an average -0.032 g/cm2 difference in total BMD at baseline (95% CI -0.062, -0.003), though longitudinal associations were non-significant. We did not find associations of other PFAS with BMD; associations of the PFAS mixture with BMD outcomes were primarily negative though non-significant. DISCUSSION: PFOS exposure was associated with lower BMD in adolescence and young adulthood, important periods for bone development, which may have implications on future bone health and risk of osteoporosis in adulthood.

Exposure to per- and polyfluoroalkyl substances and alterations in plasma microRNA profiles in children.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that persist in the environment and can accumulate in humans, leading to adverse health effects. MicroRNAs (miRNAs) are emerging biomarkers that can advance the understanding of the mechanisms of PFAS effects on human health. However, little is known about the associations between PFAS exposures and miRNA alterations in humans. OBJECTIVE: To investigate associations between PFAS concentrations and miRNA levels in children. METHODS: Data from two distinct cohorts were utilized: 176 participants (average age 16.6 years; 75.6% female) from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort in the United States, and 64 participants (average age 6.5 years, 39.1% female) from the Rhea study, a mother-child cohort in Greece. PFAS concentrations and miRNA levels were assessed in plasma samples from both studies. Associations between individual PFAS and plasma miRNA levels were examined after adjusting for covariates. Additionally, the cumulative effects of PFAS mixtures were evaluated using an exposure burden score. Ingenuity Pathways Analysis was employed to identify potential disease functions of PFAS-associated miRNAs. RESULTS: Plasma PFAS concentrations were associated with alterations in 476 miRNAs in the Teen-LABs study and 13 miRNAs in the Rhea study (FDR p < 0.1). Specifically, plasma PFAS concentrations were consistently associated with decreased levels of miR-148b-3p and miR-29a-3p in both cohorts. Pathway analysis indicated that PFAS-related miRNAs were linked to numerous chronic disease pathways, including cardiovascular diseases, inflammatory conditions, and carcinogenesis. CONCLUSION: Through miRNA screenings in two independent cohorts, this study identified both known and novel miRNAs associated with PFAS exposure in children. Pathway analysis revealed the involvement of these miRNAs in several cancer and inflammation-related pathways. Further studies are warranted to enhance our understanding of the relationships between PFAS exposure and disease risks, with miRNA emerging as potential biomarkers and/or mediators in these complex pathways.

Machine Learning Assisted Discovery of Interactions between Pesticides, Phthalates, Phenols, and Trace Elements in Child Neurodevelopment.

A growing body of literature suggests that developmental exposure to individual or mixtures of environmental chemicals (ECs) is associated with autism spectrum disorder (ASD). However, investigating the effect of interactions among these ECs can be challenging. We introduced a combination of the classical exposure-mixture Weighted Quantile Sum (WQS) regression and a machine-learning method termed Signed iterative Random Forest (SiRF) to discover synergistic interactions between ECs that are (1) associated with higher odds of ASD diagnosis, (2) mimic toxicological interactions, and (3) are present only in a subset of the sample whose chemical concentrations are higher than certain thresholds. In a case-control Childhood Autism Risks from Genetics and Environment (CHARGE) study, we evaluated multiordered synergistic interactions among 62 ECs measured in the urine samples of 479 children in association with increased odds for ASD diagnosis (yes vs no). WQS-SiRF identified two synergistic two-ordered interactions between (1) trace-element cadmium (Cd) and the organophosphate pesticide metabolite diethyl-phosphate (DEP); and (2) 2,4,6-trichlorophenol (TCP-246) and DEP. Both interactions were suggestively associated with increased odds of ASD diagnosis in the subset of children with urinary concentrations of Cd, DEP, and TCP-246 above the 75th percentile. This study demonstrates a novel method that combines the inferential power of WQS and the predictive accuracy of machine-learning algorithms to discover potentially biologically relevant chemical-chemical interactions associated with ASD.

Paired Liver:Plasma PFAS Concentration Ratios from Adolescents in the Teen-LABS Study and Derivation of Empirical and Mass Balance Models to Predict and Explain Liver PFAS Accumulation.

