Early Life Lead Exposure Research Articles

Low-Level, Early Life Lead Exposure and School Behavior.

To measure how early childhood exposure to lead affects school behavior from third to eighth grade, measured by the number and days of total school suspensions and out-of-school suspensions (OSS). We estimate Poisson models using a cohort of 284 701 students with school records from 2006-2008 in North Carolina. We adjust for demographic and socioeconomic variables and school-grade-year cohort effects, and use coarsened exact matching to ensure similar characteristics across children with blood lead levels (BLLs) 2-10 μg/dL and children in the reference group with BLLs ≤1 μg/dL. BLLs ≥3 µg/dL are positively and significantly associated with all school suspension measures for sixth through eighth graders. The estimated effects on OSS for sixth through eighth graders are larger than the effects on total suspensions. For example, students with BLL = 3 µg/dL receive OSS 16% (95% confidence interval 3.6%-30%) more often and for 22% (95% confidence interval 7.3%-33%) more days than students with BLL ≤1 µg/dL. For third through fifth grade students, we only find a significant effect of lead exposure on suspensions at relatively high BLLs of 8-10 µg/dL. Our analysis demonstrates that BLL has significant adverse effects on third through eighth grade students' behavior, including at levels below the current Centers for Disease Control and Prevention's blood lead reference value of 3.5 μg/dL. We find that the adverse effects of lead are most strongly associated with more severe disruptive behavior in sixth through eighth graders, as measured by OSS. Our results underscore the long-term benefits of preventing early childhood exposure to lead.

Pre-natal and early life lead exposure and childhood inhibitory control: an item response theory approach to improve measurement precision of inhibitory control

BackgroundNeurodevelopmental performance tasks are often separately analyzed, even when they tap into a similar construct. This may yield mixed findings for associations of an exposure-neurobehavioral outcome. We develop an item response theory (IRT) approach to integrate multiple task variables together to improve measurement precision of the underlying construct. We apply this approach to create an integrative measure of childhood inhibitory control, and study impacts of pre/post-natal lead exposure.MethodsUsing data from a prospective cohort based in Mexico (N = 533), we created an inhibitory control scale that integrates accuracy and reaction time information from four inhibitory control tasks (Go/NoGo Letter, Go/NoGo Neutral, Go/NoGo Happy, Delis-Kaplan Executive Function System (D-KEFS) Color-Word Interference Test, Condition 3). Using a generalized partial credit item response theory model, we estimated an inhibitory control index for each participant. We then assessed adjusted associations between umbilical cord blood and 4-year lead and childhood inhibitory control. We developed a resampling approach to incorporate error estimates from the inhibitory control variable to confirm the consistency of the lead-inhibitory control associations. We modeled time-varying associations of lead with each inhibitory control measure separately.ResultsParticipants had a median age of 9 years; 51.4% were males. Umbilical cord blood [-0.06 (95% CI: -0.11, -0.01)] and 4-year lead [-0.07 (95% CI: -0.12, -0.02)] were associated with inhibitory control index at 8–10 years. A resampling approach confirmed that 4-year lead was consistently associated with childhood inhibitory control index. Umbilical cord blood and 4-year lead were each associated with 3 out of 8 measures in separate models.ConclusionThis is the first application of IRT in environmental epidemiology to create a latent variable for inhibitory control that integrates accuracy and reaction time information from multiple, related tasks. This framework can be applied to other correlated neurobehavioral assessments or other phenotype data.

Influences of quality of maternal care and environmental enrichment on associative memory function in rats with early life lead exposure.

Children in low socioeconomic status (SES) communities are at higher risk of exposure to lead (Pb) and potentially more severe adverse outcomes from Pb exposures. While the factors encompassing SES are complex, low SES households often have less enriching home environments and parent-child interactions. This study investigated the extent to which environmental/behavioral factors (quality of maternal care and richness of the postnatal environment) may modify adverse effects from Pb exposure. Long-Evans female rats were randomly assigned to Control (no Pb), Early Postnatal (EPN: birth through weaning), or Perinatal (PERI: 14 days pre-mating through weaning) Pb exposure groups. From postnatal days (PNDs) 2-9, maternal care behaviors were observed, and dams were classified as low or high maternal care based on amounts of licking/grooming and arched back nursing. At weaning, pups were randomly assigned to enriched or non-enriched environments. At PND 55, animals began trace fear conditioning and associative memory was tested on days 1, 2, and 10 postconditioning. Control offspring showed no significant effects of maternal care or enrichment on task performance. Females with EPN-Pb exposure and males with PERI-Pb exposure living in the non-enriched environment and having an LMC mother had significant memory impairments at days 2 and 10 that were not observed in comparably housed animals with HMC mothers. Enriched animals had no deficits, regardless of maternal care status. These results show the potential for modulatory influences of maternal care and housing environment on protecting against or reversing at least one aspect of Pb-induced cognitive/behavioral dysfunction.

