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Purpose: Childhood lead exposure is linked to poorer neurobehavioral function in adolescence, but the relationship between lead and adolescent sleep health remains inconsistent. This study aimed to investigate concurrent and longitudinal associations between lead exposure and multiple sleep health domains in adolescents., Methods: A total of 972 adolescents from China Jintan Child Cohort were included in analyses. The Blood lead levels (BLLs) were assessed in two Waves, at ages 3-5 years (mean 6.50 ± 2.76 μg/dL) and 11-13 years (mean 3.12 ± 1.17 μg/dL). Sleep problems at age 11-13 were parent-reported via the Child Sleep Health Questionnaire (CSHQ) and self-reported by adolescents using the Pittsburgh Sleep Quality Index (PSQI)., Results: Both early and later BLLs were associated positively with parental reported sleep problems, including sleep onset delay, night waking, short duration, parasomnias, and disordered breathing. Sex-stratified analyzes showed that most adjusted associations between two-Wave BLLs and sleep outcomes (CSHQ and PSQI) remained statistically significant in males, with a minor increase in the magnitude of these associations. The association between Wave II BLLs and shorter self-reported sleep duration was only statistically significant in female adolescents. Compared to children with consistently low BLLs at both ages, those with persistently high BLLs at both ages had significantly shorter parental-reported sleep duration and worse sleep onset delay., Conclusion: Findings suggest that both early and later childhood lead exposures link to more adolescent sleep problems, with recent BLLs showing stronger associations with poor adolescent sleep health reported by their parents., Competing Interests: Declarations Conflict of interest The authors declare no conflict of interest. Ethical approval The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of the University of Pennsylvania and the Ethical Committee for Research at Jintan Hospital in China. Informed consent Informed consent was obtained from all subjects involved in the study., (© 2024. The Author(s).)

The biological pathways linking lead exposure to adverse outcomes are beginning to be understood. Rodent models suggest lead exposure induces dysfunction within the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoid regulation, a primary physiological stress response system. Over time, HPA axis and glucocorticoid dysfunction has been associated with adverse neurocognitive and cardiometabolic health, much like lead exposure. This systematic review utilized PRISMA guidelines to synthesize the literature regarding associations between lead exposure and downstream effector hormones of the HPA axis, including cortisol, a glucocorticoid, and dehydroepiandrosterone (DHEA), a glucocorticoid antagonist. We additionally determined the state of the evidence regarding lead exposure and allostatic load, a measure of cumulative body burden resultant of HPA axis and glucocorticoid dysfunction. A total of 18 articles were included in the review: 16 assessed cortisol or DHEA and 3 assessed allostatic load. Generally, the few available child studies suggest a significant association between early life lead exposure and altered cortisol, potentially suggesting the impact of developmental exposure. In adulthood, only cross sectional studies were available. These reported significant associations between lead and reduced cortisol awakening response and increased cortisol reactivity, but few associations with fasting serum cortisol. Two studies reported significant associations between increasing lead exposure and allostatic load in adults and another between early life lead exposure and adolescent allostatic load. The paucity of studies examining associations between lead exposure and allostatic load or DHEA and overall heterogeneity of allostatic load measurements limit conclusions. However, these findings cautiously suggest associations between lead and dysregulation of physiological stress pathways (i.e., glucocorticoids) as seen through cortisol measurement in children and adults. Future research would help to elucidate these associations and could further examine the physiological stress pathway as a mediator between lead exposure and detrimental health outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Few studies have related early life lead exposure to adolescent biological aging, a period characterized by marked increases in maturational tempo. We examined associations between prenatal and childhood lead exposure and adolescent biological age (mean 14.5 years) utilizing multiple epigenetic clocks including: intrinsic (IEAA), extrinsic (EEAA), Horvath, Hannum, PhenoAge, GrimAge, Skin-Blood, Wu, PedBE, as well as DNA methylation derived telomere length (DNAmTL). Epigenetic clocks and DNAmTL were calculated via adolescent blood DNA methylation measured by Infinium MethylationEPIC BeadChips. We constructed general linear models (GLMs) with individual lead measures predicting biological age. We additionally examined sex-stratified models and lead by sex interactions, adjusting for adolescent age and lead levels, maternal smoking and education, and proportion of cell types. We also estimated effects of lead exposure on biological age using generalized estimating equations (GEE). First trimester blood lead was positively associated with a 0.14 increase in EEAA age in the GLMs though not the GEE models (95%CI 0.03, 0.25). First and 2nd trimester blood lead levels were associated with a 0.02 year increase in PedBE age in GLM and GEE models (1st trimester, 95%CI 0.004, 0.03; 2nd trimester, 95%CI 0.01, 0.03). Third trimester and 24 month blood lead levels were associated with a -0.06 and -0.05 decrease in Skin-Blood age, respectively, in GLM models. Additionally, 3rd trimester blood lead levels were associated with a 0.08 year decrease in Hannum age in GLM and GEE models (95%CI -0.15, -0.01). There were multiple