Animal studies have pointed at the liver as a hotspot for per- and polyfluoroalkyl substances (PFAS) accumulation and toxicity; however, these findings have not been replicated in human populations. We measured concentrations of seven PFAS in matched liver and plasma samples collected at the time of bariatric surgery from 64 adolescents in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. Liver:plasma concentration ratios were perfectly explained (r2 > 0.99) in a multilinear regression (MLR) model based on toxicokinetic (TK) descriptors consisting of binding to tissue constituents and membrane permeabilities. Of the seven matched plasma and liver PFAS concentrations compared in this study, the liver:plasma concentration ratio of perfluoroheptanoic acid (PFHpA) was considerably higher than the liver:plasma concentration ratio of other PFAS congeners. Comparing the MLR model with an equilibrium mass balance model (MBM) suggested that complex kinetic transport processes are driving the unexpectedly high liver:plasma concentration ratio of PFHpA. Intratissue MBM modeling pointed to membrane lipids as the tissue constituents that drive the liver accumulation of long-chain, hydrophobic PFAS, whereas albumin binding of hydrophobic PFAS dominated PFAS distribution in plasma. The liver:plasma concentration data set, empirical MLR model, and mechanistic MBM modeling allow the prediction of liver from plasma concentrations measured in human cohort studies. Our study demonstrates that combining biomonitoring data with mechanistic modeling can identify underlying mechanisms of internal distribution and specific target organ toxicity of PFAS in humans.

Gene-environment interactions in the associations of PFAS exposure with insulin sensitivity and beta-cell function in a Faroese cohort followed from birth to adulthood.

BACKGROUND: Exposure to perfluoroalkyl substances (PFAS) has been associated with changes in insulin sensitivity and pancreatic beta-cell function in humans. Genetic predisposition to diabetes may modify these associations; however, this hypothesis has not been yet studied. OBJECTIVES: To evaluate genetic heterogeneity as a modifier in the PFAS association with insulin sensitivity and pancreatic beta-cell function, using a targeted gene-environment (GxE) approach. METHODS: We studied 85 single-nucleotide polymorphisms (SNPs) associated with type 2 diabetes, in 665 Faroese adults born in 1986-1987. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were measured in cord whole blood at birth and in participants' serum from age 28 years. We calculated the Matsuda-insulin sensitivity index (ISI) and the insulinogenic index (IGI) based on a 2 h-oral glucose tolerance test performed at age 28. Effect modification was evaluated in linear regression models adjusted for cross-product terms (PFAS*SNP) and important covariates. RESULTS: Prenatal and adult PFOS exposures were significantly associated with decreased insulin sensitivity and increased beta-cell function. PFOA associations were in the same direction but attenuated compared to PFOS. A total of 58 SNPs were associated with at least one PFAS exposure variable and/or Matsuda-ISI or IGI in the Faroese population and were subsequently tested as modifiers in the PFAS-clinical outcome associations. Eighteen SNPs showed interaction p-values (PGxE) < 0.05 in at least one PFAS-clinical outcome association, five of which passed False Discovery Rate (FDR) correction (PGxE-FDR<0.20). SNPs for which we found stronger evidence for GxE interactions included ABCA1 rs3890182, FTO rs9939609, FTO rs3751812, PPARG rs170036314 and SLC12A3 rs2289116 and were more clearly shown to modify the PFAS associations with insulin sensitivity, rather than with beta-cell function. DISCUSSION: Findings from this study suggest that PFAS-associated changes in insulin sensitivity could vary between individuals as a result of genetic predisposition and warrant replication in independent larger populations.

Transmission and Risk Factors of COVID-19 among Health Care Workers.

Coronavirus disease 2019 (COVID-19) poses a significant occupational risk factor to health care workers (HCWs). As in previous events, this occupational risk amplifies and compounds the adverse impact of the pandemic. We conducted a narrative review summarizing risk factors associated with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) transmission in HCWs. We searched for original observational studies (including case-control, cross-sectional, prospective and retrospective cohorts) using PubMed, Scopus, and Google Scholar. A total of 22 articles were reviewed, including eligible English articles published between April 2020 and May 2022. Job category, work environment, personal protective equipment (PPE) noncompliance, lack of PPE awareness and training, unvaccinated status, and competing community and household exposures were identified as risk factors for SARS-CoV-2 transmission among HCWs. Effective measures to protect HCWs from SARS-CoV-2 need to account for the identified occupational risk factors. Identifying and understanding COVID-19 risk factors among HCWs must be considered a public health priority for policy makers to mitigate occupational and community transmission in current and future epidemics.

