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Apurva Lad
Department of Medicine, The University of Toledo College of Medicine and Life Sciences, 3000 Arlington Avenue, Toledo, OH 43614, USA

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Journal article
Published: 08 June 2020 in Toxins
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Harmful algal blooms (HAB) have become a major health concern worldwide, not just to humans that consume and recreate on contaminated waters, but also to the fauna that inhabit the environments surrounding affected areas. HABs contain heterotrophic bacteria, cyanobacterial lipopolysaccharide, and cyanobacterial toxins such as microcystins, that can cause severe toxicity in many aquatic species as well as bioaccumulation within various organs. Thus, the possibility of trophic transference of this toxin through the food chain has potentially important health implications for other organisms in the related food web. While some species have developed adaptions to attenuate the toxic effects of HAB toxins, there are still numerous species that remain vulnerable, including Lithobates catesbeiana (American bullfrog) tadpoles. In the current study we demonstrate that acute, short-term exposure of tadpoles to HAB toxins containing 1 µg/L (1 nmol/L) of total microcystins for only 7 days results in significant liver and intestinal toxicity within tadpoles. Exposed tadpoles had increased intestinal diameter, decreased intestinal fold heights, and a constant number of intestinal folds, indicating pathological intestinal distension, similar to what is seen in various disease processes, such as toxic megacolon. HAB-toxin-exposed tadpoles also demonstrated hepatocyte hypertrophy with increased hepatocyte binucleation consistent with carcinogenic and oxidative processes within the liver. Both livers and intestines of HAB-toxin-exposed tadpoles demonstrated significant increases in protein carbonylation consistent with oxidative stress and damage. These findings demonstrate that short-term exposure to HAB toxins, including microcystins, can have significant adverse effects in amphibian populations. This acute, short-term toxicity highlights the need to evaluate the influence HAB toxins may have on other vulnerable species within the food web and how those may ultimately also impact human health.

ACS Style

Robin C. Su; Casey M. Meyers; Emily A. Warner; Jessica A. Garcia; Jeanine M. Refsnider; Apurva Lad; Joshua D. Breidenbach; Nikolai Modyanov; Deepak Malhotra; Steven T. Haller; David J. Kennedy. Harmful Algal Bloom Toxicity in Lithobates catesbeiana Tadpoles. Toxins 2020, 12, 378 .

AMA Style

Robin C. Su, Casey M. Meyers, Emily A. Warner, Jessica A. Garcia, Jeanine M. Refsnider, Apurva Lad, Joshua D. Breidenbach, Nikolai Modyanov, Deepak Malhotra, Steven T. Haller, David J. Kennedy. Harmful Algal Bloom Toxicity in Lithobates catesbeiana Tadpoles. Toxins. 2020; 12 (6):378.

Chicago/Turabian Style

Robin C. Su; Casey M. Meyers; Emily A. Warner; Jessica A. Garcia; Jeanine M. Refsnider; Apurva Lad; Joshua D. Breidenbach; Nikolai Modyanov; Deepak Malhotra; Steven T. Haller; David J. Kennedy. 2020. "Harmful Algal Bloom Toxicity in Lithobates catesbeiana Tadpoles." Toxins 12, no. 6: 378.

