Proximal tubular transport of Metallothionein-Mercury complexes and protection against nephrotoxicity.

Mercury (Hg) is an important environmental toxicant to which humans are exposed on a regular basis. Mercuric ions within biological systems do not exist as free ions. Rather, they are bound to free sulfhydryl groups (thiols) on biological molecules. Metallothionein (MT) is a cysteine-rich, metal-binding protein that has been shown to bind to heavy metals and reduce their toxic effects in target cells and organs. Little is known about the effect of MT on the handing and disposition of Hg. Therefore, the current study was designed to test the hypothesis that overexpression of MT alters the corporal disposition of Hg and reduces its nephrotoxicity. Furthermore, the current study examined the transport of Hg-MT complexes in isolated proximal tubules. Rats were treated with saline or Zn followed by injection with a non-nephrotoxic (0.5 µmol kg-1), moderately nephrotoxic (1.5 µmol kg-1), or significantly nephrotoxic (2.25 µmol kg-1) dose of HgCl2 (containing radioactive Hg). Pretreatment with Zn increased mRNA expression of MT and enhanced accumulation of Hg in the renal cortex of male and female rats. In addition, injection with Zn also protected animals from Hg-induced nephrotoxicity. Studies using isolated proximal tubules from rabbit kidney demonstrated that Hg-MT is taken up rapidly at the apical and basolateral membranes. The current findings suggest that at least part of this uptake occurs through an endocytic process. This study is the first to examine the uptake of Hg-MT complexes in isolated proximal tubules. Overall, the findings of this study suggest that supplementation with Zn may be a viable strategy for reducing the risk of Hg intoxication in at-risk populations.

Climate Change is an Emerging Threat to Perinatal Mental Health.

OBJECTIVE: In this discussion, we build the case for why climate change is an emerging threat to perinatal mental health. METHOD: A search of current literature on perinatal and maternal mental health and extreme weather events was conducted in PubMed/MEDLINE and Web of Science databases. Only articles focusing on maternal mental health were included in this narrative review. RESULTS: The perinatal period represents a potentially challenging timeframe for women for several reasons. Necessary role adjustments (reprioritization), changes in one's ability to access pre-birth levels (and types) of social support, fluctuating hormones, changes in body shape, and possible complications during pregnancy, childbirth, or postpartum are just a few of the factors that can impact perinatal mental health. Trauma is also a risk factor for negative mood symptoms and can be experienced as the result of many different types of events, including exposure to extreme weather/natural disasters. CONCLUSION: While the concepts of "eco-anxiety," "climate despair," and "climate anxiety" have garnered attention in the mainstream media, there is little to no discussion of how the climate crisis impacts maternal mental health. This is an important omission as the mother's mental health impacts the family unit as a whole.

Molecular Mechanisms of Cellular Injury and Role of Toxic Heavy Metals in Chronic Kidney Disease.

Chronic kidney disease (CKD) is a progressive disease that affects millions of adults every year. Major risk factors include diabetes, hypertension, and obesity, which affect millions of adults worldwide. CKD is characterized by cellular injury followed by permanent loss of functional nephrons. As injured cells die and nephrons become sclerotic, remaining healthy nephrons attempt to compensate by undergoing various structural, molecular, and functional changes. While these changes are designed to maintain appropriate renal function, they may lead to additional cellular injury and progression of disease. As CKD progresses and filtration decreases, the ability to eliminate metabolic wastes and environmental toxicants declines. The inability to eliminate environmental toxicants such as arsenic, cadmium, and mercury may contribute to cellular injury and enhance the progression of CKD. The present review describes major molecular alterations that contribute to the pathogenesis of CKD and the effects of arsenic, cadmium, and mercury on the progression of CKD.

Transporters and Toxicity: Insights From the International Transporter Consortium Workshop 4.

Over the last decade, significant progress been made in elucidating the role of membrane transporters in altering drug disposition, with important toxicological consequences due to changes in localized concentrations of compounds. The topic of "Transporters and Toxicity" was recently highlighted as a scientific session at the International Transporter Consortium (ITC) Workshop 4 in 2021. The current white paper is not intended to be an extensive review on the topic of transporters and toxicity but an opportunity to highlight aspects of the role of transporters in various toxicities with clinically relevant implications as covered during the session. This includes a review of the role of solute carrier transporters in anticancer drug-induced organ injury, transporters as key players in organ barrier function, and the role of transporters in metal/metalloid toxicity.