Early-life lead exposure is associated with cognition in late adulthood

Early-life lead exposure is associated with cognition in late adulthood

Early life lead exposure associated with higher BMI in late adulthood

Early life lead exposure associated with higher BMI in late adulthood

Childhood blood-lead level predicts lower general, non-selective hippocampal subfield volumes in midlife

Millions of adults and children are exposed to high levels of lead, a neurotoxicant, each year. Recent evidence suggests that lead exposure may precipitate neurodegeneration, particularly if the exposure occurs early or late in life, with unique alterations to the structure or function of specific subfields of the hippocampus, a region involved in memory and Alzheimer’s disease. It has been proposed that specific hippocampal subfields may thus be useful biomarkers for lead-associated neurological disease. We turned to a population-representative New Zealand birth cohort where the extent of lead exposure was not confounded by social class (the Dunedin Study; born 1972–1973 and followed to age 45) to test the hypothesis that early life lead exposure (blood-lead level at age 11 years) is associated with smaller MRI-assessed gray matter volumes of specific subfields of the hippocampus at age 45 years. Among the 508 Dunedin Study members with childhood lead data and adult MRI data passing quality control (93.9 % of those with lead data who attended the age-45 assessment wave, 240[47.2 %] female), childhood blood-lead levels ranged from 4 to 31 µg/dL (M[SD]=10.9[4.6]). Total hippocampal volumes were lower among adults with higher childhood blood-lead levels (b=-102.6 mm3 per 5 ug/dL-unit greater blood-lead level, 95 %CI: −175.4 to −29.7, p=.006, β=-.11), as were all volumes of the 24 hemisphere-specific subfields of the hippocampus. Of these 24 subfields, 20 demonstrated negative lead-associations greater than β=-.05 in size, 14 were statistically significant after adjustment for multiple comparisons (pFDR<.05), and 9 remained significant after adjustment for potential confounders and multiple comparisons. Children exposed to lead demonstrate smaller volumes across all subfields of the hippocampus in midlife. The hypothesis that lead selectively impairs specific subfields of the hippocampus, or that specific subfields may be markers for lead-associated neurological disease, requires further evaluation.

Sensitivity analysis for matched observational studies with continuous exposures and binary outcomes

Summary Matching is one of the most widely used study designs for adjusting for measured confounders in observational studies. However, unmeasured confounding may exist and cannot be removed by matching. Therefore, a sensitivity analysis is typically needed to assess a causal conclusion’s sensitivity to unmeasured confounding. Sensitivity analysis frameworks for binary exposures have been well-established for various matching designs and are commonly used in various studies. However, unlike the binary exposure case, there still lacks valid and general sensitivity analysis methods for continuous exposures, except in some special cases such as pair matching. To fill this gap in the binary outcome case, we develop a sensitivity analysis framework for general matching designs with continuous exposures and binary outcomes. First, we use probabilistic lattice theory to show our sensitivity analysis approach is finite-population- exact under Fisher’s sharp null. Second, we prove a novel design sensitivity formula as a powerful tool for asymptotically evaluating the performance of our sensitivity analysis approach. Third, to allow effect heterogeneity with binary outcomes, we introduce a framework for conducting asymptotically exact inference and sensitivity analysis on generalized attributable effects with binary outcomes via mixed- integer programming. Fourth, for the continuous outcomes case, we show that conducting an asymptotically exact sensitivity analysis in matched observational studies when both the exposures and outcomes are continuous is generally NP-hard, except in some special cases such as pair matching. As a real data application, we apply our new methods to study the effect of early-life lead exposure on juvenile delinquency. An implementation of the methods in this work is available in the R package doseSens.

Early-Life Lead Exposure: Risks and Neurotoxic Consequences.