Journal article
Published: 02 June 2020 in Biomedicines
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Inflammatory Bowel Disease (IBD) is one of the most common gastrointestinal (GI) disorders around the world, and includes diagnoses such as Crohn’s disease and ulcerative colitis. The etiology of IBD is influenced by genetic and environmental factors. One environmental perturbagen that is not well studied within the intestines is microcystin-leucine arginine (MC-LR), which is a toxin produced by cyanobacteria in freshwater environments around the world. We recently reported that MC-LR has limited effects within the intestines of healthy mice, yet interestingly has significant toxicity within the intestines of mice with pre-existing colitis induced by dextran sulfate sodium (DSS). MC-LR was found to prolong DSS-induced weight loss, prolong DSS-induced bloody stools, exacerbate DSS-induced colonic shortening, exacerbate DSS-induced colonic ulceration, and exacerbate DSS-induced inflammatory cytokine upregulation. In addition, we previously reported a significant increase in expression of the pro-inflammatory receptor CD40 in the colons of these mice, along with downstream products of CD40 activation, including plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattractant protein-1 (MCP-1). In the current study, we demonstrate that knocking out CD40 attenuates the effects of MC-LR in mice with pre-existing colitis by decreasing the severity of weight loss, allowing a full recovery in bloody stools, preventing the exacerbation of colonic shortening, preventing the exacerbation of colonic ulceration, and preventing the upregulation of the pro-inflammatory and pro-fibrotic cytokines IL-1β, MCP-1, and PAI-1. We also demonstrate the promising efficacy of a CD40 receptor blocking peptide to ameliorate the effects of MC-LR exposure in a proof-of-concept study. Our findings suggest for the first time that MC-LR acts through a CD40-dependent mechanism to exacerbate colitis.

ACS Style

Robin C. Su; Emily A. Warner; Joshua D. Breidenbach; Apurva Lad; Thomas M. Blomquist; Andrew L. Kleinhenz; Nikolai Modyanov; Deepak Malhotra; David J. Kennedy; Steven T. Haller. CD40 Receptor Knockout Protects against Microcystin-LR (MC-LR) Prolongation and Exacerbation of Dextran Sulfate Sodium (DSS)-Induced Colitis. Biomedicines 2020, 8, 149 .

AMA Style

Robin C. Su, Emily A. Warner, Joshua D. Breidenbach, Apurva Lad, Thomas M. Blomquist, Andrew L. Kleinhenz, Nikolai Modyanov, Deepak Malhotra, David J. Kennedy, Steven T. Haller. CD40 Receptor Knockout Protects against Microcystin-LR (MC-LR) Prolongation and Exacerbation of Dextran Sulfate Sodium (DSS)-Induced Colitis. Biomedicines. 2020; 8 (6):149.

Chicago/Turabian Style

Robin C. Su; Emily A. Warner; Joshua D. Breidenbach; Apurva Lad; Thomas M. Blomquist; Andrew L. Kleinhenz; Nikolai Modyanov; Deepak Malhotra; David J. Kennedy; Steven T. Haller. 2020. "CD40 Receptor Knockout Protects against Microcystin-LR (MC-LR) Prolongation and Exacerbation of Dextran Sulfate Sodium (DSS)-Induced Colitis." Biomedicines 8, no. 6: 149.

Journal article
Published: 18 May 2020 in Chemosphere
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Microcystin-leucine arginine (MC-LR) is a potent liver toxin produced by freshwater cyanobacteria, also known as blue-green algae. While harmful algal blooms are increasing in frequency and severity worldwide, there is still no established method for the diagnosis and assessment of MC-LR induced liver damage. The guidelines for MC-LR safe exposure limits have been previously established based on healthy animal studies, however we have previously demonstrated that pre-existing non-alcoholic fatty liver disease (NAFLD) increases susceptiblity to the hepatotoxic effects of MC-LR. In this study, we sought to investigate the suitability of clinically used biomarkers of liver injury, specifically alanine aminotransferase (ALT) and alkaline phosphatase (ALP), as potential diagnostic tools for liver damage induced by chronic low dose administration of MC-LR in the setting of pre-existing NAFLD. In our Leprdb/J mouse model of NAFLD, we found that while MC-LR induced significant histopathologic damage in the setting of NAFLD, gene expression of ALT and ALP failed to increase with MC-LR exposure. Serum ALT and ALP also failed to increase with MC-LR exposure, except for a moderate increase in ALP with the highest dose of MC-LR used (100 μg/kg). In HepG2 human liver epithelial cells, we observed that increasing MC-LR exposure levels do not lead to an increase in ALT or ALP gene expression, intracellular enzyme activity, or extracellular activity, despite a significant increase in MC-LR induced cytotoxicity. These findings demonstrate that ALT and ALP may be unsuitable as diagnostic biomarkers for MC-LR induced liver damage.