Hepatic processing of mercuric ions facilitates delivery to renal proximal tubules.

Mercury (Hg) is a toxic heavy metal to which humans are exposed on a regular basis. Hg has a high affinity for thiol-containing biomolecules with the majority of Hg in blood being bound to albumin. The current study tested the hypothesis that circulating Hg-albumin complexes are taken up into hepatocytes and processed to form Hg-glutathione (GSH) conjugates (GSH-Hg-GSH). Subsequently, GSH-Hg-GSH conjugates are exported from hepatocytes into blood via multidrug resistance transporters (MRP) 3 and 5. To test this hypothesis, the portal vein and hepatic artery in Wistar rats were ligated to prevent delivery of Hg to the liver. Ligated and control rats were injected with HgCl2 or GSH-Hg-GSH (containing radioactive Hg) and the disposition of Hg was assessed in various organs. Renal accumulation of Hg was reduced significantly in ligated rats exposed to HgCl2. In contrast, when rats were exposed to GSH-Hg-GSH, the renal accumulation of Hg was similar in control and ligated rats. Experiments using HepG2 cells indicate that Hg-albumin conjugates are taken up by hepatocytes and additional experiments using inside-out membrane vesicles showed that MRP3 and MRP5 mediate the export of GSH-Hg-GSH from hepatocytes. These data are the first to show that Hg-albumin complexes are processed within hepatocytes to form GSH-Hg-GSH, which is, in part, exported back into blood via MRP3 and MRP5 for eventual excretion in urine.

Are Pediatric Providers On-Board With Current Recommendations Related to Maternal Mental Health Screening at Well-Child Visits in the State of Georgia?

BACKGROUND: The American Academy of Pediatrics (AAP) recommends that pediatric providers screen mothers for postpartum depression at the 1-, 2-, 4-, and 6-month well-child visits. However, compliance with this recommendation varies greatly and is far from 100%. This is significant, as perinatal mood and anxiety disorders (PMADs) represent the most common complication of childbearing. AIMS: This investigation was conducted to explore barriers to screening in the pediatric setting, reported advantages of screening, providers' knowledge of mental health supports in the community, and commonly observed (and explicitly stated) mental health issues in new mothers. All data collection took place in the state of Georgia, which has the worst rates of maternal mortality and morbidity in the United States. METHODS: A convenience sample of five pediatric practices was selected through the Mercer University School of Medicine's community preceptor network. All clinical staff at each site participated in one of five focus groups for a total of 31 participants. The conversations were audio-taped, transcribed, and thematically analyzed. RESULTS: Providers from two practices were formally screening for Postpartum Depression; they indicated that it added value to their practice. Those not screening cited several barriers including lack of time, training, and access to the mother's medical records. Several clinicians asserted that they were not trained to address mental health issues in their pediatric patients' mothers and that it was out of their realm of expertise. CONCLUSIONS: Provider compliance with the current AAP recommendations may increase with mandatory, specialized training in recognizing and treating PMADs.

Prophylactic supplementation with selenium alters disposition of mercury in aged rats.

Mercury (Hg) is a prevalent environmental toxicant to which older individuals are particularly susceptible. Selenium (Se) has been used as an antidote following exposure to Hg. However, little is known about the effect of prophylactic supplementation with Se on the handling of Hg. The current study was designed to test the hypothesis that oral pre-treatment with Se alters the corporal disposition of Hg and reduces the risk of Hg-induced toxicity. Young and aged rats were gavaged for 10 days with sodium selenite or saline. On day 11, rats were injected intravenously with 0.5 µmol HgCl2·kg-1·2 mL-1 normal saline. After 24 h, rats were euthanized and organs and tissues were harvested for determination of Hg content. Accumulation of Hg in the kidney was reduced significantly by pre-treatment with Se in both young and aged rats. In the renal cortex, the magnitude of the reduction was greater in aged rats than in young rats but in the outer stripe of the outer medulla, the magnitude of the reduction was similar between groups of rats. Urinary excretion of Hg was also reduced in rats pre-treated with Se. In contrast, the hepatic and hematologic burden of Hg increased in rats pre-treated with Se. Fecal excretion of Hg was decreased significantly by pre-treatment with Se in young rats but not in aged rats. These data suggest that prophylactic supplementation with Se alters the corporal disposition of Hg in a way that may reduce Hg-induced toxicity in target organs.