Lead (Pb) does not have any biological function in a human, and it is likely no safe level of Pb in the human body. The Pb exposure impacts are a global concern for their potential neurotoxic consequences. Despite decreasing both the environmental Pb levels and the average blood Pb levels in the survey populations, the lifetime redistribution from the tissues-stored Pb still poses neurotoxic risks from the low-level exposure in later life. The growing fetus and children hold their innate high-susceptible to these Pb-induced neurodevelopmental and neurobehavioral effects. This article aims to evaluate cumulative studies and insights on the topic of Pb neurotoxicology while assessing the emerging trends in the field. The Pb-induced neurochemical and neuro-immunological mechanisms are likely responsible for the high-level Pb exposure with the neurodevelopmental and neurobehavioral impacts at the initial stages. Early-life Pb exposure can still produce neurodegenerative consequences in later life due to the altered epigenetic imprints and the ongoing endogenous Pb exposure. Several mechanisms contribute to the Pb-induced neurotoxic impacts, including the direct neurochemical effects, the induction of oxidative stress and inflammation through immunologic activations, and epigenetic alterations. Furthermore, the individual nutritional status, such as macro-, micro-, or antioxidant nutrients, can significantly influence the neurotoxic impacts even at low-level exposure to Pb. The prevention of early-life Pb exposure is, therefore, the critical determinant for alleviating various Pb-induced neurotoxic impacts across the different age groups.

Prenatal and early life lead exposure induced neurotoxicity.

Lead (Pb) has become a major environmental contaminant. There are several ways in which lead can enter the human body and cause toxic effects on human health. This review focuses on the impact of lead toxicity at prenatal and early life stages and its effect on neurodevelopment. Lead exposure to the developing foetus targets foetal neural stem cells. Hence, it has detrimental effects on developing neural and glial cells, adversely influencing cognition and behaviour. Lead has a profound influence on the movement of calcium ions (Ca2+), which can be attributed to most of the mechanisms by which lead affects neurodevelopment. There is no known safe threshold of lead exposure for children. Lead can affect foetal neurodevelopment leading to various neurological disorders, and neurotoxic effects on behavioural and cognitive outcomes. In this review, we discuss prenatal and early-life lead exposure, its mechanism, and consequences for neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease in later stages of life. This review further highlights the importance of lead exposure during pregnancy and lactation periods as well as early development of the child in understanding the extent of lead-induced neurological damage to the foetus/children and the associated future risks.

Prenatal and childhood lead exposure is prospectively associated with biological markers of aging in adolescence

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.

Impact of early-life lead exposure on adult delta-9-tetrahydrocannabinol sensitivity in male and female C57BL6/J mice

Environmental exposure to lead (Pb) and cannabis use are two of the largest public health issues facing modern society in the United States and around the world. Exposure to Pb in early life has been unequivocally shown to have negative impacts on development, and recent research is mounting showing that it may also predispose individuals for risk of developing substance use disorders (SUD). At the same time, societal and legal attitudes towards cannabis (the main psychoactive component of which is delta-9-tetrahydrocannabinol) have been shifting, and many American states have legalized the recreational use of cannabis. It is also the 3rd most widely used drug of abuse in the US, and rates of cannabis use disorder are on the rise. Here we establish a link between early life Pb exposure and later THC-related behavior in C57BL6/J mice, as has been demonstrated for other drugs of abuse. The study seeks to answer whether Pb exposure affects physiological/behavioral THC sensitivity (as measured by the cannabinoid-induced tetrad). It was hypothesized that Pb exposure would decrease THC sensitivity and that sex-dependent effects of Pb-exposure and THC would be observed. Interestingly, results showed that THC sensitivity was increased by Pb exposure, but only in female mice. Future research will fully explore the implications of these findings, namely how these effects impact THC self-administration and the mechanism(s) by which developmental Pb exposure produces these effects.

Early-life exposure to lead changes cardiac development and compromises long-term cardiac function