In Utero Exposure to Mercury Is Associated With Increased Susceptibility to Liver Injury and Inflammation in Childhood.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of liver disease in children. Mercury (Hg), a ubiquitous toxic metal, has been proposed as an environmental factor contributing to toxicant-associated fatty liver disease. APPROACH AND RESULTS: We investigated the effect of prenatal exposure to Hg on childhood liver injury by combining epidemiological results from a multicenter mother-child cohort with complementary in vitro experiments on monocyte cells that are known to play a key role in liver immune homeostasis and NAFLD. We used data from 872 mothers and their children (median age, 8.1 years; interquartile range [IQR], 6.5-8.7) from the European Human Early-Life Exposome cohort. We measured Hg concentration in maternal blood during pregnancy (median, 2.0 µg/L; IQR, 1.1-3.6). We also assessed serum levels of alanine aminotransferase (ALT), a common screening tool for pediatric NAFLD, and plasma concentrations of inflammation-related cytokines in children. We found that prenatal Hg exposure was associated with a phenotype in children that was characterized by elevated ALT (≥22.1 U/L for females and ≥25.8 U/L for males) and increased concentrations of circulating IL-1ß, IL-6, IL-8, and TNF-α. Consistently, inflammatory monocytes exposed in vitro to a physiologically relevant dose of Hg demonstrated significant up-regulation of genes encoding these four cytokines and increased concentrations of IL-8 and TNF-α in the supernatants. CONCLUSIONS: These findings suggest that developmental exposure to Hg can contribute to inflammation and increased NAFLD risk in early life.

Plasma concentrations of lipophilic persistent organic pollutants and glucose homeostasis in youth populations.

BACKGROUND: Exposure to lipophilic persistent organic pollutants (POPs) is ubiquitous. POPs are metabolic disrupting chemicals and are potentially diabetogenic. METHODS: Using a multi-cohort study including overweight adolescents from the Study of Latino Adolescents at Risk (SOLAR, N = 301, 2001-2012) and young adults from the Southern California Children's Health Study (CHS, N = 135, 2014-2018), we examined associations of POPs and risk factors for type 2 diabetes. SOLAR participants underwent annual visits for a median of 2.2 years and CHS participants performed a single visit, during which a 2-h oral glucose tolerance test was performed. Linear mixed models were used to examine associations between plasma concentrations of POPs [4,4'-dichlorodiphenyldichloroethylene (4,4'-DDE), hexachlorobenzene (HCB), PCBs-153, 138, 118, 180 and PBDEs-154, 153, 100, 85, 47] and changes in glucose homeostasis across age and pubertal stage. RESULTS: In SOLAR, exposure to HCB, PCB-118, and PBDE-153 was associated with dysregulated glucose metabolism. For example, each two-fold increase in HCB was associated with approximately 2 mg/dL higher glucose concentrations at 30 min (p = 0.001), 45 min (p = 0.0006), and 60 min (p = 0.03) post glucose challenge. Compared to individuals with low levels of PCB-118, individuals with high levels exhibited a 4.7 mg/dL (p = 0.02) higher glucose concentration at 15 min and a 3.6 mg/dL (p = 0.01) higher glucose concentration at 30 min. The effects observed with exposure to organochlorine compounds were independent of pubertal stages. PBDE-153 was associated with the development of dysregulated glucose metabolism beginning in late puberty. At Tanner stage 4, exposure to PBDE-153 was associated with a 12.7 mg/dL higher 60-min glucose concentration (p = 0.009) and a 16.1 mg*dl-1*hr-1 higher glucose AUC (p = 0.01). These associations persisted at Tanner 5. In CHS, PBDE-153 and total PBDE were associated with similar increases in glucose concentrations. CONCLUSION: Our results suggest that childhood exposure to lipophilic POPs is associated with dysregulated glucose metabolism.

Prenatal Exposure to Perfluoroalkyl Substances Associated With Increased Susceptibility to Liver Injury in Children.

