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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.

BackgroundExperimental evidence indicates that exposure to certain pollutants is associated with liver damage. Per- and polyfluoroalkyl substances (PFAS) are persistent synthetic chemicals widely used in industry and consumer products and bioaccumulate in food webs and human tissues, such as the liver.ObjectiveThe objective of this study was to conduct a systematic review of the literature and meta-analysis evaluating PFAS exposure and evidence of liver injury from rodent and epidemiological studies.MethodsPubMed and Embase were searched for all studies from earliest available indexing year through 1 December 2021 using keywords corresponding to PFAS exposure and liver injury. For data synthesis, results were limited to studies in humans and rodents assessing the following indicators of liver injury: serum alanine aminotransferase (ALT), nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, or steatosis. For human studies, at least three observational studies per PFAS were used to conduct a weighted z-score meta-analysis to determine the direction and significance of associations. For rodent studies, data were synthesized to qualitatively summarize the direction and significance of effect.ResultsOur search yielded 85 rodent studies and 24 epidemiological studies, primarily of people from the United States. Studies focused primarily on legacy PFAS: perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid. Meta-analyses of human studies revealed that higher ALT levels were associated with exposure to PFOA (z-score= 6.20, p

RationaleAsthma and obesity often co-occur. It has been hypothesized that asthma may contribute to childhood obesity onset.ObjectivesTo determine if childhood asthma is associated with incident obesity and examine the role of asthma medication in this association.MethodsWe studied 8,716 children between ages 6 and 18.5 years who were nonobese at study entry participating in 18 US cohorts of the Environmental influences on Child Health Outcomes program (among 7,299 children with complete covariate data mean [SD] study entry age = 7.2 [1.6] years and follow up = 5.3 [3.1] years).Measurements and main resultsWe defined asthma based on caregiver report of provider diagnosis. Incident obesity was defined as the first documented body mass index ≥95th percentile for age and sex following asthma status ascertainment. Over the study period, 26% of children had an asthma diagnosis and 11% developed obesity. Cox proportional hazards models with sex-specific baseline hazards were fitted to assess the association of asthma diagnosis with obesity incidence. Children with asthma had a 23% (95% confidence intervals [CI] = 4, 44) higher risk for subsequently developing obesity compared with those without asthma. A novel mediation analysis was also conducted to decompose the total asthma effect on obesity into pathways mediated and not mediated by asthma medication use. Use of asthma medication attenuated the total estimated effect of asthma on obesity by 64% (excess hazard ratios = 0.64; 95% CI = -1.05, -0.23).ConclusionsThis nationwide study supports the hypothesis that childhood asthma is associated with later risk of obesity. Asthma medication may reduce this association and merits further investigation as a potential strategy for obesity prevention among children with asthma.

We conducted a systematic review and meta-analysis of the associations between prenatal exposure to persistent organic pollutants (POPs) and childhood obesity. We focused on organochlorines (dichlorodiphenyltrichloroethane [DDT], dichlorodiphenyldichloroethylene [DDE], hexachlorobenzene [HCB], and polychlorinated biphenyls [PCBs]), perfluoroalkyl and polyfluoroalkyl substances (PFAS), and polybrominated diphenyl ethers (PBDEs) that are the POPs more widely studied in environmental birth cohorts so far. We search two databases (PubMed and Embase) through July/09/2021 and identified 33 studies reporting associations with prenatal organochlorine exposure, 21 studies reporting associations with prenatal PFAS, and five studies reporting associations with prenatal PBDEs. We conducted a qualitative review. Additionally, we performed random-effects meta-analyses of POP exposures, with data estimates from at least three prospective studies, and BMI-z. Prenatal DDE and HCB levels were associated with higher BMI z-score in childhood (beta: 0.12, 95% CI: 0.03, 0.21; I2 : 28.1% per study-specific log increase of DDE and beta: 0.31, 95% CI: 0.09, 0.53; I2 : 31.9% per study-specific log increase of HCB). No significant associations between PCB-153, PFOA, PFOS, or pentaPBDEs with childhood BMI were found in meta-analyses. In individual studies, there was inconclusive evidence that POP levels were positively associated with other obesity indicators (e.g., waist circumference).

Childhood obesity represents a public health crisis with serious long-term consequences. (1) The 'metabolism-disrupting chemical' hypothesis postulates that environmental chemicals with endocrine-disrupting ability have the potential to alter the body's [...]