Lead (Pb) is widely used in industrial and daily-use consumer products. Early-life exposure may increase the risk of lead-related heart problems in childhood. However, the effects of early-life lead exposure on fetal heart development and long-term cardiac outcomes are unknown. In this study, pregnant ICR mice were exposed to lead acetate trihydrate (50 mg/kg/d) via oral gavage from gestation day 1.5 until offspring weaning. Thereafter, the second hit model was established, two groups of offspring (4 weeks old) were either administered sterile saline or Angiotensin II (Ang II) for 4 weeks until euthanasia. We investigated lead-induced offspring heart damage from embryonic period to adulthood by echocardiographic analysis, pathological H&E staining, and ultrastructural examination, as well as mitochondrial function detection. The results showed early-life lead exposure predisposed offspring mice to decreased ejection fraction, increased left ventricular volume, accompanied by hypertrophy and dilation, cardiomyocyte sarcomere dysplasia, abnormal mitochondrial structure, mitochondrial dysfunction, and decreased expression of key sarcomeric and mitochondrial genes, rendering them more susceptible to cardiac hypertrophy, vascular wall thickening, cardiac fibrosis, apoptosis, and heart failure induced by Ang II infusion. This study elucidates early-life low dose lead exposure compromises cardiac development and exacerbates second hit-induced cardiac pathological responses in adulthood, which furnishes crucial scientific evidence pertaining to the cardiac toxicity and risk evaluation associated with early-life exposure to lead.

Differential expression of SLC30A10 and RAGE in mouse pups by early life lead exposure

BackgroundSLC30A10 and RAGE are widely recognized as pivotal regulators of Aβ plaque transport and accumulation. Prior investigations have established a link between early lead exposure and cerebral harm in offspring, attributable to Aβ buildup and amyloid plaque deposition. However, the impact of lead on the protein expression of SLC30A10 and RAGE has yet to be elucidated. This study seeks to confirm the influence of maternal lead exposure during pregnancy, specifically through lead-containing drinking water, on the protein expression of SLC30A10 and RAGE in mice offspring. Furthermore, this research aims to provide further evidence of lead-induced neurotoxicity. MethodsFour cohorts of mice were subjected to lead exposure at concentrations of 0 mM, 0.25 mM, 0.5 mM, and 1 mM over a period of 42 uninterrupted days, spanning from pregnancy to the weaning phase. On postnatal day 21, the offspring mice underwent assessments. The levels of lead in the blood, hippocampus, and cerebral cortex were scrutinized, while the mice's cognitive abilities pertaining to learning and memory were probed through the utilization of the Morris water maze. Furthermore, Western blotting and immunofluorescence techniques were employed to analyze the expression levels of SLC30A10 and RAGE in the hippocampus and cerebral cortex. ResultsThe findings revealed a significant elevation in lead concentration within the brains and bloodstreams of mice, mirroring the increased lead exposure experienced by their mothers during the designated period (P < 0.05). Notably, in the Morris water maze assessment, the lead-exposed group exhibited noticeably diminished spatial memory compared to the control group (P < 0.05). Both immunofluorescence and Western blot analyses effectively demonstrated the concomitant impact of varying lead exposure levels on the hippocampal and cerebral cortex regions of the offspring. The expression levels of SLC30A10 displayed a negative correlation with lead doses (P < 0.05). Surprisingly, under identical circumstances, the expression of RAGE in the hippocampus and cortex of the offspring exhibited a positive correlation with lead doses (P < 0.05). ConclusionSLC30A10 potentially exerts distinct influence on exacerbated Aβ accumulation and transportation in contrast to RAGE. Disparities in brain expression of RAGE and SLC30A10 may contribute to the neurotoxic effects induced by lead.

Biomarkers of maternal lead exposure during pregnancy using micro-spatial child deciduous dentine measurements

BackgroundLead is a toxic chemical of public health concern, however limited biomarkers are able to reconstruct prior lead exposures in early-life when biospecimens are not collected and stored. Although child tooth dentine measurements accurately assess past child perinatal lead exposure, it has not been established if they reflect maternal exposure in pregnancy. AimTo assess the prenatal relationship between child tooth dentine and maternal blood lead measurements and to estimate maternal lead exposure during the 2nd and 3rd trimesters of pregnancy from weekly child dentine profiles. MethodsWe measured early-life lead exposure in child tooth dentine and maternal blood from 419 child-mother dyads enrolled in the Programming Research in Obesity, Growth, Environment and Social Stress (PROGRESS) cohort. We employed the Super-Learner algorithm to determine the relationship of dentine lead data with maternal blood lead concentrations and to predict maternal lead from child dentine lead data in blinded analyses. We validated and quantified the bias of our results internally. ResultsMothers had moderate blood lead levels (trimesters: 2nd = 29.45 ug/L, 3rd = 31.78 ug/L). Trimester-averaged and weekly child dentine lead measurements were highly correlated with maternal blood levels in the corresponding trimesters. The predicted trimester-specific maternal lead levels were significantly correlated with actual measured blood values (trimesters: 2nd = 0.83; 3rd = 0.88). Biomarkers of maternal lead exposure discriminated women highly exposed to lead (>mean) with 85 % and 96 % specificity in the 2nd and 3rd trimesters, respectively, with 80 % sensitivity. DiscussionWeekly child dentine lead levels can serve as biomarkers of past child and maternal lead exposures during pregnancy.