Knowledge of and Attitudes Toward Perinatal Home Visiting in Women with High-Risk Pregnancies.

INTRODUCTION: Published research indicates that some perinatal home visiting programs are highly effective. However, there is a dearth of information regarding how these services apply to women experiencing a high-risk pregnancy. The aim of this study was to determine the potential acceptability of home visiting services within this vulnerable population and identify what services women want. METHODS: Four focus groups (N = 32) were conducted with a population of low-income, pregnant individuals in medically underserved central Georgia (United States). Participants were evaluated based on their current exposure to home visiting, receptiveness to home visiting, and reasons for apprehension regarding home visiting. RESULTS: The results of this study were mixed, with women expressing both interest in and reluctance about home visiting programs. Themes of distrust and fear of judgment or persecution existed. Women also varied with regard to what home visiting services they would like offered. Those discussed included assistance with maternal or infant medical needs, maternal function tasks, household tasks, and child care. DISCUSSION: Home visiting programs can be effective for improving maternal and child health outcomes. However, not all home visiting programs effectively reach their target population. More research is needed to determine what women who have high-risk conditions during pregnancy want help with and how to increase receptiveness. The results of this study could be informative to health care providers who treat persons with high-risk conditions in identifying adjunctive services for those in need of additional support.

Transport and Toxicity of Methylmercury-Cysteine in Cultured BeWo Cells.

Mercury is a heavy metal toxicant that is prevalent throughout the environment. Organic forms of mercury, such as methylmercury (MeHg), can cross the placenta and can lead to lasting detrimental effects in the fetus. The toxicological effects of MeHg on the placenta itself have not been clearly defined. Therefore, the purpose of the current study was to assess the transport of MeHg into placental syncytiotrophoblasts and to characterize the mechanisms by which MeHg exerts its toxic effects. Cultured placental syncytiotrophoblasts (BeWo) were used for these studies. The transport of radioactive MeHg was measured to identify potential mechanisms involved in the uptake of this compound. The toxicological effects of MeHg on BeWo cells were determined by assessing visible pathological change, autophagy, mitochondrial viability, and oxidative stress. The findings of this study suggest that MeHg compounds are transported into BeWo cells primarily by sodium-independent amino acid carriers and organic anion transporters. The MeHg altered mitochondrial function and viability, decreased mitophagy and autophagy, and increased oxidative stress. Exposure to higher concentrations of MeHg inhibited the ability of cells to protect against MeHg-induced injury. The findings show that MeHg is directly toxic to syncytiotrophoblasts and may lead to disruptions in the fetal/maternal transfer of nutrients and wastes.

Maternal Functioning and Depression Scores Improve Significantly With Participation in Visiting Moms® Program.

BACKGROUND: Postpartum depression is the most common complication of childbearing can affect the entire family unit. Health professionals must strive to identify and develop effective, feasible solutions for women during this critical period. AIMS: To determine whether postpartum maternal functioning (as measured by the Barkin Index of Maternal Functioning) and depression symptoms (as measured by the Patient Health Questionnaire-9) were improved after participation in the Visiting Moms program. METHOD: Paired data were collected from women at program intake and after completion of the Visiting Moms program. Visiting Moms provides services through eastern and central Massachusetts and was designed to support new mothers throughout the infant's first year of life. The study population was composed of adult women living in the Jewish Family and Children's Services geographic catchment area, who enrolled in Visiting Moms between January 1, 2013, and December 31, 2015. Descriptive statistics were calculated for all 402 women enrolled in this timeframe. Utilizing a pretest/posttest design, paired t tests were performed for the Barkin Index of Maternal Functioning (n = 149) and for the Patient Health Questionnaire-9 (n = 156), where women had complete scores at both intake and completion, to determine the program's potential impact on depressive symptoms and functional status. RESULTS: Functioning and depression scores were significantly improved after participation in the program. CONCLUSIONS: Visiting moms, and similar programs, aimed at delivery of enhanced social support, may be effective in promoting mental and emotional wellness among new mothers who are require additional support in the postpartum period.