BACKGROUND: Prenatal exposure to persistent organic pollutants (POPs) may contribute to the development of childhood obesity and metabolic disorders. However, little is known about whether the maternal nutritional status during pregnancy can modulate these associations. OBJECTIVES: The main objective was to characterize the joint associations and interactions between prenatal levels of POPs and nutrients on childhood obesity. METHODS: We used data from to the Spanish INfancia y Medio Ambiente-Environment and Childhood (INMA) birth cohort, on POPs and nutritional biomarkers measured in maternal blood collected at the first trimester of pregnancy and child anthropometric measurements at 7 years of age. Six organochlorine compounds (OCs) [dichlorodiphenyldichloroethylene, hexachlorobenzene (HCB), [beta]-hexachlorocyclohexane ([beta]-HCH) and polychlorinated biphenyls 138, 153, 180] and four per- and polyfluoroalkyl substances (PFAS) were measured. Nutrients included vitamins (D, B12, and folate), polyunsaturated fatty acids (PUFAs), and dietary carotenoids. Two POPs-nutrients mixtures data sets were established: a) OCs, PFAS, vitamins, and carotenoids (n = 660), and b) OCs, PUFAs, and vitamins (n = 558). Joint associations of mixtures on obesity were characterized using Bayesian kernel machine regression (BKMR). Relative importance of biomarkers and two-way interactions were identified using gradient boosting machine, hierarchical group lasso regularization, and BKMR. Interactions were further characterized using multivariate regression models in the multiplicative and additive scale. RESULTS: Forty percent of children had overweight or obesity. We observed a positive overall joint association of both POPs-nutrients mixtures on overweight/obesity risk, with HCB and vitamin B12 the biomarkers contributing the most. Recurrent interactions were found between HCB and vitamin B12 across screening models. Relative risk for a natural log increase of HCB was 1.31 (95% CI: 1.11, 1.54, p- interaction =0.02) in the tertile 2 of vitamin B12 and in the additive scale a relative excess risk due to interaction of 0.11 (95% CI: 0.02, 0.20) was found. Interaction between perfluorooctane sulfonate and [beta]-cryptoxanthin suggested a protective effect of the antioxidant on overweight/obesity risk. CONCLUSION: These results support that maternal nutritional status may modulate the effect of prenatal exposure to POPs on childhood overweight/ obesity. These findings may help to develop a biological hypothesis for future toxicological studies and to better interpret inconsistent findings in epidemiological studies. https://doi.org/10.1289/EHP11258, Introduction Growing evidence supports that environment insults and nutrition during the early stages of development may influence subsequent health during childhood, including obesity and metabolic diseases. (1,2) Childhood obesity remains [...]

BACKGROUND: Exposure to per- and polyfluoroalkyl substances (PFAS), a prevalent class of persistent pollutants, may increase the risk of type 2 diabetes. OBJECTIVE: We examined associations between PFAS exposure and glucose metabolism in youth. METHODS: Overweight/obese adolescents from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR; n = 310) participated in annual visits for an average of 3.3 [+ or -]2.9 y. Generalizability of findings were tested in young adults from the Southern California Children's Health Study (CHS; n = 135) who participated in a clinical visit with a similar protocol. At each visit, oral glucose tolerance tests were performed to estimate glucose metabolism and [beta]-cell function via the insulinogenic index. Four PFAS were measured at baseline using liquid chromatography-high-resolution mass spectrometry; high levels were defined as concentrations >66th percentile. RESULTS: In females from the SOLAR, high perfluorohexane sulfonate (PFHxS) levels ([greater than or equal to]2.0ng/mL) were associated with the development of dysregulated glucose metabolism beginning in late puberty. The magnitude of these associations increased postpuberty and persisted through 18 years of age. For example, postpuberty, females with high PFHxS levels had 25-mg/dL higher 60-min glucose (95% CI: 12,39 mg/dL; p DISCUSSION: Youth exposure to PFHxS was associated with dysregulated glucose metabolism in females, which may be due to changes in [beta]-cell function. These associations appeared during puberty and were most pronounced postpuberty. https://doi.org/10.1289/EHP9200, Introduction Youth-onset type 2 diabetes is a growing epidemic (Nadeau et al. 2016). This disease displays a more aggressive phenotype than adult onset type 2 diabetes and results in the [...]