It remains unclear whether in utero and childhood exposure to air pollution affects pubertal development, particularly age of menarche in girls. The aim of this study was to determine whether residential ambient particulate matter (PM) exposure in utero and during childhood is associated with age of menarche. We studied 5,201 girls in the Growing Up Today Study 2 (2004-present) who were 10-17 y of age at enrollment (47.7% premenarchal; 52.3% postmenarchal). Exposure to three size fractions of PM [fine PM with aerodynamic diameter (), PM with aerodynamic diameters (), and PM with aerodynamic diameter ()] was assigned based on maternal residential address, updated every 2 y, using nationwide spatiotemporal models. We estimated average PM exposure in utero, and time-varying windows: annual average exposure in the prior 1 and 2 y and cumulative average from birth. Age of menarche was self-reported on three surveys administered in 2004, 2006, and 2008. We calculated hazard ratios (HR) for menarche for an interquartile range (IQR) increase in PM exposure using Cox proportional hazard models adjusting for potential confounders. Girls attained menarche at 12.3 y of age on average. In the adjusted model, higher residential exposure to ambient during all time windows was associated with earlier age of menarche. The HRs of menarche for each IQR () increase in exposure to during the in utero period, 1 y prior to menarche, and throughout childhood were 1.03 [95% confidence interval (CI): 1.00, 1.06], 1.06 (95% CI: 1.02, 1.10) and 1.06 (95% CI: 1.02, 1.10), respectively. Effect estimates for exposure were similar, albeit attenuated, for all time windows. exposure was not associated with age of menarche. Among a large, nationwide, prospective cohort of U.S. girls, higher exposure to and in utero and throughout childhood was associated with an earlier age of menarche. Our results suggest that and may have endocrine-disrupting properties that could lead to altered timing of menarche. https://doi.org/10.1289/EHP12110.

Living in neighborhoods with higher levels of walkability has been associated with a reduced risk of obesity and higher levels of physical activity. Obesity has been linked to increased risk of 13 cancers in women. However, long-term prospective studies of neighborhood walkability and risk for obesity-related cancer are scarce. We evaluated the association between long-term average neighborhood walkability and obesity-related cancer risk in women. The New York University Women's Health Study (NYUWHS) is a prospective cohort with 14,274 women recruited between 1985 and 1991 in New York City and followed over nearly three decades. We geocoded residential addresses for each participant throughout follow-up and calculated an average annual measure of neighborhood walkability across years of follow-up using data on population density and accessibility to destinations associated with geocoded residential addresses. We used ICD-9 codes to characterize first primary obesity-related cancers and employed Cox proportional hazards models to assess the association between average neighborhood walkability and risk of overall and site-specific obesity-related cancers. Residing in neighborhoods with a higher walkability level was associated with a reduced risk of overall and site-specific obesity-related cancers. The hazards ratios associated with a 1-standard deviation increase in average annual neighborhood walkability were 0.88 (95% CI: 0.85, 0.93) for overall obesity-related cancer, 0.89 (95% CI: 0.84, 0.95) for postmenopausal breast cancer, 0.82 (95% CI: 0.68, 0.99) for ovarian cancer, 0.87 (95% CI: 0.76, 0.99) for endometrial cancer, and 0.68 (95% CI: 0.49, 0.94) for multiple myeloma, adjusting for potential confounders at both the individual and neighborhood level. The association between neighborhood walkability and risk of overall obesity-related cancer was stronger among women living in neighborhoods with higher levels of poverty compared with women living in areas with lower poverty levels (). Our study highlights a potential protective role of neighborhood walkability in preventing obesity-related cancers in women. https://doi.org/10.1289/EHP11538.

