Environmental Health Perspectives最新文献

Background: Evidence on lead and the burden of cardiovascular disease (CVD) derived from National Health and Nutrition Examination Survey (NHANES) data, a general sample of the U.S. population, lacks sufficient representation of American Indians. Moreover, there is limited prospective evidence on lead and incident CVD outcomes.

Objectives: We evaluated if blood lead levels were associated with CVD mortality and incidence in American Indian adults from the Strong Heart Study (SHS).

Methods: Whole blood samples collected in 1998-1999 among 1,818 participants was analyzed for lead using inductively coupled plasma mass spectrometry. CVD incidence and mortality were available through 2019. We used progressively adjusted multivariable Cox proportional hazards models to estimate the risk of composite CVD and coronary heart disease (CHD) mortality and incidence by baseline blood lead levels.

Results: The median (p20, p80) blood lead was 22.5 (14.2, 37.3) µg/L, similar to that of a representative sample of US adults in NHANES 1999-2000. During follow-up, 578 (31.8%) participants had a composite CVD event and 454 (25.0%) participants had a CHD event. After adjustment for demographic, lifestyle, and cardiovascular risk factors, the hazard ratio (95% CI) per change across the 80^th to 20^th quantiles in blood lead was 1.15 (1.02-1.30) and 1.22 (1.08- 1.37) for CVD and CHD mortality, respectively, and 1.13 (1.02-1.24) and 1.12 (0.99-1.25) for CVD and CHD incidence, respectively. In flexible dose-response models, the associations appeared to be non-linear, with a clear increased risk of CVD and CHD mortality at blood lead concentrations above 35 µg/L.

Discussion: Blood lead levels in American Indian adults, which are comparable to populations in the U.S. and globally, were associated with increased risk of CVD and CHD incidence and mortality. These findings highlight the importance of further reducing lead exposure, including American Indian communities. https://doi.org/10.1289/EHP16309.

Background: Exposure to endocrine-disrupting chemicals (EDCs), such as bisphenol (BP) A, disrupts reproduction across generations. Germ cell epigenetic alterations are proposed to mediate these transgenerational defects. Previously, we have shown that prenatal exposure to environmentally relevant doses of BPA or its substitute, BPS, caused transgenerationally maintained reproductive impairments associated with neonatal spermatogonial epigenetic changes in male mice. However, the mechanisms sustaining these changes across generations remain unclear.

Objectives: This study aimed to systematically elucidate the mechanism of transgenerational inherence by prenatal BPA and BPS exposure in the murine germline from F1 to F3 generations at both transcriptomic and epigenetic levels.

Methods: Pregnant CD-1 females (F0) were orally administered BPA or BPS at doses of 0 (vehicle control), 0.5, 50, or 1000 µg/kg/b.w./day from gestational day 7 to birth. Sperm counts and motility were examined in F1, F2, and F3 adult males. THY1⁺ germ cells on postnatal day 6 from F1, F2, and F3 males at a dose of 50 µg/kg/b.w./day were used for analysis by single-nucleus (sn) multi-omics (paired snRNA-seq and snATAC-seq on the same nucleus).

Results: Prenatal exposure to BPA and BPS with 0.5, 50, and 1000 µg/kg/b.w./day reduced sperm counts in mice across F1 to F3 generations. In the F1 generation, BPA or BPS exposure with 50 µg/kg/b.w./day disrupted the balance between maintaining the undifferentiated and differentiating spermatogonial populations. Differentially accessible peaks (DAPs) by snATAC-seq were primarily located in the promoter regions, with elevated activity of key transcription factors, including SP1, SP4, and DMRT1. Notably, similar gene expression and chromatin changes were observed in directly exposed F1 and F2 generations but differed in the indirectly exposed F3 generation. Approximately 80% of DAPs in F1 and F2 spermatogonia overlapped with histone post-translational modifications linked to transcription activation (e.g., H3K4me1/2/3 and H3K27ac). Across F1 to F3 generations, although BPA exerted more potent effects on gene expression in F1 spermatogonia, BPS induced longer-lasting effects. Interestingly, DMRT1 motif activity was persistently elevated in all three generations following ancestral BPA or BPS exposure.