BACKGROUND AND AIMS: Per- and polyfluoroalkyl substances (PFAS) are widespread and persistent pollutants that have been shown to have hepatotoxic effects in animal models. However, human evidence is scarce. We evaluated how prenatal exposure to PFAS associates with established serum biomarkers of liver injury and alterations in serum metabolome in children. APPROACH AND RESULTS: We used data from 1,105 mothers and their children (median age, 8.2 years; interquartile range, 6.6-9.1) from the European Human Early-Life Exposome cohort (consisting of six existing population-based birth cohorts in France, Greece, Lithuania, Norway, Spain, and the United Kingdom). We measured concentrations of perfluorooctane sulfonate, perfluorooctanoate, perfluorononanoate, perfluorohexane sulfonate, and perfluoroundecanoate in maternal blood. We assessed concentrations of alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase in child serum. Using Bayesian kernel machine regression, we found that higher exposure to PFAS during pregnancy was associated with higher liver enzyme levels in children. We also measured child serum metabolomics through a targeted assay and found significant perturbations in amino acid and glycerophospholipid metabolism associated with prenatal PFAS. A latent variable analysis identified a profile of children at high risk of liver injury (odds ratio, 1.56; 95% confidence interval, 1.21-1.92) that was characterized by high prenatal exposure to PFAS and increased serum levels of branched-chain amino acids (valine, leucine, and isoleucine), aromatic amino acids (tryptophan and phenylalanine), and glycerophospholipids (phosphatidylcholine [PC] aa C36:1 and Lyso-PC a C18:1). CONCLUSIONS: Developmental exposure to PFAS can contribute to pediatric liver injury.

The Association of Mediterranean Diet during Pregnancy with Longitudinal Body Mass Index Trajectories and Cardiometabolic Risk in Early Childhood.

OBJECTIVE: To evaluate the associations between maternal adherence to the Mediterranean diet during pregnancy and their offspring's longitudinal body mass index (BMI) trajectories and cardiometabolic risk in early childhood. STUDY DESIGN: We included mother-child pairs from the Infancia y Medio Ambiente (INMA) longitudinal cohort study in Spain. We measured dietary intake during pregnancy using a validated food frequency questionnaire and calculated the relative Mediterranean diet score (rMED). We estimated offspring's BMI z score trajectories from birth to age 4 years using latent class growth analyses (n = 2195 mother-child pairs). We measured blood pressure, waist circumference, and cardiometabolic biomarkers to construct a cardiometabolic risk score at 4 years (n = 697 mother-child pairs). We used multivariable adjusted linear and multinomial regression models. RESULTS: A higher maternal rMED in pregnancy was associated with a lower risk in offspring of larger birth size, followed by accelerated BMI gain (reference trajectory group: children with average birth size and subsequent slower BMI gain) (relative risk of high vs low rMED score, 0.68; 95% CI, 0.47-0.99). rMED score during pregnancy was not associated with the cardiometabolic risk score, its components, or related biomarkers. CONCLUSIONS: Higher adherence to the Mediterranean diet in pregnancy was associated with lower risk of having offspring with an accelerated growth pattern. This dietary pattern was not associated with the offspring's cardiometabolic risk at 4 years.

Proatherogenic Lipid Profile in Early Childhood: Association with Weight Status at 4 Years and Parental Obesity.

OBJECTIVES: To determine lipid profiles in early childhood and evaluate their association with weight status at 4 years of age. Additionally, we evaluated whether the risk of overweight or having an altered lipid profile was associated with parental weight status. STUDY DESIGN: Five hundred eighty two mothers and their 4-year-old children from 2 Spanish population-based cohorts were studied. Weight status in children at 4 years of age was classified as overweight or obese using the International Obesity Task Force criteria. Plasma total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were determined in children and lipid ratios were calculated. A proatherogenic lipid profile was defined as having the 3 lipid ratios in the third tertile. RESULTS: A total of 12.9% of children were overweight and 6.4% were obese. Weight status at 4 years of age was related to maternal prepregnancy body mass index, paternal body mass index, gestational diabetes, and birth weight, but not with other sociodemographic characteristics of the mother. We found no association with gestational age, sex of the child, or breastfeeding. The risk of overweight/obesity was increased 4.17-fold if mothers were overweight/obese (95% CI 1.76-9.88) and 5.1-fold (95% CI 2.50-10.40) if both parents were overweight/obese. There were 133 children (22.8%) with a proatherogenic lipid profile. The risk of a proatherogenic lipid profile was increased 2.44-fold (95% CI 1.54-3.86) if they were overweight/obese at 4 years of age and 2-fold if the father was overweight/obese (95% CI 1.22-3.35). CONCLUSIONS: Four-year-old overweight/obese children have higher lipid risk profiles. Offspring of overweight/obese parents have an increased risk for obesity and a proatherogenic lipid profile.

