Lead exposure may alter the body’s response to stress
Chris Giang and Olivia M. Halabicky, PhD, RN
Researchers in the Child Health and Development Lab at Michigan Public Health
Global estimates suggest that 1 in 3 children worldwide have elevated blood lead levels (UNICEF & Pure Earth, 2020). In 2015, Flint, Michigan made national news when elevated levels of lead were found in the drinking water resulting in high childhood blood lead levels across the city (Pell & Schneyer, 2016). While Flint garnered national attention, in the United States alone there are close to 3,000 cities with lead poisoning rates double those measured in Flint during the water crisis. More than 1,100 of these communities had a rate of elevated blood tests that were at least four times higher than Flint (Pell & Schneyer, 2016).
Lead is a well-known neurotoxicant, with there being no safe level of lead exposure in children (Ruckart et al., 2021). Since children’s brains are still developing, they are particularly vulnerable to lead exposure. Even small amounts of lead exposure in childhood is associated with poor neurocognitive and cardiometabolic outcomes such as lower IQ scores (Heidari et al., 2022), increased aggression (Tlotleng et al., 2022), and elevated blood pressure (Zhang et al., 2012). Furthermore, the effects of lead exposure appear to be long-lasting. For example, chronic lead exposure in childhood has been associated with reduced brain volume in adults (Cecil et al., 2008).
Global estimates suggest that 1 in 3 children worldwide have elevated blood lead levels.
Despite knowing how harmful lead exposure is, we still don’t know how lead may cause such harmful health and neurocognitive outcomes. Identifying potential biological pathways is key for developing interventions to mitigate health risk. Findings from rodent studies suggest that the hypothalamic-pituitary-adrenal (HPA) axis may be a plausible biological pathway through which lead may cause such harmful health and neurocognitive outcomes (Cory-Slechta et al., 2008). The HPA axis is responsible for the body’s physiological response to external stress and is usually thought of when referring to the body’s ‘fight or flight’ response (Smith & Vale, 2006). When functioning appropriately, the HPA axis will release cortisol, among other hormones, and begin a cascade of physiological responses to help the body respond to a stressor such as increasing heart rate and slowing digestion. However, dysfunction of the HPA axis can lead to over-responsivity to a stressor or being in a continued state of physiological stress, which is harmful to the multiple organ systems that are part of the stress response system. These disruptions, over time, have been associated with negative neurocognitive and cardiometabolic outcomes, much like lead exposure.
Dysfunctional physiological stress responses can be difficult to measure in humans. Oftentimes, researchers use allostatic load to measure physiological stress. Allostatic load attempts to quantify physiological wear and tear on the body (McEwen, 1998; Seeman et al., 1997) by examining biomarkers of physiological dysregulation from multiple body systems including cardiovascular, metabolic, neuroendocrine, and immune function (Rodriquez et al., 2019). Increasing allostatic load is associated with detrimental health outcomes and increased mortality, making it a significant public health concern (Castagné et al., 2018; Parker et al., 2022). Because allostatic load requires many biomarkers, it is often difficult for researchers to measure. Cortisol is therefore often used to measure physiological stress and potential dysfunction, as it is a primary hormone in the stress response pathway (i.e., HPA axis) (Noushad et al., 2021).
To better understand the relationship between lead exposure and stress response system dysfunction in humans, we reviewed 15 articles and synthesized all existing literature regarding associations between lead exposure and allostatic load, as well as individual measures of cortisol, in human samples across the life course. For children, no studies were available examining allostatic load outcomes. Furthermore, only three studies were available examining cortisol outcomes which reported prenatal lead exposure was associated with altered cortisol responses to external stressors, which may suggest a dysregulated HPA axis. Lead was also associated with changes in infant cortisol levels throughout the day, again suggesting dysregulation of the HPA axis. Though no child studies were available examining allostatic load, two cross-sectional adult studies did report significant associations between lead exposure and increasing allostatic load.
Lead exposure is an ever-prevalent toxicant in children’s lives and is a significant public health concern. Though the conclusions of the review were limited due to lack of available studies in children, the findings suggest potential associations between lead exposure and alterations to stress response pathway function. Over time, dysfunction of stress response pathways, such as the HPA axis, can lead to allostatic load and long-term poor health and neurocognitive outcomes. Therefore, research is needed examining associations between lead exposure and allostatic load, especially as children age into adolescents and young adults. As more research becomes available, environmental health researchers can begin to test whether stress response pathways are in fact a biological mechanism between lead and poor health outcomes. From there, researchers can further develop interventions that target stress response pathways in order to prevent such harmful outcomes for children exposed to lead.