Chronic early-life lead exposure sensitizes adolescent rats to cocaine: Role of the dopaminergic system

Exposure to heavy metals has been associated with psychiatric disorders and recent studies suggest an association between childhood lead (Pb2+) intoxication and schizophrenia (SZ). In animal models, Pb2+ exposure recapitulates key neuropathological and dopaminergic system alterations present in SZ. Given the high comorbidity of mental disorders such as SZ and substance abuse, coupled with evidence showing that Pb2+ exposure affects addiction circuits, we hypothesized that early life Pb2+ exposure could sensitize neuronal systems relevant to SZ and substance abuse. To this goal, we examined the effects of chronic developmental Pb2+ exposure on the acute locomotor response to cocaine (0, 5, and 15 mg kg–1) and behavioral sensitization. We also examined the role of the dopaminergic system in the psychostimulant effects of cocaine, and measured D1-dopamine receptor (D1R) levels in the rat brain using [3H]-SCH23390 quantitative receptor autoradiography, as well as the ability of the D1R antagonist SCH23390 to block the cocaine effects on locomotor activation. These studies were performed in male and female rats at different developmental ages consisting of juveniles (postnatal, PN14), early-adolescent (PN28), late adolescent (PN50), and adults (PN120). Our results show that chronic developmental Pb2+ exposure increases the acute locomotor response to the higher dose of cocaine in Pb2+-exposed male adolescent (PN28 and PN50) rats, and to the lower dose of cocaine in adolescent female rats. No changes in the locomotor activity were detected in adult rats. Behavioral sensitization experiments showed a sustained sensitization in early adolescent Pb2+-exposed male but not female rats. The cocaine-induced effects on locomotor activity were abrogated by injection of a D1R antagonist suggesting the involvement of this dopamine receptor subtype. Furthermore, Pb2+-induced increases D1R levels in several brain regions were prominent in juveniles and early adolescence but not in late adolescence or in adults. In summary, early chronic developmental Pb2+ exposure results in age and sex-dependent effect on the locomotor response to cocaine, suggesting differential susceptibilities to the neurotoxic effects of Pb2+ exposure. Our data provides further support to the notion that Pb2+ exposure is an environmental risk factor for psychiatric disorders and substance abuse.

Altered genome-wide hippocampal gene expression profiles following early life lead exposure and their potential for reversal by environmental enrichment

Early life lead (Pb) exposure is detrimental to neurobehavioral development. The quality of the environment can modify negative influences from Pb exposure, impacting the developmental trajectory following Pb exposure. Little is known about the molecular underpinnings in the brain of the interaction between Pb and the quality of the environment. We examined relationships between early life Pb exposure and living in an enriched versus a non-enriched postnatal environment on genome-wide transcription profiles in hippocampus CA1. RNA-seq identified differences in the transcriptome of enriched vs. non-enriched Pb-exposed animals. Most of the gene expression changes associated with Pb exposure were reversed by enrichment. This was also true for changes in upstream regulators, splicing events and long noncoding RNAs. Non-enriched rats also had memory impairments; enriched rats had no deficits. The results demonstrate that an enriched environment has a profound impact on behavior and the Pb-modified CA1 transcriptome. These findings show the potential for interactions between Pb exposure and the environment to result in significant transcriptional changes in the brain and, to the extent that this may occur in Pb-exposed children, could influence neuropsychological/educational outcomes, underscoring the importance for early intervention and environmental enrichment for Pb-exposed children.