Prenatal mercury exposure and birth outcomes.

BACKGROUND: Results regarding the association between mercury exposure and anthropometry at birth, gestational length and placental weight are inconsistent, as is the role of seafood intake in these associations. OBJECTIVE: We assessed whether prenatal mercury exposure is associated with anthropometry at birth, placental weight and gestational length in a population with a relatively high exposure to mercury from seafood consumption. METHODS: Total mercury (T-Hg) was determined in cord blood from 1869 newborns with birth outcome measures, within the Spanish multicenter INMA cohort from 2004 to 2008. We adjusted cohort specific linear and Cox regression models to evaluate the association between T-Hg and birth anthropometry (weight, length, and head circumference), placental weight and gestational length. Non-spontaneous labor was taken to be censoring in the survival analysis. Final estimates were obtained using meta-analysis. RESULTS: Geometric mean T-Hg was 8.2µg/L. A doubling of T-Hg was associated with a 7.7g decrease in placental weight (95% CI: -13.6, -1.8) and marginally with head circumference (beta: -0.052cm, 95% CI: -0.109, 0.005). T-Hg was also inversely related to weight and length, although with weaker estimates. Mercury exposure was not associated with the length of gestation. The inverse relation between T-Hg and growth was enhanced when the intake of different seafood groups was adjusted for in the models. CONCLUSIONS: Prenatal mercury exposure may be associated with reduced placental and fetal growth. Confounding by fish intake should be considered when assessing these relationships.

Prenatal exposure to bisphenol A and phthalates and childhood respiratory tract infections and allergy.

BACKGROUND: There is growing concern that prenatal exposure to bisphenol A (BPA) and phthalates, which are widely used in consumer products, might affect susceptibility to infections and the development of allergy and asthma in children, but there are currently very few prospective studies. OBJECTIVE: We sought to evaluate whether prenatal exposure to BPA and phthalates increases the risk of respiratory and allergic outcomes in children at various ages from birth to 7 years. METHODS: We measured BPA and metabolites of high-molecular-weight phthalates, 4 di-(2-ethylhexyl) phthalate (DEHP) metabolites (Σ4DEHP) and mono-benzyl phthalate (MBzP), and 3 low-molecular-weight phthalate (LMWP) metabolites (Σ3LMWP) in urine samples collected during the first and third trimesters in pregnant women participating in the Infancia y Medio Ambiente-Sabadell birth cohort study. The occurrence of chest infections, bronchitis, wheeze, and eczema in children was assessed at ages 6 and 14 months and 4 and 7 years through questionnaires given to the mothers. Atopy (specific IgE measurement) and asthma (questionnaire) were assessed at ages 4 and 7 years, respectively. RESULTS: The relative risks (RRs) of wheeze (RR, 1.20; 95% CI, 1.03-1.40; P = .02), chest infections (RR, 1.15; 95% CI, 1.00-1.32; P = .05), and bronchitis (RR, 1.18; 95% CI, 1.01-1.37; P = .04) at any age increased for each doubling in concentration of maternal urinary BPA. Σ4DEHP metabolites were associated with the same outcomes (wheeze: RR, 1.25; 95% CI, 1.04-1.50, P = .02; chest infections: RR, 1.15; 95% CI, 0.97-1.35; P = .11; bronchitis: RR, 1.20; 95% CI, 1.01-1.43; P = .04). MBzP was associated with higher risk of wheeze (RR, 1.15; 95% CI, 1.00-1.33; P = .05). The risk of asthma at age 7 years was also increased with increasing prenatal BPA, Σ4DEHP, and MBzP exposure. There were no other exposure-outcome associations. CONCLUSIONS: Prenatal exposure to BPA and high-molecular-weight phthalates might increase the risk of asthma symptoms and respiratory tract infections throughout childhood.