significant results in sex-stratified models and significant lead by sex interactions, where males experienced accelerated biological age, compared to females who saw a decelerated biological age, with respect to IEAA, EEAA, Horvath, Hannum, and PedBE clocks. Further research is needed to understand sex-specific relationships between lead exposure and measures of biological aging in adolescence and the trajectory of biological aging into young adulthood., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The biological pathways which link lead (Pb) and long-term outcomes are unclear, though rodent models and a few human studies suggest Pb may alter the body's stress response systems, which over time, can elicit dysregulated stress responses with cumulative impacts. This study examined associations between prenatal and early childhood Pb exposure and adolescent allostatic load, an index of an individual's body burden of stress in multiple biological systems, and further examined sex-based associations. Among 391 (51% male) participants in the ELEMENT birth cohort, we related trimester-specific maternal blood Pb, 1-month postpartum maternal tibia and patella Pb, and child blood Pb at 12-24 months to an allostatic load index in adolescence comprised of biomarkers of cardiovascular, metabolic, neuroendocrine, and immune function. The results were overall mixed, with prenatal exposure, particularly maternal bone Pb, being positively associated with allostatic load, and early childhood Pb showing mixed results for males and females. In adjusted Poisson regression models, 1 mcg/g increase in tibia Pb was associated with a 1% change in expected allostatic load (IRR = 1.01; 95%CI 0.99, 1.02). We found a significant Pb × sex interaction (IRR = 1.05; 95%CI 1.01, 1.10); where males saw an increasing percent change in allostatic load as 12 month Pb levels increased compared to females who saw a decreasing allostatic load. Further examination of allostatic load will facilitate the determination of potential mechanistic pathways between developmental toxicant exposures and later-in-life cardiometabolic outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The independent effect of lead exposure and parental education on children's neurocognition is well-documented. However, few studies have examined the combined effect of childhood lead exposure and parental education on adolescent neurocognition, especially in China., Objective: Examine both the combined and interactive effect of childhood blood lead levels (BLLs) and parental education on early adolescent neurocognition., Methods: 417 children from a longitudinal cohort study in Jintan, China had BLLs measured at 3-5 years and 12 years, parental education levels assessed at 3-5 years, and neurocognitive outcomes tested at 12 years., Results: BLLs at 3-5 years were inversely associated with adolescent IQ (β -0.55 95% CI: -0.97, -0.13) but not working memory (β -0.06 95% CI: -0.23, 0.11) and parental education was positively associated with adolescent IQ (β 0.68 95% CI: 0.19, 1.17) and working memory (β 0.24 95% CI: 0.04, 0.44). BLLs and parental education evidenced combined effects on neurocognition, where children with higher BLLs and lower fathers' education had mean IQ scores 7.84 (95% CI: -13.15, -2.53) points lower than children with lower BLLs and higher fathers' education. There were significant associations between parental education and working memory, however, not with BLLs. The interaction between mother and father high school education and BLLs was insignificant for effects on IQ and working memory., Significance: Childhood lead exposure and parental education levels have a combined and long-term impact on IQ, evidence that may partially explain disparities in lead exposure associated outcomes and highlight those children at greatest risk for neurocognitive deficits., Impact Statement: Children continue to be exposed to low-levels of environmental lead in China and globally, warranting examination of the impact of such exposures. This paper demonstrates that even relatively low-level lead exposure in early childhood significantly influences adolescent neurocognitive functioning. Furthermore, co-existing social determinant of health-related variables, measured here as parental education, have a combined impact on neurocognition. These results highlight children at greater risk for neurocognitive deficits and demonstrate the need to examine the influence of lead exposure within the broader socio- ecological environment, as these factors work in tandem to influence longer-term neurocognitive outcomes., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

It is well documented that childhood lead exposure is associated with long-term decreases in intelligence quotients (IQ). Lesser known is the relationship with neurobehavioral domains, especially in adolescence. This study sought to identify cross-sectional and longitudinal associations between lead exposure and adolescent executive and visual-motor functioning and examine sex-based differences. Participants were 681 children from Jintan, China who had their blood lead levels (BLLs) assessed at age 3-5 years and 12 years old and neurobehavioral functioning assessed through the University of Pennsylvania Computerized Neurocognitive Battery (PennCNB) platform http://www.med.upenn.edu/bbl at 12 years old. Mean BLLs were 6.41 mcg/dl at age 3-5 years and 3.10 mcg/dl at 12. BLLs at 3-5 years and 12 years were used as predictors for the individual neurobehavioral domains in general linear models while controlling for father and mother occupation and education, residence location, age, and adolescent IQ. Models were run separately for males and females. In adjusted models, males BLLs at 3-5 years were associated with increased time to correctly complete tasks in multiple domains including abstraction/flexibility (β = 19.90, 95% CI( 4.26, 35.54) and spatial processing (β = 96.00, 95% CI 6.18, 185.82) at 12 years. For females in adjusted