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<p>Mercury is a pollutant of global concern and is considered a priority compound
to many organizations, including the Agency for Toxic Substances and Disease Registry
(ATSDR), the US Environmental Protection Agency (USEPA), the World Health Organization
(WHO), and the United Nations Environment Programme (UNEP), due to mercury’s toxicity
profile and the potential for human exposure (ATSDR, EPA, WHO, UNEP) (USEPA 2014,
ATSDR 2015). Toxic outcomes depend greatly on the chemical compound, as adverse nervous
system impacts are associated with organic mercury exposures and renal system impacts
with elemental and inorganic mercury exposures (Lebel et al. 1996, Drake et al. 2001,
Jarosinska et al. 2008). In particular, developmental delays and nervous system impacts
occur at low dose exposures (Grandjean et al. 1997, NRC 2000). Chronic exposure has
broad impacts from disrupting many cellular processes, including genotoxic and immunomodulatory
impacts (Asmuß et al. 2000, Gallagher et al. 2011), however, the extent of impacts
from chronic low-dose exposures is not well understood. Understanding the impacts
of chronic low-dose exposures is important because globally many populations, including
US coastal populations, have this type of exposure from regularly consuming seafood
contaminated with methylmercury and because in some regions the risk for this type
of exposure is increasing. Populations near artisanal and small-scale gold mining
(ASGM), which uses mercury in the process to retrieve gold, have increased risk for
chronic exposure. In some regions ASGM is rapidly expanding (Swenson et al. 2011,
Emel et al. 2014, Snapir et al. 2017), increasing the concern for human health risks.
</p><p>The goals of this dissertation were to investigate mercury’s influence on mitochondrial
toxicity, focusing on genotoxic and immunotoxic endpoints, and determine the extent
that co-exposures, including selenium and other dietary factors, modify exposure and
adverse outcomes. Mercury has the potential to induce DNA damage indirectly through
inducing reactive oxygen species (ROS) that damage DNA (Yee and Choi 1996, Ni et al.
2010) and impair DNA repair enzymes (Crespo-Lopez et al. 2009). Studies to date have
primarily assessed nuclear DNA damage, and though mitochondrial damage is plausible,
it has not been directly measured. Concerning immune impacts, in both laboratory and
field animal studies, mercury exposure induces T-cell mediated immunosuppression and
reduced antibody titers (Koller 1973, Snoeijs et al. 2004, Hawley et al. 2009, Fallacara
et al. 2011b, a). There is also evidence for immunomodulation in humans including
altered innate and adaptive immune responses, but this data has not been consistent
between studies (Gardner et al. 2010b, Heilmann et al. 2010a, Gallagher et al. 2011).
Diet and nutritional status appear to be important modifying factors to neurotoxic
and immune outcomes. Omega-3 fatty acids have beneficial impacts on neurological development
and mitigate mercury induced neruotoxicity to an extent (Oken et al. 2005). When nutritional
status was considered in a US population, mercury significantly reduced measles and
rubella antibody concentrations in the majority of children and was associated with
an increase in antibodies in a nutritionally deficient subpopulation (vitamin B12,
folate) (Gallagher et al. 2011, Gallagher et al. 2013). </p><p>In order to address
these goals, laboratory and human studies were conducted. Laboratory studies using
Caenorhabditis elegans were utilized to test the hypothesis that the mitochondrial
DNA (mtDNA), and thus mitochondria in general, may be more susceptible to damage from
being spatially closer to ROS production and from having different DNA repair pathways
from nuclear DNA repair. To test this hypothesis DNA damage and repair, mitochondrial
parameters such as DNA copy number and steady-state ATP levels were measured. Results
suggested that co-exposures to stressors including H2O2 and UVC were important to
DNA damage and mitochondrial impacts. Though exposure to MeHg and HgCl2 increased
nuclear and mitochondrial DNA damage, mtDNA damage was particularly increased with
MeHg and H2O2 co-exposure. MeHg co-exposures with both DNA damage agents also decreased
mtDNA copy number by approximately 60%. Species dependent impacts were also observed
with ATP levels. For the hypothesis that innate immune signaling may be altered, experiments
focused on PMK-1, a p38 mitogen-activated protein kinase that has a protective role
in infection and is required for immune induction, and measured the survival of immunocompetent
nematodes (pmk-1) and expression of genes involved in the PMK-1 pathway. I observed
that both MeHg and HgCl2 impact this pathway as both mercury species reduced pmk-1
expression. </p><p>Cross-sectional human studies were used to identify factors important
to mercury exposure and determine the influence of nutritional status and mercury
exposure on child immune response to immunization. Human studies were conducted communities
located near ASGM in Madre de Dios, Peru. Important findings included that reduced
mercury exposure, using hair mercury content as a proxy, was associated with frequent
consumption of antioxidant-rich dietary items including quinoa, kiwicha, and some
fruits. Similar to co-exposures, co-morbidity was also important to child immune response
to routine vaccinations, though the direction of impact was not identical for all
antibodies analyzed. Children that had high mercury exposure and were anemic had increased
antibodies in some cases (total IgG and measles) and reduced antibodies for others
(hepatitis B, Hib, and pertussis). These observations indicate that while mercury
has impacts on adaptive immunity and disease susceptibility, the impacts may not be
the same for all diseases. </p><p>In conclusion, I observed that mitochondrial toxicities
are dependent on mercury species, that frequent consumption of antioxidant rich dietary
items is associated with lower mercury exposure, and that nutritional status can influence
mercury related immune outcomes. This work demonstrated the importance of considering
co-exposures and co-morbidities when assessing mercury exposure impacts and highlights
potential health hazards that include mitochondrial and immune system impacts.</p>
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