Exposure to bisphenol A during pregnancy and child neuropsychological development in the INMA-Sabadell cohort.

BACKGROUND: Bisphenol A (BPA) may be a neurodevelopmental toxicant, but evidence is not consistent in terms of the sex-specific patterns of the associations and the specific behavioral or cognitive domains most affected. OBJECTIVE: To examine the effects of prenatal BPA exposure on cognitive, psychomotor, and behavioral development in 438 children at 1, 4 and 7 years of age. METHODS: BPA was measured in spot urine samples collected in trimester 1 and 3 of pregnancy from women participating in the INMA-Sabadell birth cohort study. Cognitive and psychomotor development was assessed at 1 and 4 years using psychologist-based scales. Attention deficit hyperactivity disorder (ADHD) symptoms and other behavioral problems were assessed at 4 years by teachers and at 7 years by parents using questionnaire-based rating scales. RESULTS: Geometric mean creatinine-adjusted BPA concentration of the averaged samples was 2.6 µg/g creatinine. BPA exposure was not associated with the cognitive scores or their subscales at 1 and 4 years of age. At 1 year of age, exposure in the highest tertile of BPA concentrations was associated with a reduction of psychomotor scores (T3 vs T1 ß=-4.28 points, 95% CI: -8.15, -0.41), but there was no association with psychomotor outcomes at 4 years. At 4 years, BPA exposure was associated with an increased risk of ADHD-hyperactivity symptoms (Incidence Rate Ratio (IRR) per log10 µg BPA/g creatinine increase=1.72; 1.08, 2.73) and this association was stronger in boys than in girls. Further, boys had an increased risk of ADHD-inattention symptoms whereas girls showed a reduced risk (p for interaction <0.1). At 7 years, these associations were not statistically significant nor were any other behavioral problems. CONCLUSIONS: These results suggest that prenatal BPA exposure does not affect cognitive development up to age 4 years. Associations are observed with psychomotor development and ADHD-related symptoms at early ages, but these do not appear to persist until later ages.

Longitudinal associations between early-life fluoride exposures and cardiometabolic outcomes in school-aged children.

BACKGROUND/AIM: Fluoride is a natural mineral present in food, water, and dental products, constituting ubiquitous long-term exposure in early childhood and across the lifespan. Experimental evidence shows fluoride-induced lipid disturbances with potential implications for cardiometabolic health. However, epidemiological studies are scarce. For the first time, we evaluated associations between repeated fluoride measures and cardiometabolic outcomes in children. METHODS: We studied âˆ¼ 500 Mexican children from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort with measurements on urinary fluoride at age 4, and dietary fluoride at ages 4, 6, and 8 years approximately. We used covariate-adjusted linear mixed-effects and linear regression models to assess fluoride associations with multiple cardiometabolic outcomes (ages 4-8): lipids (total cholesterol, HDL, LDL, and triglycerides), glucose, HbA1c, adipokines (leptin and adiponectin), body fat, and age- and sex-specific z-scores of body mass index (zBMI), waist circumference, and blood pressure. RESULTS: Dietary fluoride intake at age 4 was associated with annual increases in triglycerides [ß per-fluoride-doubling = 2.02 (95 % CI: 0.37, 3.69)], cholesterol [ß = 1.46 (95 % CI: 0.52, 2.39)], HDL [ß = 0.39 (95 % CI: 0.02, 0.76)], LDL [ß = 0.87 (95 % CI: 0.02, 1.71)], and HbA1c [ß = 0.76 (95 % CI: 0.28, 1.24)], and decreased leptin [ß = -3.58 (95 % CI: -6.34, -0.75)] between the ages 4 and 8. In cross-sectional analyses at age 8, higher tertiles of fluoride exposure were associated with increases in zBMI, triglycerides, glucose, and leptin (p-tertile trend < 0.05). Stronger associations were observed in boys at year 8 and in girls prior to year 8 (p-sex interaction < 0.05). Fewer but consistent associations were observed for urinary fluoride at age 4, indicating increased annual changes in HDL and HbA1c with higher fluoride levels. CONCLUSION: Dietary fluoride exposures in early- and mid-childhood were associated with adverse cardiometabolic outcomes in school-aged children. Further research is needed to elucidate whether these associations persist at later ages.