Discussion: Our work provides the first systematic analyses of transgenerational gene and chromatin dynamics following prenatal exposure to BPA or BPS. These results suggest that prenatal exposure to environmentally relevant doses of BPA or BPS alters chromatin accessibility and transcription factor motif activities, consequently contributing to disrupted transcriptional levels in neonatal spermatogonia, and some are sustained to F3 generations, ultimately leading to the reduction of sperm counts in adults. https://doi.org/

Background: Exposure to metals and metalloids (hereafter referred to as 'metals') during gestation and early childhood may affect children's neurodevelopment. However, few studies have simultaneously evaluated the impact of exposure to both essential and non-essential metals across specific windows of exposure on children's neurodevelopmental outcomes.

Objective: To investigate whether levels of metals during gestation and the early postnatal period, individually and as a mixture, are related to child cognition at 5 years of age among participants in the New Hampshire Birth Cohort Study (NHBCS).

Methods: We followed 278 NHBCS pregnancy-offspring dyads up to approximately 5 years of age. Total arsenic (As), copper (Cu), manganese (Mn), lead (Pb), selenium (Se), and zinc (Zn) were measured in toenail samples collected from pregnant persons at ~24 to 28 weeks of gestation (representing periconception and early pregnancy), and at ~6 weeks postpartum (representing mid-pregnancy), and their infants at ~6 weeks of age (representing early infancy). Cognitive development at 5 years was assessed using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) which includes measures of full-scale intelligence quotient (FSIQ) and five composite indices. Associations between ln-metal toenail concentrations across multiple exposure windows and the six WPPSI-IV scores were estimated through mean field variational Bayes for lagged kernel machine regression (MFVB-LKMR). Potential effect modification by other elements in the mixture as well as sex were further explored.

Results: Biomarkers of As exposures of periconception and early pregnancy, mid-pregnancy and early infancy were associated with lower cognitive scores at 5 years of age (e.g., FSIQ: -0.16 (95% Credible Interval (CrI): -0.24, -0.08) SD change). Periconception and early pregnancy exposures to Mn and Cu were associated with higher child cognitive scores. Sex differences were observed, especially with Mn exposure, with stronger positive associations among males during periconception and early pregnancy and among females during mid-pregnancy. For Pb and Zn exposures, associations with cognitive scores differed across exposure windows, exhibiting both positive and negative associations.

Discussion: By evaluating multiple essential and non-essential elements across the three previously mentioned exposure windows, we found evidence of sensitive periods of susceptibility to child cognitive measures. While results for As indicated detrimental effects, those for Cu and Mn suggested beneficial trends across all exposure windows. https://doi.org/10.1289/EHP16752.

Background: Bariatric surgery is an intervention for severe obesity, leading to significant weight loss and metabolic improvements. However, the release of lipophilic chemicals accumulated in adipose tissue during weight loss presents a unique clinical challenge and research opportunity. Dichlorodiphenyldichloroethylene (DDE) is a persistent organic pollutant increasingly recognized as obesogen, while the biological mechanisms through which DDE influences body mass index (BMI) and waist circumference remain underexplored.

Objectives: We aimed to identify metabolic signatures mediating the association between DDE exposure and weight loss by plasma and adipose tissue metabolomics.

Methods: We conducted a longitudinal study involving 60 adolescents with severe obesity undergoing bariatric surgery. We quantified p,p'-DDE concentrations in visceral adipose tissue collected during surgery and analyzed metabolic profiles from both adipose tissues collected at surgery and plasma samples collected at surgery, 6 months, 1 year, and 3 years postoperatively, using gas/liquid chromatography and high-resolution mass spectrometry. We used meet-in-the-middle approach coupled with a series of metabolome-wide association analyses to identify overlapping metabolite associated with both DDE exposure and weight loss outcomes.

Results: Our findings revealed that DDE concentrations in visceral adipose tissue are associated with significant alterations in metabolites locally in adipose tissue pre-surgery and systemically in plasma post-surgery. Eight plasma metabolites were significantly associated with DDE exposure over time, while 27 were associated with BMI. Notably, methylbutyroylcarnitine was identified as a potential mediator, showing a positive association with both exposure and outcome. Eight adipose tissue metabolites were associated with both DDE and longitudinal changes in plasma metabolites, suggesting an indirect pathway linking DDE and weight changes.

Discussion: These findings enhance our understanding of DDE's obesogenic effect. The involved metabolic changes could attenuate the efficacy of bariatric surgery in achieving sustained weight loss, underscoring the importance of integrating environmental health considerations into clinical practice. https://doi.org/10.1289/EHP16341.