ACS Style

Robin C. Su; Apurva Lad; Joshua D. Breidenbach; Andrew L. Kleinhenz; Nikolai Modyanov; Deepak Malhotra; Steven T. Haller; David J. Kennedy. Assessment of diagnostic biomarkers of liver injury in the setting of microcystin-LR (MC-LR) hepatotoxicity. Chemosphere 2020, 257, 127111 .

AMA Style

Robin C. Su, Apurva Lad, Joshua D. Breidenbach, Andrew L. Kleinhenz, Nikolai Modyanov, Deepak Malhotra, Steven T. Haller, David J. Kennedy. Assessment of diagnostic biomarkers of liver injury in the setting of microcystin-LR (MC-LR) hepatotoxicity. Chemosphere. 2020; 257 ():127111.

Chicago/Turabian Style

Robin C. Su; Apurva Lad; Joshua D. Breidenbach; Andrew L. Kleinhenz; Nikolai Modyanov; Deepak Malhotra; Steven T. Haller; David J. Kennedy. 2020. "Assessment of diagnostic biomarkers of liver injury in the setting of microcystin-LR (MC-LR) hepatotoxicity." Chemosphere 257, no. : 127111.

Journal article
Published: 19 April 2020 in Toxins
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A method was developed to extract and quantify microcystins (MCs) from mouse liver with limits of quantification (LOQs) lower than previously reported. MCs were extracted from 40-mg liver samples using 85:15 (v:v) CH3CN:H2O containing 200 mM ZnSO4 and 1% formic acid. Solid-phase extraction with a C18 cartridge was used for sample cleanup. MCs were detected and quantified using HPLC-orbitrap-MS with simultaneous MS/MS detection of the 135.08 m/z fragment from the conserved Adda amino acid for structural confirmation. The method was used to extract six MCs (MC-LR, MC-RR, MC-YR, MC-LA, MC-LF, and MC-LW) from spiked liver tissue and the MC-LR cysteine adduct (MC-LR-Cys) created by the glutathione detoxification pathway. Matrix-matched internal standard calibration curves were constructed for each MC (R2 ≥ 0.993), with LOQs between 0.25 ng per g of liver tissue (ng/g) and 0.75 ng/g for MC-LR, MC-RR, MC-YR, MC-LA, and MC-LR-Cys, and 2.5 ng/g for MC-LF and MC-LW. The protocol was applied to extract and quantify MC-LR and MC-LR-Cys from the liver of mice that had been gavaged with 50 µg or 100 µg of MC-LR per kg bodyweight and were euthanized 2 h, 4 h, or 48 h after final gavage. C57Bl/6J (wild type, control) and Leprdb/J (experiment) mice were used as a model to study non-alcoholic fatty liver disease. The Leprdb/J mice were relatively inefficient in metabolizing MC-LR into MC-LR-Cys, which is an important defense mechanism against MC-LR exposure. Trends were also observed as a function of MC-LR gavage amount and time between final MC-LR gavage and euthanasia/organ harvest.

ACS Style

David Baliu-Rodriguez; Daria Kucheriavaia; Dilrukshika S. W. Palagama; Apurva Lad; Grace M. O’Neill; Johnna A. Birbeck; David J. Kennedy; Steven T. Haller; Judy A. Westrick; Dragan Isailovic. Development and Application of Extraction Methods for LC-MS Quantification of Microcystins in Liver Tissue. Toxins 2020, 12, 263 .

AMA Style

David Baliu-Rodriguez, Daria Kucheriavaia, Dilrukshika S. W. Palagama, Apurva Lad, Grace M. O’Neill, Johnna A. Birbeck, David J. Kennedy, Steven T. Haller, Judy A. Westrick, Dragan Isailovic. Development and Application of Extraction Methods for LC-MS Quantification of Microcystins in Liver Tissue. Toxins. 2020; 12 (4):263.