Early life lead exposure from private well water increases juvenile delinquency risk among US teens

Early life exposure to environmental lead (Pb) has been linked to decreased IQ, behavior problems, lower lifetime earnings, and increased criminal activity. Beginning in the 1970s, limits on Pb in paint, gasoline, food cans, and regulated water utilities sharply curtailed US environmental Pb exposure. Nonetheless, hundreds of thousands of US children remain at risk. This study reports on how unregulated private well water is an underrecognized Pb exposure source that is associated with an increased risk of teenage juvenile delinquency. We build a longitudinal dataset linking blood Pb measurements for 13,580 children under age 6 to their drinking water source, individual- and neighborhood-level demographics, and reported juvenile delinquency records. We estimate how early life Pb exposure from private well water influences reported delinquency. On average, children in homes with unregulated private wells had 11% higher blood Pb than those with community water service. This higher blood Pb was significantly associated with reported delinquency. Compared to children with community water service, those relying on private wells had a 21% (95% CI: 5 to 40%) higher risk of being reported for any delinquency and a 38% (95% CI: 10 to 73%) increased risk of being reported for serious delinquency after age 14. These results suggest that there could be substantial but as-yet-unrecognized social benefits from intervention programs to prevent children's exposure to Pb from private wells, on which 13% of the US population relies.

Differential Expression of SLC30A10 and RAGE in Mouse Pups by Early Life Lead Exposure

Differential Expression of SLC30A10 and RAGE in Mouse Pups by Early Life Lead Exposure

Early-life lead exposure induces long-term toxicity in the central nervous system: From zebrafish larvae to juveniles and adults

Lead induced neurotoxicity has been extensively investigated. However, the potential connections between early-life lead exposure and the frequently observed aberrant neurobehavior in juveniles and adults remain unclear. In this study, zebrafish model was used to explore the immediate and long-term effects of early-life exposure to environmental levels of lead on the central nervous system, and the cellular and molecular mechanisms underlying the consequent abnormal neurobehavior. Lead exposed zebrafish larvae exhibited neurologic damage and defective neurobehavior. Consistent with clinical studies, despite being raised in lead-free conditions, the juvenile and adult fish experienced lead exposure earlier, presented ADHD-like symptoms, and the adult fish exhibited remarkably affected vitality and shoaling behavior. Their anxiety levels were elevated, whereas their social interaction, as well as learning and memory were strongly depressed. The expression profiles of key genes involved in neurodevelopment and neurotransmitter systems were significantly modulated, in similar patterns as in the larval stage. Notably, the density of neurons was decreased and varicosities in neuronal axons were frequently observed in the lead-exposed groups. It's tempting to speculate that the disruption of early neurodevelopment as well as the prolonged modulation of neuromorphic and neurotransmitter systems contribute to the lead-induced neurobehavioral disorders observed in juveniles and adulthood.

Prenatal blood lead levels and reduced preadolescent glomerular filtration rate: Modification by body mass index

BackgroundFor the developing kidney, the prenatal period may represent a critical window of vulnerability to environmental insults resulting in permanent nephron loss. Given that the majority of nephron formation is complete in the 3rd trimester, we set out to test whether 1) prenatal lead exposure is associated with decreased preadolescent kidney function and 2) whether preadolescent obesity acts synergistically with early life lead exposure to reduce kidney function. MethodsOur study included 453 mother–child pairs participating in the PROGRESS birth cohort. We assessed prenatal blood lead levels (BLLs) in samples collected in the 2nd and 3rd trimesters and at delivery, as well as tibial and patellar bone lead measures assessed one-month postpartum. Preadolescent estimated glomerular filtration rate (eGFR) was derived from serum levels of creatinine and/or cystatin C measured at age 8–12 years. We applied linear regression to assess the relationship between prenatal bone and BLL with preadolescent eGFR, and adjusted for covariates including age, sex, BMI z-score, indoor tobacco smoke exposure, and socioeconomic status. We also examined sex-specific associations and tested for effect modification by BMI status. ResultsWe observed null associations between prenatal lead exposure and eGFR. However, in interaction analyses we found that among overweight children, there was an inverse association between BLL (assessed at 2nd and 3rd trimester and at delivery) and preadolescent eGFR. For example, among overweight participants, a one ln-unit increase in 2nd trimester BLL was associated with a 10.5 unit decrease in cystatin C-based eGFR (95% CI: −18.1, −2.8; p = 0.008). Regardless of lead exposure, we also observed null relationships between BMI z-score and eGFR overall, as well as among overweight participants. However, among participants with preadolescent obesity, we observed a significant 5.9-unit decrease in eGFR. We observed no evidence of sex-specific effects. ConclusionsOur findings, if confirmed in other studies, suggest a complex interplay between the combined adverse effects of adiposity and perinatal lead exposure as they relate to adolescent kidney function. Future studies will assess kidney function and adiposity trajectories through adolescence to better understand environmental risk factors for kidney function decline.