Associations of dietary intake and longitudinal measures of per- and polyfluoroalkyl substances (PFAS) in predominantly Hispanic young Adults: A multicohort study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are pollutants linked to adverse health effects. Diet is an important source of PFAS exposure, yet it is unknown how diet impacts longitudinal PFAS levels. OBJECTIVE: To determine if dietary intake and food sources were associated with changes in blood PFAS concentrations among Hispanic young adults at risk of metabolic diseases. METHODS: Predominantly Hispanic young adults from the Children's Health Study who underwent two visits (CHS; n = 123) and young adults from NHANES 2013-2018 who underwent one visit (n = 604) were included. Dietary data at baseline was collected using two 24-hour dietary recalls to measure individual foods and where foods were prepared/consumed (home/restaurant/fast-food). PFAS were measured in blood at both visits in CHS and cross-sectionally in NHANES. In CHS, multiple linear regression assessed associations of baseline diet with longitudinal PFAS; in NHANES, linear regression was used. RESULTS: In CHS, all PFAS except PFDA decreased across visits (all p < 0.05). In CHS, A 1-serving higher tea intake was associated with 24.8 %, 16.17 %, and 12.6 % higher PFHxS, PFHpS, and PFNA at follow-up, respectively (all p < 0.05). A 1-serving higher pork intake was associated with 13.4 % higher PFOA at follow-up (p < 0.05). Associations were similar in NHANES, including unsweetened tea, hot dogs, and processed meats. For food sources, in CHS each 200-gram increase in home-prepared food was associated with 0.90 % and 1.6 % lower PFOS at baseline and follow-up, respectively, and in NHANES was associated with 0.9 % lower PFDA (all p < 0.05). CONCLUSION: Results suggest that beverage consumption habits and food preparation are associated with differences in PFAS levels in young adults. This highlights the importance of diet in determining PFAS exposure and the necessity of public monitoring of foods and beverages for PFAS contamination.

Postprandial Metabolite Profiles and Risk of Prediabetes in Young People: A Longitudinal Multicohort Study.

OBJECTIVE: Prediabetes in young people is an emerging epidemic that disproportionately impacts Hispanic populations. We aimed to develop a metabolite-based prediction model for prediabetes in young people with overweight/obesity at risk for type 2 diabetes. RESEARCH DESIGN AND METHODS: In independent, prospective cohorts of Hispanic youth (discovery; n = 143 without baseline prediabetes) and predominately Hispanic young adults (validation; n = 56 without baseline prediabetes), we assessed prediabetes via 2-h oral glucose tolerance tests. Baseline metabolite levels were measured in plasma from a 2-h postglucose challenge. In the discovery cohort, least absolute shrinkage and selection operator regression with a stability selection procedure was used to identify robust predictive metabolites for prediabetes. Predictive performance was evaluated in the discovery and validation cohorts using logistic regression. RESULTS: Two metabolites (allylphenol sulfate and caprylic acid) were found to predict prediabetes beyond known risk factors, including sex, BMI, age, ethnicity, fasting/2-h glucose, total cholesterol, and triglycerides. In the discovery cohort, the area under the receiver operator characteristic curve (AUC) of the model with metabolites and known risk factors was 0.80 (95% CI 0.72-0.87), which was higher than the risk factor-only model (AUC 0.63 [0.53-0.73]; P = 0.001). When the predictive models developed in the discovery cohort were applied to the replication cohort, the model with metabolites and risk factors predicted prediabetes more accurately (AUC 0.70 [95% CI 40.55-0.86]) than the same model without metabolites (AUC 0.62 [0.46-0.79]). CONCLUSIONS: Metabolite profiles may help improve prediabetes prediction compared with traditional risk factors. Findings suggest that medium-chain fatty acids and phytochemicals are early indicators of prediabetes in high-risk youth.

Exposure to per- and polyfluoroalkyl substances and high-throughput proteomics in Hispanic youth.