Background: Maximum contaminant level violations occur more frequently among some public water systems (PWS) serving marginalized communities across the United States. Spatially resolved PWS service area data are now available, allowing for better understanding of relationships between sociodemographic factors and water quality.

Objectives: We examined associations between detection and concentrations of arsenic (As), chromium (Cr), manganese (Mn), and selenium (Se) and the sociodemographic characteristics of residents served by PWS at two spatial scales: PWS service areas and counties.

Methods: We leveraged data on inorganic contaminants in $>\mathrm{273,000}$ drinking water samples from $>\mathrm{21,000}$ PWS collected by state agencies and the US Environmental Protection Agency over the decade between 2005-2015 and curated in a national database developed by the Environmental Working Group. Sociodemographic data were from the 2006-2015 American Community Survey. We developed two-step hurdle models that included: a) a categorical model predicting contaminant detection and b) a continuous model predicting contaminant concentration. We developed these hurdle models using PWS service areas or counties as spatial units of analysis and compared results.

Results: PWS serving 5% higher proportions of limited English-speaking households had significantly greater detections of As, Cr, and Se, ranging from 1.25 [95% confidence interval (CI): 1.18, 1.32] times higher probability of Cr detection to 1.69 (95% CI: 1.58, 1.80) times higher probability of Se detection. Small PWS ($\le \mathrm{10,000}$ customers) had higher concentrations of these same three contaminants. PWS serving greater proportions of Black residents had a lower probability of detecting As, Cr, and Se, but significantly higher concentrations of Cr, Mn, and Se, particularly outside large urban areas. The direction of significant associations was consistent between spatial units of analysis, but county results tended to exhibit greater effect sizes and fewer significant associations.

Discussion: PWS service area data help to identify drinking water concerns specific to served communities and reduce issues related to statistical bias at larger spatial scales. Targeted subsidies for water infrastructure in communities served by small PWS would help reduce disparities in exposures to drinking water contaminants. https://doi.org/10.1289/EHP14793.

Background: Liver injury is a frequent complication of heatstroke and constitutes a direct cause of death. However, only a few studies examined the mechanism underlying heatstroke-induced liver injury.

Objective: We aimed to evaluate the role of peroxisome proliferator-activated receptor α (PPARα) in heatstroke-induced liver injury and explore the potential mechanisms.

Methods: Male C57BL/6N mice were subjected to control (22 ± 1°C) or extreme heat temperature (39.5 ± 0.5°C) to induce a heatstroke-associated liver injury animal model. PPARα agonist, ferroptosis inhibitor and AAV8-mediated PPARα overexpression were administered to the mice to investigate the role of PPARα and ferroptosis in the heatstroke-induced liver injury. Serum was collected for liver function evaluation. Liver tissues were applied for morphological observation, staining detection, ferroptosis examination and mechanistic exploration.

Results: Compared with the control group, extreme heat exposure induced temperature dysregulation, impaired liver function and morphological damage in mice. Proteomics screened PPARα as protein of interest, with its level being significantly decreased in response to extreme heat exposure. Both PPARα activation and overexpression attenuated extreme heat-induced heatstroke and liver injury. Hmox1 was next screened and higher Hmox1 expression was identified, accompanied with elevated markers of ferroptosis including prostaglandin-endoperoxide synthase 2 (Ptgs2), malondialdehyde (MDA), lipid peroxidation (LPO) and Fe²⁺ levels. Ferroptosis inhibition mitigated heatstroke and liver injury induced by heat exposure. In the setting of extreme heat exposure, PPARα activation suppressed Hmox1 expression and levels of ferroptosis markers. It not only induced differences in the expression of members of iron generation, efflux and uptake process and reduced hepatic intracellular Fe²⁺ accumulation, but also stimulated expression of molecules for countering lipid peroxidation including Nrf2-SLC7A11-GPX4 axis and FSP1 signaling.

Discussion: PPARα played an essential role in extreme heat exposure-induced heatstroke and liver injury, and PPARα intervention conferred protection against it via inhibition of ferroptosis. https://doi.org/10.1289/EHP15326.

Background: The vertebrate nervous system is vulnerable to chemical toxicity and the widespread release of chemicals into the environment outstrips the capacity to assess their safety. The zebrafish (Danio rerio) is a powerful vertebrate model that can bridge the gap between in vitro and mammalian-based in vivo studies. However, the behavior-rich repertoire of larval zebrafish, a 3R-compliant model amenable to higher-throughput chemical screens, has yet to be fully deployed to identify and characterize chemical compounds that cause neurotoxicity.