Previous evidence has identified exposure to fine ambient particulate matter () as a leading risk factor for adverse health outcomes. However, to date, only a few studies have examined the potential association between long-term exposure to and bone homeostasis. We sought to examine the relationship between long-term exposure and bone health and explore its potential mechanism. This research included both observational and experimental studies. First, based on human data from UK Biobank, linear regression was used to explore the associations between long-term exposure to (i.e., annual average concentration for 2010) and bone mineral density [BMD; i.e., heel BMD () and femur neck and lumbar spine BMD ()], which were measured during 2014-2020. For the experimental animal study, C57BL/6 male mice were assigned to ambient or filtered air for 6 months via a whole-body exposure system. Micro-computed tomography analyses were applied to measure BMD and bone microstructures. Biomarkers for bone turnover and inflammation were examined with histological staining, immunohistochemistry staining, and enzyme-linked immunosorbent assay. We also performed tartrate-resistant acid phosphatase (TRAP) staining and bone resorption assay to determine the effect of exposure on osteoclast activity in vitro. In addition, the potential downstream regulators were assessed by real-time polymerase chain reaction and western blot. We observed that long-term exposure to was significantly associated with lower BMD at different anatomical sites, according to the analysis of UK Biobank data. In experimental study, mice exposed long-term to exhibited excessive osteoclastogenesis, dysregulated osteogenesis, higher tumor necrosis factor-alpha () expression, and shorter femur length than control mice, but they demonstrated no significant differences in femur structure or BMD. In vitro, cells stimulated with conditional medium of macrophages had aberrant osteoclastogenesis and differences in the protein/mRNA expression of members of the pathway, which could be partially rescued by inhibition. Our prospective observational evidence suggested that long-term exposure to is associated with lower BMD and further experimental results demonstrated exposure to could disrupt bone homeostasis, which may be mediated by inflammation-induced osteoclastogenesis. https://doi.org/10.1289/EHP11646.

Polybrominated biphenyls (PBB) and polychlorinated biphenyls (PCB) are persistent organic pollutants with potential endocrine-disrupting effects linked to adverse health outcomes. In this study, we utilize high-resolution metabolomics (HRM) to identify internal exposure and biological responses underlying PCB and multigenerational PBB exposure for participants enrolled in the Michigan PBB Registry. HRM profiling was conducted on plasma samples collected from 2013 to 2014 from a subset of participants enrolled in the Michigan PBB Registry, including 369 directly exposed individuals (F0) who were alive when PBB mixtures were accidentally introduced into the food chain and 129 participants exposed to PBB in utero or through breastfeeding, if applicable (F1). Metabolome-wide association studies were performed for PBB-153 separately for each generation and (PCB-118, PCB-138, PCB-153, and PCB-180) in the two generations combined, as both had direct PCB exposure. Metabolite and metabolic pathway alterations were evaluated following a well-established untargeted HRM workflow. Mean levels were [standard deviation (SD): 13.9] for PBB-153 and (SD: 0.788) for . Sixty-two and 26 metabolic features were significantly associated with PBB-153 in F0 and F1 [false discovery rate (FDR) ], respectively. There were 2,861 features associated with (FDR ). Metabolic pathway enrichment analysis using a bioinformatics tool revealed perturbations associated with in numerous oxidative stress and inflammation pathways (e.g., carnitine shuttle, glycosphingolipid, and vitamin B9 metabolism). Metabolic perturbations associated with PBB-153 in F0 were related to oxidative stress (e.g., pentose phosphate and vitamin C metabolism) and in F1 were related to energy production (e.g., pyrimidine, amino sugars, and lysine metabolism). Using authentic chemical standards, we confirmed the chemical identity of 29 metabolites associated with levels (level 1 evidence). Our results demonstrate that serum PBB-153 is associated with alterations in inflammation and oxidative stress-related pathways, which differed when stratified by generation. We also found that was associated with the downregulation of important neurotransmitters, serotonin, and 4-aminobutanoate. These findings provide novel insights for future investigations of molecular mechanisms underlying PBB and PCB exposure on health. https://doi.org/10.1289/EHP12657.