Reaction of Cyanide with Hg0-Contaminated Gold Mining Tailings Produces Soluble Mercuric Cyanide Complexes.

Elemental mercury (Hg0) contamination in artisanal and small-scale gold mining (ASGM) communities is widespread, and Hg0-contaminated tailings are often reprocessed with cyanide (-CN) to extract residual gold remaining after amalgamation. Hg0 reacts with -CN under aerobic conditions to produce Hg(CN)42- and other Hg(CN)nn-2 complexes. The production of solvated Hg(CN)nn-2 complexes increases upon agitation in the presence of synthetic and authentic Hg0-contaminated tailings that aid in dispersing the Hg0, increasing its reactive surface area. Adult rats were exposed to various concentrations of Hg(CN)2, and accumulation in organs and tissues was quantified using direct mercury analysis. The primary site of Hg(CN)2 accumulation was the kidney, although accumulation was also detected in the liver, spleen, and blood. Little accumulation was observed in the brain, suggesting that Hg(CN)2 complexes do not cross the blood-brain barrier. Renal tissue was particularly sensitive to the effects of Hg(CN)2, with pathological changes observed at low concentrations. Hg(CN)2 complexes are handled by mammalian systems in a manner similar to other inorganic species of Hg, yet appear to be more toxic to organ systems. The findings from this study are the first to show that Hg(CN)2 complexes are highly stable complexes that can lead to cellular injury and death in mammalian organ systems.

Chronic kidney disease in pregnant mothers affects maternal and fetal disposition of mercury.

Chronic kidney disease (CKD) affects over 15 % of the adults in the United States. Pregnant women with CKD present an additional challenge in that they are at increased risk for adverse events such as preterm birth. Exposure to environmental toxicants, such as methylmercury, may exacerbate maternal disease and increase the risk of adverse fetal outcomes. We hypothesized that fetuses of mothers with CKD are more susceptible to accumulation of methylmercury than fetuses of healthy mothers. The current data show that when mothers are in a state of renal insufficiency, uptake of mercury in fetal kidneys is enhanced significantly. Accumulation of Hg in fetal kidneys may be related to the flow of amniotic fluid, maternal handling of Hg, and/or underdeveloped mechanisms for cellular export and urinary excretion. The results of this study indicate that renal insufficiency in mothers leads to significant alterations in the way toxicants such as mercury are handled by maternal and fetal organs.

Sex differences in renal handling of inorganic mercury in aged rats.

The sex of an individual/animal has been shown to play an important role in many biological processes. Furthermore, sex may also be a factor in the way environmental toxicants, such as heavy metals, are handled by organisms. However, the effect of sex on the handling and disposition of heavy metals, such as mercury (Hg), has not been shown. Aging has also been shown to be a factor in the accumulation of heavy metals in that older individuals tend to have higher burdens of these metals. Therefore, the purpose of the current study was to evaluate the effect of sex on the accumulation of mercury in aged animals. Aged male and female rats were injected intravenously with 0.5 µmol or 2.0 µmol·kg-1 HgCl2 (containing radioactive Hg) and organs were harvested after 24 h. In general, the renal accumulation of Hg was significantly greater in males than in females. Similarly, urinary excretion of Hg was greater in males than in females. There were no significant differences between males and females in the burden of Hg in other organs. Sex differences in the renal accumulation of Hg may be related to differences in the expression of membrane transporters involved in the uptake of mercuric species into tubular epithelial cells. The results of the current study illustrate the need to evaluate both sexes when assessing the renal effects of environmental toxicants.

Co-administration of Selenium with Inorganic Mercury Alters the Disposition of Mercuric Ions in Rats.

