-transparent.png){kind=logo}
Chronic Low Dose Oral Exposure to Microcystin-LR Exacerbates Hepatic Injury in a Murine Model of Non-Alcoholic Fatty Liver Disease. 2019
Apurva Lad, and
Robin C Su, and
Joshua D Breidenbach, and
Paul M Stemmer, and
Nicholas J Carruthers, and
Nayeli K Sanchez, and
Fatimah K Khalaf, and
Shungang Zhang, and
Andrew L Kleinhenz, and
Prabhatchandra Dube, and
Chrysan J Mohammed, and
Judy A Westrick, and
Erin L Crawford, and
Dilrukshika Palagama, and
David Baliu-Rodriguez, and
Dragan Isailovic, and
Bruce Levison, and
Nikolai Modyanov, and
Amira F Gohara, and
Deepak Malhotra, and
Steven T Haller, and
David J Kennedy
Department of Medicine, University of Toledo, Toledo, OH 43614, USA.
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.
Related Publications
Apurva Lad, and
Robin C Su, and
Joshua D Breidenbach, and
Paul M Stemmer, and
Nicholas J Carruthers, and
Nayeli K Sanchez, and
Fatimah K Khalaf, and
Shungang Zhang, and
Andrew L Kleinhenz, and
Prabhatchandra Dube, and
Chrysan J Mohammed, and
Judy A Westrick, and
Erin L Crawford, and
Dilrukshika Palagama, and
David Baliu-Rodriguez, and
Dragan Isailovic, and
Bruce Levison, and
Nikolai Modyanov, and
Amira F Gohara, and
Deepak Malhotra, and
Steven T Haller, and
David J Kennedy
August 2022,
Antioxidants (Basel, Switzerland),
Apurva Lad, and
Robin C Su, and
Joshua D Breidenbach, and
Paul M Stemmer, and
Nicholas J Carruthers, and
Nayeli K Sanchez, and
Fatimah K Khalaf, and
Shungang Zhang, and
Andrew L Kleinhenz, and
Prabhatchandra Dube, and
Chrysan J Mohammed, and
Judy A Westrick, and
Erin L Crawford, and
Dilrukshika Palagama, and
David Baliu-Rodriguez, and
Dragan Isailovic, and
Bruce Levison, and
Nikolai Modyanov, and
Amira F Gohara, and
Deepak Malhotra, and
Steven T Haller, and
David J Kennedy
January 2018,
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology,
Apurva Lad, and
Robin C Su, and
Joshua D Breidenbach, and
Paul M Stemmer, and
Nicholas J Carruthers, and
Nayeli K Sanchez, and
Fatimah K Khalaf, and
Shungang Zhang, and
Andrew L Kleinhenz, and
Prabhatchandra Dube, and
Chrysan J Mohammed, and
Judy A Westrick, and
Erin L Crawford, and
Dilrukshika Palagama, and
David Baliu-Rodriguez, and
Dragan Isailovic, and
Bruce Levison, and
Nikolai Modyanov, and
Amira F Gohara, and
Deepak Malhotra, and
Steven T Haller, and
David J Kennedy
March 2016,
Toxicon : official journal of the International Society on Toxinology,
Apurva Lad, and
Robin C Su, and
Joshua D Breidenbach, and
Paul M Stemmer, and
Nicholas J Carruthers, and
Nayeli K Sanchez, and
Fatimah K Khalaf, and
Shungang Zhang, and
Andrew L Kleinhenz, and
Prabhatchandra Dube, and
Chrysan J Mohammed, and
Judy A Westrick, and
Erin L Crawford, and
Dilrukshika Palagama, and
David Baliu-Rodriguez, and
Dragan Isailovic, and
Bruce Levison, and
Nikolai Modyanov, and
Amira F Gohara, and
Deepak Malhotra, and
Steven T Haller, and
David J Kennedy
November 2011,
Clinical and experimental immunology,
Apurva Lad, and
Robin C Su, and
Joshua D Breidenbach, and
Paul M Stemmer, and
Nicholas J Carruthers, and