Objective: We sought to establish a multi-behavioral phenotyping approach in larval zebrafish to identify and mechanistically elucidate neuroactive chemicals, with particular focus on chemical compounds that affect non-associative habituation learning.

Methods: We devised a battery of automated behavior assays in larval zebrafish. The battery captures stereotypical visual and acoustic behaviors including habituation, a form of non-associative learning. To elucidate mechanisms underlying exposure-induced behavioral alterations in zebrafish, in silico target predictions, pharmacological interventions, patch-clamp recordings in cultured mouse cortical neurons, and human multi-neurotransmitter (hMNR) assay in 3D BrainSpheres were used.

Results: Known pharmacological modulators of habituation in zebrafish evoked distinct behavioral patterns. By screening chemicals positive for ex vivo N-methyl-D-aspartate receptor (NMDAR) modulation, we identified chlorophene, a biocide that caused sedation, paradoxical excitation, and reduced habituation in zebrafish. Using in silico target predictions and pharmacological interventions, we discovered that chlorophene acts via gamma-aminobutyric acid A receptors (GABA_ARs), a previously unknown target site. Orthogonal validation in cultured mouse cortical neurons and human stem cell-derived BrainSpheres confirmed chlorophene's interaction with GABA_ARs. Chlorophene's behavioral profile resembled that of flupirtine, a Kv7 potassium channel (M-current) activator, suggesting that habituation deficits stem from M-current rather than GABA_AR modulation.

Conclusions: These studies combined a series of behavior assays in a phenotypically rich, rapid, and inexpensive non-mammalian vertebrate test system to screen chemicals for neurotoxicity. Together with in silico target predictions and mouse- and human-based models, our findings establish multi-behavioral phenotyping in zebrafish as a powerful toolkit for neurotoxicity testing and mechanism identification, with relevance for humans. https://doi.org/10.1289/EHP16568.

Background: Children may be involuntarily exposed to chemical residue from thirdhand tobacco smoke (THS) in environments where tobacco has previously been used. Factors contributing to this exposure among children of nonsmokers with no known secondhand smoke (SHS) exposure are currently unknown.

Objective: To understand the contribution of THS residue to the overall tobacco smoke exposure (TSE) among children of nonsmokers and smokers.

Methods: We conducted a prospective observational cohort study of parents and their children (≤11 years; N=1013) at a children's hospital in the US. Hand nicotine (HN) and saliva cotinine (SC) were markers of THS pollution and TSE, respectively. Children were considered protected from tobacco smoke if there were no household smokers or vapers, strict household smoking bans, and no SHS exposure during the past week. Cluster-adjusted regression models were used to test hypotheses about HN and SC levels.

Results: Overall, 94.5% and 98.9% of protected and unprotected children had detectable HN, respectively. Children who were Black and protected (GeoM= 6.0 ng/wipe; 95%CI=[3.8, 9.1]) or unprotected (GeoM= 43.8 ng/wipe; 95%CI=[33.6; 57.1]) had approximately three times higher HN levels than children who were White and protected (GeoM= 1.8 ng/wipe; 95%CI=1.6; 2.0]) or unprotected (GeoM= 15.0 ng/wipe; 95%CI=[11.2; 19.8]). Unprotected children whose parents had ≤high school education had HN levels that were almost 12 times higher (87.8 ng/wipe) than unprotected children of parents who graduated college (7.5 ng/wipe). Unprotected children with ≤$15,000 household income had HN levels >25 times higher (73.3 ng/wipe) than unprotected children with >$90,000 income (≤ 2.8 ng/wipe). Household smoking bans were unsuccessful in lowering HN levels in Black children, but they were successful for White children (χ²(3)=12.7, p<0.01). HN was associated with SC in children with no SHS exposure (βˆ= 0.10), with stronger associations in the presence of 1 (βˆ= 0.28) and 2+ active smokers (βˆ= 0.32; all p<0.01).

Discussion: THS is a pervasive source of exposure to tobacco smoke pollutants. Stark disparities were noted, with higher exposure in Black and lower income children. Findings provide the strongest evidence to date on the contribution of THS as a significant source of overall TSE in children. https://doi.org/10.1289/EHP16332.