Graduate Thesis Or Dissertation
 

Prenatal and Early-life Metals Exposure and Immune Function in Children

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  • Immune system development during prenatal and early-life periods are essential for healthy development. Environmental and nutritional factors during these periods have strong influences on immune development and can have impacts on disease susceptibility for an individual throughout adulthood. Globally, hundreds of millions of people experience elevated environmental exposure to arsenic, lead, and manganese. These metals often co-occur in the environment and are potential risk factors for developmental immunotoxicity as they readily cross the placenta and have the capacity to modulate immune function. Regions of the world with higher levels of infectious disease tend to have higher exposure levels to each of these chemicals, which indicates exposures may be influencing disease burdens. Exposure to inorganic arsenic, an established carcinogen, primarily occurs through contaminated drinking water. Increased child mortality, reduced thymus development, and suppression of T-cell subpopulation have been shown to occur from prenatal arsenic exposures. Lead, a potent neurotoxicant, has diverse anthropogenic exposure sources that vary between communities. Lead exposure has been shown to modulate immune responses, leading to significant shifts in T-cell subpopulations. Elevated manganese exposure primarily occurs through contaminated drinking water, which currently transpires in more than 50 countries globally. Although manganese is an essential nutrient it can be neurotoxic at high exposures. Previous evidence shows that prenatal manganese exposure is associated with increased perinatal mortality and experimental studies demonstrate that it can modulate immune function. The first study of this dissertation provides evidence that arsenic exposure reduces humoral immunity and that the prenatal period represents the most susceptible window of susceptibility compared to toddlerhood and early childhood. This study also suggests that susceptible subpopulations, including females and children with potentially deficient nutritional status, are the most susceptible to the effects of arsenic immunotoxicity. The second study evaluated the association between co-exposures to arsenic, manganese, and lead to changes in humoral immunity. Our results show that although prenatal arsenic is associated with lower vaccine antibody at age 5, prenatal lead exposure is associated with higher vaccine antibody. Additionally, we showed that this potential modulated vaccine antibody response following combined metal co-exposures is likely due to the direct effects of metal exposures and not due to indirect effects mediated by children’s nutritional status. We did not observe increased susceptibility to humoral immunomodulation associated with manganese exposures. These results provide evidence that exposure to arsenic and lead during pregnancy can influence humoral immunity in children at age 5, while elevated manganese exposure does not. Pregnancy is a critical period of immunological development and environmental exposure to metals during this developmental window likely induces the most serious immune impairments in subsequent early childhood periods. The influence of child sex and nutritional status were evident in this population, which may help to identify key subpopulations at risk of immunomodulation following early life metals exposures. Overall, these results will help provide evidence to inform public health interventions and influence future studies investigating the biological mechanisms underlying metal-induced immune function impairment.
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Déclaration de droits
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  • National Institutes of Environmental Health Science (R01 ES023441 and R01 ES015533) of the National Institutes of Health
  • National Center for Advancing Translational Sciences (TL1 TR002371) of the National Institutes of Health
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file details WelchBarrettM2019.pdf 2019-05-20 Public Télécharger