Nayeli K Sanchez, and
Fatimah K Khalaf, and
Shungang Zhang, and
Andrew L Kleinhenz, and
Prabhatchandra Dube, and
Chrysan J Mohammed, and
Judy A Westrick, and
Erin L Crawford, and
Dilrukshika Palagama, and
David Baliu-Rodriguez, and
Dragan Isailovic, and
Bruce Levison, and
Nikolai Modyanov, and
Amira F Gohara, and
Deepak Malhotra, and
Steven T Haller, and
David J Kennedy
September 2015,
Toxicon : official journal of the International Society on Toxinology,
Apurva Lad, and
Robin C Su, and
Joshua D Breidenbach, and
Paul M Stemmer, and
Nicholas J Carruthers, and
Nayeli K Sanchez, and
Fatimah K Khalaf, and
Shungang Zhang, and
Andrew L Kleinhenz, and
Prabhatchandra Dube, and
Chrysan J Mohammed, and
Judy A Westrick, and
Erin L Crawford, and
Dilrukshika Palagama, and
David Baliu-Rodriguez, and
Dragan Isailovic, and
Bruce Levison, and
Nikolai Modyanov, and
Amira F Gohara, and
Deepak Malhotra, and
Steven T Haller, and
David J Kennedy
January 2017,
Scientific reports,
Apurva Lad, and
Robin C Su, and
Joshua D Breidenbach, and
Paul M Stemmer, and
Nicholas J Carruthers, and
Nayeli K Sanchez, and
Fatimah K Khalaf, and
Shungang Zhang, and
Andrew L Kleinhenz, and
Prabhatchandra Dube, and
Chrysan J Mohammed, and
Judy A Westrick, and
Erin L Crawford, and
Dilrukshika Palagama, and
David Baliu-Rodriguez, and
Dragan Isailovic, and
Bruce Levison, and
Nikolai Modyanov, and
Amira F Gohara, and
Deepak Malhotra, and
Steven T Haller, and
David J Kennedy
August 2019,
British journal of clinical pharmacology,
Apurva Lad, and
Robin C Su, and
Joshua D Breidenbach, and
Paul M Stemmer, and
Nicholas J Carruthers, and
Nayeli K Sanchez, and
Fatimah K Khalaf, and
Shungang Zhang, and
Andrew L Kleinhenz, and
Prabhatchandra Dube, and
Chrysan J Mohammed, and
Judy A Westrick, and
Erin L Crawford, and
Dilrukshika Palagama, and
David Baliu-Rodriguez, and
Dragan Isailovic, and
Bruce Levison, and
Nikolai Modyanov, and
Amira F Gohara, and
Deepak Malhotra, and
Steven T Haller, and
David J Kennedy
January 2017,
Annals of hepatology,
Apurva Lad, and
Robin C Su, and
Joshua D Breidenbach, and
Paul M Stemmer, and
Nicholas J Carruthers, and
Nayeli K Sanchez, and
Fatimah K Khalaf, and
Shungang Zhang, and
Andrew L Kleinhenz, and
Prabhatchandra Dube, and
Chrysan J Mohammed, and
Judy A Westrick, and
Erin L Crawford, and
Dilrukshika Palagama, and
David Baliu-Rodriguez, and
Dragan Isailovic, and
Bruce Levison, and
Nikolai Modyanov, and
Amira F Gohara, and
Deepak Malhotra, and
Steven T Haller, and
David J Kennedy
October 2017,
Abdominal radiology (New York),
Apurva Lad, and
Robin C Su, and
Joshua D Breidenbach, and
Paul M Stemmer, and
Nicholas J Carruthers, and
Nayeli K Sanchez, and
Fatimah K Khalaf, and
Shungang Zhang, and
Andrew L Kleinhenz, and
Prabhatchandra Dube, and
Chrysan J Mohammed, and
Judy A Westrick, and
Erin L Crawford, and
Dilrukshika Palagama, and
David Baliu-Rodriguez, and
Dragan Isailovic, and
Bruce Levison, and
Nikolai Modyanov, and
Amira F Gohara, and
Deepak Malhotra, and
Steven T Haller, and
David J Kennedy
September 2020,
Biomolecules,