BACKGROUND: Strong epidemiological evidence shows positive associations between exposure to per- and polyfluoroalkyl substances (PFAS) and adverse cardiometabolic outcomes (e.g., diabetes, hypertension, and dyslipidemia). However, the underlying cardiometabolic-relevant biological activities of PFAS in humans remain largely unclear. AIM: We evaluated the associations of PFAS exposure with high-throughput proteomics in Hispanic youth. MATERIAL AND METHODS: We included 312 overweight/obese adolescents from the Study of Latino Adolescents at Risk (SOLAR) between 2001 and 2012, along with 137 young adults from the Metabolic and Asthma Incidence Research (Meta-AIR) between 2014 and 2018. Plasma PFAS (i.e., PFOS, PFOA, PFHxS, PFHpS, PFNA) were quantified using liquid-chromatography high-resolution mass spectrometry. Plasma proteins (n = 334) were measured utilizing the proximity extension assay using an Olink Explore Cardiometabolic Panel I. We conducted linear regression with covariate adjustment to identify PFAS-associated proteins. Ingenuity Pathway Analysis, protein-protein interaction network analysis, and protein annotation were used to investigate alterations in biological functions and protein clusters. RESULTS: Results after adjusting for multiple comparisons showed 13 significant PFAS-associated proteins in SOLAR and six in Meta-AIR, sharing similar functions in inflammation, immunity, and oxidative stress. In SOLAR, PFNA demonstrated significant positive associations with the largest number of proteins, including ACP5, CLEC1A, HMOX1, LRP11, MCAM, SPARCL1, and SSC5D. After considering the mixture effect of PFAS, only SSC5D remained significant. In Meta-AIR, PFAS mixtures showed positive associations with GDF15 and IL6. Exploratory analysis showed similar findings. Specifically, pathway analysis in SOLAR showed PFOA- and PFNA-associated activation of immune-related pathways, and PFNA-associated activation of inflammatory response. In Meta-AIR, PFHxS-associated activation of dendric cell maturation was found. Moreover, PFAS was associated with common protein clusters of immunoregulatory interactions and JAK-STAT signaling in both cohorts. CONCLUSION: PFAS was associated with broad alterations of the proteomic profiles linked to pro-inflammation and immunoregulation. The biological functions of these proteins provide insight into potential molecular mechanisms of PFAS toxicity.

PFHpA alters lipid metabolism and increases the risk of metabolic dysfunction-associated steatotic liver disease in youth-a translational research framework.

To address the growing epidemic of liver disease, particularly in pediatric populations, it is crucial to identify modifiable risk factors for the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Per- and polyfluoroalkyl substances (PFAS) are persistent ubiquitous chemicals and have emerged as potential risk factors for liver damage. However, their impact on the etiology and severity of MASLD remains largely unexplored in humans. This study aims to bridge the gap between human and in vitro studies to understand how exposure to perfluoroheptanoic acid (PFHpA), one of the emerging PFAS replacements which accumulates in high concentrations in the liver, contributes to MASLD risk and progression. First, we showed that PFHpA plasma concentrations were significantly associated with increased risk of MASLD in obese adolescents. Further, we examined the impact of PFHpA on hepatic metabolism using 3D human liver spheroids and single-cell transcriptomics to identify major hepatic pathways affected by PFHpA. Next, we integrated the in vivo and in vitro multi-omics datasets with a novel statistical approach which identified signatures of proteins and metabolites associated with MASLD development triggered by PFHpA exposure. In addition to characterizing the contribution of PFHpA to MASLD progression, our study provides a novel strategy to identify individuals at high risk of PFHpA-induced MASLD and develop early intervention strategies. Notably, our analysis revealed that the proteomic signature exhibited a stronger correlation between both PFHpA exposure and MASLD risk compared to the metabolomic signature. While establishing a clear connection between PFHpA exposure and MASLD progression in humans, our study delved into the molecular mechanisms through which PFHpA disrupts liver metabolism. Our in vitro findings revealed that PFHpA primarily impacts lipid metabolism, leading to a notable increase of lipid accumulation in human hepatocytes after PFHpA exposure. Among the pathways involved in lipid metabolism in hepatocytes, regulation of lipid metabolism by PPAR-a showed a remarkable activation. Moreover, the translational research framework we developed by integrating human and in vitro data provided us biomarkers to identify individuals at a high risk of MASLD due to PFHpA exposure. Our framework can inform policies on PFAS-induced liver disease and identify potential targets for prevention and treatment strategies.