Commonly encountered nontraumatic, moderate noise is increasingly implicated in anxiety; however, the neural substrates underlying this process remain unclear. We investigated the neural circuit mechanism through which chronic exposure to moderate-level noise causes anxiety-like behaviors. Mice were exposed to chronic, moderate white noise [85 decibel (dB) sound pressure level (SPL)], 4 h/d for 4 wk to induce anxiety-like behaviors, which were assessed by open field, elevated plus maze, light-dark box, and social interaction tests. Viral tracing, immunofluorescence confocal imaging, and brain slice patch-clamp recordings were used to characterize projections from auditory brain regions to the lateral amygdala. Neuronal activities were characterized by invivo multielectrode and fiber photometry recordings in awake mice. Optogenetics and chemogenetics were used to manipulate specific neural circuitry. Mice chronically (4 wk) exposed to moderate noise (85 dB SPL, 4 h/d) demonstrated greater neuronal activity in the lateral amygdala (LA), and the LA played a critical role in noise-induced anxiety-like behavior in these model mice. Viral tracing showed that the LA received monosynaptic projections from the medial geniculate body (MG) and auditory cortex (ACx). Optogenetic excitation of the or circuits acutely evoked anxiety-like behaviors, whereas their chemogenetic inactivation abolished noise-induced anxiety-like behavior. Moreover, mice chronically exposed to moderate noise were more susceptible to acute stress, with more neuronal firing in the LA, even after noise withdrawal. Mice exposed to 4 wk of moderate noise (85 dB SPL, 4 h/d) demonstrated behavioral and physiological differences compared to controls. The neural circuit mechanisms involved greater excitation from glutamatergic neurons of the MG and ACx to LA neurons under chronic, moderate noise exposure, which ultimately promoted anxiety-like behaviors. Our findings support the hypothesis that nontraumatic noise pollution is a potentially serious but unrecognized public health concern. https://doi.org/10.1289/EHP12532.

Herbicides are the most used class of pesticides worldwide, and insect repellents are widely used globally. Yet, there is a dearth of studies characterizing the associations between these chemical groups and human neurobehavior. Experimental studies suggest that glyphosate and 2,4-dichlorophenoxyacetic acid (2,4-D) herbicides can affect neurobehavior and the cholinergic and glutamatergic pathways in the brain. We aim to assess whether herbicides and insect repellents are associated with neurobehavioral performance in adolescents. We assessed 519 participants (11-17 years of age) living in agricultural communities in Ecuador. We quantified urinary concentrations of glyphosate, 2,4-D, and two N,N-diethyl-meta-toluamide (DEET) insect repellent metabolites [3-(diethylcarbamoyl)benzoic acid (DCBA) and 3-(ethylcarbamoyl)benzoic acid (ECBA)] using isotope-dilution mass spectrometry. We assessed neurobehavioral performance using 9 subtests across 5 domains (attention/inhibitory control, memory/learning, language, visuospatial processing, and social perception). We characterized the associations using generalized estimating equations and multiple imputation for metabolites below detection limits. Models were adjusted for demographic and anthropometric characteristics, urinary creatinine, and sexual maturation. Mediation by salivary cortisol, dehydroepiandrosterone, , and testosterone was assessed using structural equation modeling. The mean of each neurobehavioral domain score was between 7.0 and 8.7 [standard deviation (SD) range: 2.0-2.3]. Glyphosate was detected in 98.3% of participants, 2,4-D in 66.2%, DCBA in 63.3%, and ECBA in 33.4%. 2,4-D was negatively associated with all neurobehavioral domains, but statistically significant associations were observed with attention/inhibition [score difference per 50% higher metabolite concentration 95% confidence interval (CI): , ], language [ (95% CI: , )], and memory/learning [ (95% CI: , 0.01)]. Glyphosate had a statistically significant negative association only with social perception [ (95% CI: , )]. DEET metabolites were not associated with neurobehavioral performance. Mediation by gender and adrenal hormones was not observed. This study describes worse neurobehavioral performance associated with herbicide exposures in adolescents, particularly with 2,4-D. Replication of these findings among other pediatric and adult populations is needed. https://doi.org/10.1289/EHP11383.