School of Pharmacy

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Browsing School of Pharmacy by Author "Ireland, Nicholas"

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    INVOLVEMENT OF DIVALENT METAL TRANSPORTER HOMOLOGS IN THE TOXICITY OF LANTHANIDE SERIES ELEMENTS IN Caenorhabditis elegans
    (2023-04-20) Ireland, Nicholas; Miller, Lydia; Caito, Samuel
    Lanthanide series elements are transition metals that are used in a variety of electronics, including superconductors, electronic polishers, hybrid car components, and rechargeable batteries, as well as in fertilizers, antimicrobials, contrast agents for medical imaging and diesel fuel additives. Lanthanides are also present in electronic waste and are released during electronic cigarette smoking. Levels of lanthanides have risen significantly in both industrial areas and environmentally. While we are starting to recognize health effects of lanthanide exposure, it is currently unknown how lanthanide metals enter cells. If we are to understand their toxicokinetics in the human body, it is imperative to determine mechanisms by which lanthanides are distributed. We hypothesized that endogenous divalent metal transporters (DMTs) are responsible for lanthanide entry into cells, and that genetic ablation of DMT transporters in Caenorhabditis elegans would protect the worms from lanthanide-induced toxicity. In this study, we performed a competitive inhibition survival assay by pretreating wildtype worms with nonlethal doses of metals that enter cells through a variety of mechanisms, then treating the worms with increasing concentrations of lanthanum (La). Lethality was assessed 48 hours post exposure. Worms treated with either manganese or iron, metals that enter cells via DMTs, shifted the La dose-response survival curve to the right, suggesting La was competing for the same transporter as iron or manganese. However worms pretreated with zinc, magnesium, or chromium could not block lanthanum-mediated lethality. These data suggest that DMTs are responsible for lanthanides to enter cells. We then treated transgenic worms that lacked DMT homologs smf-1, smf-2, or smf-3, with increasing concentrations of La or ytterbium (Yb). Knock out of either of the smf genes shifted the dose-response curve for La or Yb to the right, showing protection. These results suggest that DMTs are important mediators for lanthanide series elements to enter eukaryotic cells.
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    SEROTONERGIC AND DOPAMINERGIC-DEPENDENT BEHAVIORS ARE ALTERED BY LANTHANIDE SERIES METALS IN Caenorhabditis elegans
    (2023-04-20) Radzimirski, Anthony; Ireland, Nicholas; Miller, Lydia; Croft, Michael; Newell-Caito, Jennifer; Caito, Samuel
    The lanthanide series elements are transition metals used as critical components of electronics, as well as rechargeable batteries, fertilizers, antimicrobials, contrast agents for medical imaging, and diesel fuel additives. Furthermore, as electronics are limited in lifespan, lanthanides are found in electronic waste. With the surge in their utilization, lanthanide metals are being found more in our environment. However, little is known about the health effects associated with lanthanide exposure. Epidemiological studies as well as studies performed in rodents exposed to lanthanum (La) suggest neurological damage, learning and memory impairment, and disruption of neurotransmitter signaling, particularly in serotonin and dopamine pathways. Unfortunately, little is known about the neurological effects of heavier lanthanides. As dysfunction of serotonergic and dopaminergic signaling are implicated in multiple neurological conditions, including Parkinson’s disease, depression, generalized anxiety disorder, and post-traumatic stress disorder, it is of utmost importance to determine the effects of La and other lanthanides on these neurotransmitter systems. We therefore hypothesized that early life exposure of light (La or cerium (Ce)) or heavy (erbium(Er) or ytterbium (Yb)) lanthanides in Caenorhabditis elegans could cause dysregulation of serotonergic and dopaminergic signaling upon adulthood. Serotonergic signaling was assessed by measuring pharyngeal pump rate, crawl-to-swim transition, as well as egg laying behaviors. Dopaminergic signaling was assessed by measuring locomotor rate, egg laying, and swim-to-crawl transition behaviors. Treatment with La, Ce, Er, or Yb caused deficits in serotonergic or dopaminergic signaling in all assays, suggesting both the heavy and light lanthanides disrupt these neurotransmitter systems. Concomitant with dysregulation of neurotransmission, all four lanthanides increased reactive oxygen species (ROS) generation, while decreased glutathione and ATP levels. This suggests increased oxidative stress, which is a known modifier of neurotransmission. Altogether, our data suggest that both heavy and light lanthanide series elements disrupt serotonergic and dopaminergic signaling and may affect the development or pharmacological management of related neurological conditions.
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    SYNERGISTIC NEUROTOXIC EFFECTS OF METHYLMERCURY AND PER-AND-POLYFLUOROALKYL SUBSTANCES (PFAS) IN CAENORHABDITIS ELEGANS
    (2024-04-18) Radzimirski, Anthony; Varney, Abigail; Ireland, Nicholas; Caito, Samuel
    Methylmercury (MeHg) is a well-known neurotoxic metal that is a major contaminant of our fish supply. Developmental exposure to MeHg causes cognitive and behavioral dysfunction in children, and cumulative exposure to MeHg has been linked to the development of neurodegenerative diseases, such as Parkinson’s disease. Recently, it has been determined that fish are becoming increasingly contaminated with per- and polyfluoroalkyl substances (PFAS). PFAS are a group of amphipathic compounds which have been used in industry for their unique property to repel both water and oils. While specific PFAS have been phased out of use and production in the United States, the environmental degradation of PFAS is slow. Both MeHg and PFAS have similar characteristics, particularly bioaccumulation and biomagnification up the food chain, ability to accumulate in the brain, and alteration in synaptic transmission of glutamate and dopamine. We therefore hypothesized that MeHg and PFAS co-exposures may synergize and produce more damage to the dopaminergic and glutamatergic nervous systems in Caenorhabditis elgans than single exposures alone. Worms were treated for 72 hours with increasing concentrations of PFOS, PFOA, or PFBS in the presence or absence of a low nontoxic dose of MeHg. Dose-response curves were generated and the lethal dose 50 (LD50) were calculated for each curve. Co-exposure of MeHg with either of the PFAS compounds shifted the dose-response curve to the left of the dose-response curve for PFAS. This suggests that the co-exposure was more toxic than PFAS exposure in worms. Glutamatergic and dopaminergic behaviors were assayed in worms treated with MeHg, PFAS, or MeHg + PFAS combination. For both behaviors, the co-exposure caused more behavioral deficits than MeHg or PFAS alone. Furthermore co-exposure to PFAS and MeHg altered both dopamine and glutamate neurotransmitter content. Taken together, our results suggest that there is a synergistic relationship between exposure to MeHg and PFAS compounds in C. elegans.