Mercury (Hg) is a common environmental toxicant to which humans are exposed regularly through occupational and dietary means. Although selenium supplementation has been reported to prevent the toxic effects of Hg in animals, the mechanisms for this prevention are not well understood. The purpose of the current study was to determine the effects of selenium on the disposition and toxicity of Hg. Wistar rats were injected intravenously with a non-nephrotoxic dose (0.5 µmol kg-1) or a nephrotoxic dose (2.5 µmol kg-1) of HgCl2 (containing radioactive Hg) with or without co-administration of sodium selenite (Na2SeO3). Twenty-four hours after exposure, rats were euthanized, and organs were harvested. Co-administration of SeO32- with HgCl2 reduced the renal burden of Hg and the urinary excretion of Hg while increasing the amount of Hg in blood and spleen. We propose that Hg reacts with reduced selenite in the blood to form large Hg-Se complexes that are unable to be filtered at the glomerulus. Consequently, these complexes remain in the blood and are able to accumulate in blood-rich organs. These complexes, which may have fewer toxic effects than other species of Hg, may be eliminated slowly over the course of weeks to months.

Chemical analysis of Hg0-containing Hindu religious objects.

Parad items used in Hindu practices and Ayurvedic medicines contain elemental mercury (Hg0) and have traditionally been used in prayer and to treat a variety of diseases including diabetes, heart conditions, and sexual dysfunction. These items are often referred to as amalgams of silver, and take the form of shivlings, statues of gods, necklaces, and other jewelry. Fourteen parad items were purchased from online vendors in India and the United States and analyzed. All items produced copious amounts of Hg0 vapor, with Hg0 concentrations exceeding 1,000,000 ng/m3 as measured using a Mercury Instruments Mercury Tracker 3000 IP atomic absorption spectrometer. Measured concentrations were highly variable, so a simple qualitative experiment employing a UV-C light source and a thin-layer chromatography plate impregnated with a fluorescent dye that glows green when irradiated at 254 nm allowed for the indirect visualization of the Hg0 being evolved. In addition, all items were screened using a hand-held X-ray fluorescence analyzer to estimate the concentration of Hg, Sn, Pb, As, and Cd on the surface of the item. Select samples were then digested in aqua regia and analyzed for Hg content using a direct mercury analyzer. All samples were found to exceed 20% by mass Hg. The digestates were analyzed using inductively-coupled plasma-optical emission spectrometry and were determined to be between 10-55% by mass Pb and contain up to 0.3% by mass As. While Article 4 of the Minamata Convention on Mercury specifically requires parties to stop importing, exporting, and manufacturing Hg-added products, products used in traditional and religious practices are excluded.

Targeting of reactive isolevuglandins in mitochondrial dysfunction and inflammation.

Inflammation is a major cause of morbidity and mortality in Western societies. Despite use of multiple drugs, both chronic and acute inflammation still represent major health burdens. Inflammation produces highly reactive dicarbonyl lipid peroxidation products such as isolevuglandins which covalently modify and cross-link proteins via lysine residues. Mitochondrial dysfunction has been associated with inflammation; however, its molecular mechanisms and pathophysiological role are still obscure. We hypothesized that inflammation-induced isolevuglandins contribute to mitochondrial dysfunction and mortality. To test this hypothesis, we have (a) investigated the mitochondrial dysfunction in response to synthetic 15-E2-isolevuglandin (IsoLG) and its adducts; (b) developed a new mitochondria-targeted scavenger of isolevuglandins by conjugating 2-hydroxybenzylamine to the lipophilic cation triphenylphosphonium, (4-(4-aminomethyl)-3-hydroxyphenoxy)butyl)-triphenylphosphonium (mito2HOBA); (c) tested if mito2HOBA protects from mitochondrial dysfunction and mortality using a lipopolysaccharide model of inflammation. Acute exposure to either IsoLG or IsoLG adducts with lysine, ethanolamine or phosphatidylethanolamine inhibits mitochondrial respiration and attenuates Complex I activity. Complex II function was much more resistant to IsoLG. We confirmed that mito2HOBA markedly accumulates in isolated mitochondria and it is highly reactive with IsoLGs. To test the role of mitochondrial IsoLGs, we studied the therapeutic potential of mito2HOBA in lipopolysaccharide mouse model of sepsis. Mito2HOBA supplementation in drinking water (0.1 g/L) to lipopolysaccharide treated mice increased survival by 3-fold, improved complex I-mediated respiration, and histopathological analyses supported mito2HOBA-mediated protection of renal cortex from cell injury. These data support the role of mitochondrial IsoLG in mitochondrial dysfunction and inflammation. We conclude that reducing mitochondrial IsoLGs may be a promising therapeutic target in inflammation and conditions associated with mitochondrial oxidative stress and dysfunction.