Chicago/Turabian Style

David Baliu-Rodriguez; Daria Kucheriavaia; Dilrukshika S. W. Palagama; Apurva Lad; Grace M. O’Neill; Johnna A. Birbeck; David J. Kennedy; Steven T. Haller; Judy A. Westrick; Dragan Isailovic. 2020. "Development and Application of Extraction Methods for LC-MS Quantification of Microcystins in Liver Tissue." Toxins 12, no. 4: 263.

Journal article
Published: 23 August 2019 in Toxins
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Microcystins are potent hepatotoxins that have become a global health concern in recent years. Their actions in at-risk populations with pre-existing liver disease is unknown. We tested the hypothesis that the No Observed Adverse Effect Level (NOAEL) of Microcystin-LR (MC-LR) established in healthy mice would cause exacerbation of hepatic injury in a murine model (Leprdb/J) of Non-alcoholic Fatty Liver Disease (NAFLD). Ten-week-old male Leprdb/J mice were gavaged with 50 μg/kg, 100 μg/kg MC-LR or vehicle every 48 h for 4 weeks (n = 15–17 mice/group). Early mortality was observed in both the 50 μg/kg (1/17, 6%), and 100 μg/kg (3/17, 18%) MC-LR exposed mice. MC-LR exposure resulted in significant increases in circulating alkaline phosphatase levels, and histopathological markers of hepatic injury as well as significant upregulation of genes associated with hepatotoxicity, necrosis, nongenotoxic hepatocarcinogenicity and oxidative stress response. In addition, we observed exposure dependent changes in protein phosphorylation sites in pathways involved in inflammation, immune function, and response to oxidative stress. These results demonstrate that exposure to MC-LR at levels that are below the NOAEL established in healthy animals results in significant exacerbation of hepatic injury that is accompanied by genetic and phosphoproteomic dysregulation in key signaling pathways in the livers of NAFLD mice.

ACS Style

Apurva Lad; Robin C. Su; Joshua D. Breidenbach; Paul M. Stemmer; Nicholas J. Carruthers; Nayeli K. Sanchez; Fatimah K. Khalaf; Shungang Zhang; Andrew L. Kleinhenz; Prabhatchandra Dube; Chrysan J. Mohammed; Judy A. Westrick; Erin L. Crawford; Dilrukshika Palagama; David Baliu-Rodriguez; Dragan Isailovic; Bruce Levison; Nikolai Modyanov; Amira F. Gohara; Deepak Malhotra; Steven T. Haller; David J. Kennedy. Chronic Low Dose Oral Exposure to Microcystin-LR Exacerbates Hepatic Injury in a Murine Model of Non-Alcoholic Fatty Liver Disease. Toxins 2019, 11, 486 .

AMA Style

Apurva Lad, Robin C. Su, Joshua D. Breidenbach, Paul M. Stemmer, Nicholas J. Carruthers, Nayeli K. Sanchez, Fatimah K. Khalaf, Shungang Zhang, Andrew L. Kleinhenz, Prabhatchandra Dube, Chrysan J. Mohammed, Judy A. Westrick, Erin L. Crawford, Dilrukshika Palagama, David Baliu-Rodriguez, Dragan Isailovic, Bruce Levison, Nikolai Modyanov, Amira F. Gohara, Deepak Malhotra, Steven T. Haller, David J. Kennedy. Chronic Low Dose Oral Exposure to Microcystin-LR Exacerbates Hepatic Injury in a Murine Model of Non-Alcoholic Fatty Liver Disease. Toxins. 2019; 11 (9):486.