Castagné, R., Garès, V., Karimi, M., Chadeau-Hyam, M., Vineis, P., Delpierre, C., & Kelly-Irving, M. (2018). Allostatic load and subsequent all-cause mortality: which biological markers drive the relationship? Findings from a UK birth cohort. Eur J Epidemiol, 33(5), 441-458. https://doi.org/10.1007/s10654-018-0364-1
Cecil, K. M., Brubaker, C. J., Adler, C. M., Dietrich, K. N., Altaye, M., Egelhoff, J. C., Wessel, S., Elangovan, I., Hornung, R., Jarvis, K., & Lanphear, B. P. (2008). Decreased brain volume in adults with childhood lead exposure. PLoS Med, 5(5), e112. https://doi.org/10.1371/journal.pmed.0050112
Cory-Slechta, D. A., Virgolini, M. B., Rossi-George, A., Thiruchelvam, M., Lisek, R., & Weston, D. (2008). Lifetime Consequences of Combined Maternal Lead and Stress. Basic Clin Pharmacol Toxicol, 102(2), 218-227. https://doi.org/10.1111/j.1742-7843.2007.00189.x
McEwen, B. S. (1998). Stress, adaptation, and disease. Allostasis and allostatic load. Ann N Y Acad Sci, 840, 33-44. https://doi.org/10.1111/j.1749-6632.1998.tb09546.x McEwen, B. S. (2006). Protective and damaging effects of stress mediators: Central role of the brain. Dialogues in clinical neuroscience, 8(4), 367-381. https://www.ncbi.nlm.nih.gov/pubmed/17290796
McEwen, B. S. (2017). Neurobiological and systemic effects of chronic stress. Chronic Stress 1, 2470547017692328. https://doi.org/10.1177/2470547017692328
Noushad, S., Ahmed, S., Ansari, B., Mustafa, U. H., Saleem, Y., & Hazrat, H. (2021). Physiological biomarkers of chronic stress: A systematic review. Int J Health Sci (Qassim), 15(5), 46-59.
Pell, M.B., & Schneyer, J. (2016). The thousands of U.S. locales where lead poisoning is worse than in Flint. Reuters. https://www.reuters.com/investigates/special-report/usa-lead-testing/
Rodriquez, E. J., Kim, E. N., Sumner, A. E., Nápoles, A. M., & Pérez-Stable, E. J. (2019). Allostatic Load: Importance, Markers, and Score Determination in Minority and Disparity Populations. Journal of urban health : bulletin of the New York Academy of Medicine, 96(Suppl 1), 3-11. https://doi.org/10.1007/s11524-019-00345-5
Ruckart, P. Z., Jones, R. L., Courtney, J. G., LeBlanc, T. T., Jackson, W., Karwowski, M. P., Cheng, P. Y., Allwood, P., Svendsen, E. R., & Breysse, P. N. (2021). Update of the Blood Lead Reference Value - United States, 2021. MMWR Morb Mortal Wkly Rep, 70(43), 1509-1512. https://doi.org/10.15585/mmwr.mm7043a4
Sasaki, N., & Carpenter, D. O. (2022). Associations between Metal Exposures and Cognitive Function in American Older Adults. Int J Environ Res Public Health, 19(4). https://doi.org/10.3390/ijerph19042327
Seeman, T. E., Singer, B. H., Rowe, J. W., Horwitz, R. I., & McEwen, B. S. (1997). Price of adaptation--allostatic load and its health consequences. MacArthur studies of successful aging. Arch Intern Med, 157(19), 2259-2268
Smith, S. M., & Vale, W. W. (2006). The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci, 8(4), 383-395. https://doi.org/10.31887/DCNS.2006.8.4/ssmith
Tlotleng, N., Naicker, N., Mathee, A., Todd, A. C., Nkomo, P., & Norris, S. A. (2022). Association between Bone Lead Concentration and Aggression in Youth from a Sub-Cohort of the Birth to Twenty Cohort. Int J Environ Res Public Health, 19(4). https://doi.org/10.3390/ijerph19042200
Parker, H. W., Abreu, A. M., Sullivan, M. C., & Vadiveloo, M. K. (2022). Allostatic Load and Mortality: A Systematic Review and Meta-Analysis. Am J Prev Med, 63(1), 131-140. https://doi.org/https://doi.org/10.1016/j.amepre.2022.02.003
UNICEF, & Pure Earth. (2020). The Toxic Truth: Children’s Exposure to Lead Pollution Undermines a Generation of Future Potential.
Wan, H., Chen, S., Cai, Y., Chen, Y., Wang, Y., Zhang, W., Chen, C., Wang, N., Guo, Y., & Lu, Y. (2021). Lead exposure and its association with cardiovascular disease and diabetic kidney disease in middle-aged and elderly diabetic patients. Int J Hyg Environ Health, 231, 113663. https://doi.org/10.1016/j.ijheh.2020.113663
Zhang, A., Hu, H., Sánchez, B. N., Ettinger, A. S., Park, S. K., Cantonwine, D., Schnaas, L., Wright, R. O., Lamadrid-Figueroa, H., & Tellez-Rojo, M. M. (2012). Association between prenatal lead exposure and blood pressure in children. Environ Health Perspect, 120(3), 445-450. https://doi.org/10.1289/ehp.1103736
About the Authors
Chris Giang is a junior majoring in Public Health Sciences at the University of Michigan School of Public Health. He is working as an undergraduate research assistant for the Child Health and Development Lab at the School of Public Health, the Prenatal Stress Study at Michigan Medicine Department of Psychiatry, and the Trauma and Grief Center at The Hackett Center for Mental Health. His research interests include childhood bereavement and grief, with a focus on how resilience and other protective factors can promote adaptive grief behaviors in bereaved youth.
Olivia M. Halabicky, PhD, RN
Olivia Halabicky is a postdoctoral fellow in the Environmental Toxicology and Epidemiology training program at the University of Michigan School of Public Health, with previous training in nursing and child health and wellbeing. The overarching goal of her research is to explain the mechanisms and co-exposures that contribute to differential vulnerability in health and neurocognitive outcomes resulting from early life lead exposure, so that improved strategies can be developed to mitigate long-term adverse health effects. In short, she seeks to understand what social, contextual, and biological factors influence the effect of lead on health and neurocognitive outcomes as children age.
Listen to the Population Healthy Podcast from Michigan Public Health.