A Case of Accidental Mercury Intoxication.

BACKGROUND: Mercury poisoning is an uncommon diagnosis in the United States, but it is a differential diagnosis that physicians should consider because it can lead to potentially fatal complications if untreated. Due to the nonspecific presentation of mercury poisoning, which includes symptoms such as fever, nausea, vomiting, and abdominal pain, misdiagnosis may occur unless a proper history is taken. CASE REPORT: In the present case, a white female patient was misdiagnosed repeatedly with a viral illness and sent home from the local hospital. The patient presented with a diffuse full-body rash, fever, myalgias, headache, peripheral neuropathy, oral paresthesias, and tender cervical posterior lymphadenopathy. After obtaining a thorough history, it was discovered that the patient and her family were exposed to mercury through a spill of elemental mercury in their home. Blood mercury levels in the patient were 170 ng/mL. The patient was treated with a course of dimercaprol. Her symptoms improved and she was discharged on hospital day 5. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Ultimately, mercury poisoning is a treatable condition, but if exposure continues and the patient is not treated, it may lead to complications such as severe pneumonitis, renal tubular necrosis, and neurological dysfunction. In some instances, neurological symptoms may persist even if the source of exposure is removed. For these reasons, recognition and prompt treatment after a suspected exposure is important.

Potential mechanisms of cellular injury following exposure to a physiologically relevant species of inorganic mercury.

Mercury is a toxic metal that is found ubiquitously in the environment. Humans are exposed to different forms of mercury via ingestion, inhalation, and/or dermal absorption. Following exposure, mercuric ions may gain access to target cells and subsequently lead to cellular intoxication. The mechanisms by which mercury accumulation leads to cellular injury and death are not understood fully. Therefore, purpose of this study was to identify the specific intracellular mechanisms that are altered by exposure to inorganic mercury (Hg2+). Normal rat kidney (NRK) cells were exposed to a physiologically relevant form of Hg2+, as a conjugate of cysteine (10 µM or 50 µM). Alterations in oxidative stress were estimated by measuring lipid peroxidation and mitochondrial oxidative stress. Alterations in actin and tubulin were measured using specific fluorescent dyes. Calcium levels were measured using Fluo-3 AM Calcium Indicator while autophagy was identified with Premo™ Autophagy Sensor LC3B-GFP. The current findings show that exposure to Hg2+ leads to enhanced oxidative stress, alterations in cytoskeletal structure, increases in intracellular calcium, and enhanced autophagy. We have established a more complete understanding of intoxication and cellular injury induced by a relevant form of Hg2+ in proximal tubule cells.

Exposure to mixtures of mercury, cadmium, lead, and arsenic alters the disposition of single metals in tissues of Wistar rats.

Humans throughout the world are exposed regularly to mixtures of environmental toxicants. Four of the most common heavy metal toxicants in the environment are mercury (Hg), cadmium (Cd), lead (Pb), and arsenic (As). Numerous studies have assessed the effects and disposition of individual metals in organ systems; however, humans are usually exposed to mixtures of toxicants or metals rather than to a single toxicant. Therefore, the purpose of the current study was to test the hypothesis that exposure to a mixture of toxic heavy metals alters the disposition of single metals in target organs. Wistar rats (Rattus norvegicus) were exposed to Hg, Cd, Pb, or As as a single metal or as a mixture of metals. Rats were injected intravenously for three days, following which kidneys, liver, brain, and blood were harvested. Samples were analyzed for content of Hg, Cd, Pb, and As via inductively coupled plasma mass spectrometry. In general, exposure to a mixture of metals reduced accumulation of single metals in target organs. Interestingly, exposure to mixtures of metals with Pb and/or As increased the concentration of these metals specifically in the liver. The findings from this study indicate that exposure to mixtures of toxic heavy metals may alter significantly the distribution and accumulation of these metals in target organs and tissues.