Chicago/Turabian Style

Apurva Lad; Robin C. Su; Joshua D. Breidenbach; Paul M. Stemmer; Nicholas J. Carruthers; Nayeli K. Sanchez; Fatimah K. Khalaf; Shungang Zhang; Andrew L. Kleinhenz; Prabhatchandra Dube; Chrysan J. Mohammed; Judy A. Westrick; Erin L. Crawford; Dilrukshika Palagama; David Baliu-Rodriguez; Dragan Isailovic; Bruce Levison; Nikolai Modyanov; Amira F. Gohara; Deepak Malhotra; Steven T. Haller; David J. Kennedy. 2019. "Chronic Low Dose Oral Exposure to Microcystin-LR Exacerbates Hepatic Injury in a Murine Model of Non-Alcoholic Fatty Liver Disease." Toxins 11, no. 9: 486.

Journal article
Published: 25 June 2019 in Toxins
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Inflammatory Bowel Disease (IBD) represents a collection of gastrointestinal disorders resulting from genetic and environmental factors. Microcystin-leucine arginine (MC-LR) is a toxin produced by cyanobacteria during algal blooms and demonstrates bioaccumulation in the intestinal tract following ingestion. Little is known about the impact of MC-LR ingestion in individuals with IBD. In this study, we sought to investigate MC-LR's effects in a dextran sulfate sodium (DSS)-induced colitis model. Mice were separated into four groups: (a) water only (control), (b) DSS followed by water (DSS), (c) water followed by MC-LR (MC-LR), and (d) DSS followed by MC-LR (DSS + MC-LR). DSS resulted in weight loss, splenomegaly, and severe colitis marked by transmural acute inflammation, ulceration, shortened colon length, and bloody stools. DSS + MC-LR mice experienced prolonged weight loss and bloody stools, increased ulceration of colonic mucosa, and shorter colon length as compared with DSS mice. DSS + MC-LR also resulted in greater increases in pro-inflammatory transcripts within colonic tissue (TNF-α, IL-1β, CD40, MCP-1) and the pro-fibrotic marker, PAI-1, as compared to DSS-only ingestion. These findings demonstrate that MC-LR exposure not only prolongs, but also worsens the severity of pre-existing colitis, strengthening evidence of MC-LR as an under-recognized environmental toxin in vulnerable populations, such as those with IBD.

ACS Style

Robin C. Su; Thomas M. Blomquist; Andrew L. Kleinhenz; Fatimah K. Khalaf; Prabhatchandra Dube; Apurva Lad; Joshua D. Breidenbach; Chrysan J. Mohammed; Shungang Zhang; Caitlin E. Baum; Deepak Malhotra; David J. Kennedy; Steven T. Haller. Exposure to the Harmful Algal Bloom (HAB) Toxin Microcystin-LR (MC-LR) Prolongs and Increases Severity of Dextran Sulfate Sodium (DSS)-Induced Colitis. Toxins 2019, 11, 371 .

AMA Style

Robin C. Su, Thomas M. Blomquist, Andrew L. Kleinhenz, Fatimah K. Khalaf, Prabhatchandra Dube, Apurva Lad, Joshua D. Breidenbach, Chrysan J. Mohammed, Shungang Zhang, Caitlin E. Baum, Deepak Malhotra, David J. Kennedy, Steven T. Haller. Exposure to the Harmful Algal Bloom (HAB) Toxin Microcystin-LR (MC-LR) Prolongs and Increases Severity of Dextran Sulfate Sodium (DSS)-Induced Colitis. Toxins. 2019; 11 (6):371.

Chicago/Turabian Style

Robin C. Su; Thomas M. Blomquist; Andrew L. Kleinhenz; Fatimah K. Khalaf; Prabhatchandra Dube; Apurva Lad; Joshua D. Breidenbach; Chrysan J. Mohammed; Shungang Zhang; Caitlin E. Baum; Deepak Malhotra; David J. Kennedy; Steven T. Haller. 2019. "Exposure to the Harmful Algal Bloom (HAB) Toxin Microcystin-LR (MC-LR) Prolongs and Increases Severity of Dextran Sulfate Sodium (DSS)-Induced Colitis." Toxins 11, no. 6: 371.