models, BLLs at 3-5 years were associated with increasing time to correctly complete tasks on the episodic memory domain task (β = 34.59, 95% CI 5.33, 63.84) at 12 years. Two adolescent cross-sectional relationships remained in the adjusted models for males only, suggesting a positive association between BLLs and increasing time for correct responses on the attentional domain task (β = 15.08, 95% CI 0.65, 29.51) and decreasing time for correct responses on the episodic memory task (β = -73.49, 95% CI -138.91, -8.06) in males at 12 years. These associations remained with and without controlling for IQ. These results suggest that lead exposure is associated with overall deficits in male and female neurobehavioral functioning, though in different domains and different timing of exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Competing interests The authors have no competing interests to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Lead is a known neurotoxicant with many detrimental health effects, including neurocognitive deficits and cardiovascular and metabolic disorders. However, few studies have tested the association between lead exposure and the physiological stress response, which in and of itself may act as a precursor to and/or underlying mechanism of detrimental health outcomes. The purpose of this study was to examine the influence of early childhood and early adolescent low-level lead exposure on early adolescent heart rate variability, a widely-used measure of physiological stress. Participants were 408 children from Jintan, China for whom blood lead levels were measured between 3 and 5 years (early childhood) and again at 12 years (early adolescence). Heart rate variability was assessed at 12 years while participants underwent an induced stress task utilizing the ratio of low to high frequency (LF/HF) ECG measures. Mean blood lead levels in the cohort were 6.63 mcg/dl and 3.10 mcg/dl at 3-5 years and 12 years, respectively. Blood lead levels at 3-5 years of age (β 0.06, p = 0.027), but not at age 12 (β -0.05, p = 0.465), were significantly associated with LF/HF measures while controlling for multiple sociodemographic variables, potentially reflecting a dysregulated stress response with a shift towards sympathetic dominance. These findings suggest that early childhood lead exposure may have a detrimental influence on early adolescent autonomic responses to acute stress, which holds implications for cardiovascular health and overall growth and development., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: The degree to which opioid-induced hyperalgesia contributes to the pain experience of patients with chronic pain remains relatively undescribed. The objective of this pilot study was to determine if experimental pain responses improve in patients with chronic pain as they undergo a planned opioid taper., Methods: This was a prospective observational study. Seven patients with chronic neuropathic pain on at least 120 mg morphine equivalents/day were enrolled. The participants were followed over the course of an individualized opioid taper to a lower dose. Measures of experimental pain sensitivity, including indicators of central pain modulation, were collected on a biweekly basis; in addition, measures of function and quality of life were collected monthly. The effect of opioid taper on pain responses and functional outcomes over time were examined using longitudinal mixed-effects regression modeling and general linear regression modeling with regularization as a function of baseline dose, end dose, and taper rate., Results: In this small sample of patients undergoing highly individualized and variable opioid taper, the opioid taper was significantly associated with improved pain responses to the cold-pressor test, with the pain threshold on average increasing by 1.14 s every 6 weeks (p = 0.0084, 95% confidence interval [CI] for 6-week change 0.3039-2.0178) and pain tolerance on average increasing by 2.87 s every 6 weeks (p = 0.0026, 95% CI for 6-week change 1.02-4.7277). Taper-related changes in central pain modulation were not observed, although conditioned modulation trended toward improvement by the completion of opioid taper. Similarly, no declines in function and quality of life were observed with the opioid taper, suggesting stability despite decreased opioid dose., Conclusions: Opioid taper was associated with improvements in experimental pain responses without a decline in function and quality of life, suggestive of diminished opioid-induced hyperalgesia in this clinical sample., Trial Registration: ClinicalTrials.gov identifier, NCT03912298., (© 2022. The Author(s).)

Lead exposure has been shown to dysregulate physiological stress responses. However, few studies have investigated the effect of lead exposure on later heart rate variability (HRV), an indicator of a stress response, in large samples of children. Furthermore, the interaction between social environmental factors and lead exposure in childhood, which commonly co-occur, remains understudied. This study examined relationships between childhood lead exposure and early adolescent physiological stress responses at different levels of parental education. Participants were 406 children from Jintan, China. Blood lead levels (BLLs) and parental education data were collected at 3-5 years of age, and HRV outcomes assessed at 12 years via frequency domain measures (LF/HF ratio) collected during an induced stress test. Results show a significant interaction between parental education and BLLs at 3-5 years. This relationship was found to be most consistent for the interaction between BLLs and mother's years of education for both the planning ( β  = 0.12, p  = 0.046) and speaking ( β  = 0.11, p  = 0.043) phase of the stress task, suggesting that increasing years of mother's education may enhance the deleterious influence of lead exposure on the HRV frequency measure, LF/HF ratio. This research highlights the complexity in lead exposure induced outcomes.