Unraveling DEHP influence on hemoglobin S polymerization in sickle cell disease: Ex vivo, in vitro and in silico analysis.

Thyago R Cardim-Pires, Rodrigo Abreu Camacho, Aghata Vitoria Machado, Fernanda de Oliveira Mendonça, Lyzes Rosa Teixeira-Alves, Camila Cristina Guimarães-Nobre, Evelyn Mendonça-Reis, Priscila Ferreira da Silva, Leandro Miranda-Alves, Clemilson Berto-Junior

Journal: Toxicology in vitro : an international journal published in association with BIBRA 2024;98():105832

PMID: 38653437

Full Text on Elsevier Science View on PubMed

Abstract

Sickle cell disease (SCD) is a hereditary hemoglobinopathy, caused by a mutation at position 6 of the β-globin chain and patients are frequently exposed to several blood transfusions in order to maintain physiological function. Transfusion blood bags are composed of PVC and phthalates (as DEHP) are often introduced to the material in order to confer malleability. In this sense, DEHP can easily elute to the blood and cause harmful effects. This study aimed to unravel DEHP effect on SCD patient's hemoglobin function. We found that HbS polymerization using whole erythrocytes is decreased by DEHP in ex vivo experiments and this effect might be mediated by the DEHP-VAL6 interaction, evaluated in silico. Isolated HbS exhibited less polymerization at low DEHP concentrations and increased polymerization rate at higher concentration. When analyzing the propensity to aggregate, HbS is more inclined to aggregate when compared to HbA due to the residue 6 mutation. Circular dichroism showed characteristic hemoglobin peaks for oxygenated HbS that are lost when oxygen is sequestered, and DEHP at higher concentration mildly recovers a peak close to the second hemoglobin one. Finally, by transmission electron microscopy we demonstrated that high DEHP concentration increased polymer formation with a more organized structure. These findings show for the first-time the beneficial effect of low-dose DEHP on HbS polymerization.

Address: Grupo de Pesquisa em Fisiologia Eritróide - GPFisEri, Universidade Federal do Rio de Janeiro, Campus Macaé, Brazil; Programa de Pós-graduação em Endocrinologia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Brazil.; Grupo de Pesquisa em Fisiologia Eritróide - GPFisEri, Universidade Federal do Rio de Janeiro, Campus Macaé, Brazil; Instituto de Ciências Farmacêuticas, Universidade Federal do Rio de Janeiro, Centro Multidisciplinar UFRJ Macaé, Brazil.; Grupo de Pesquisa em Fisiologia Eritróide - GPFisEri, Universidade Federal do Rio de Janeiro, Campus Macaé, Brazil; Programa de Pós-graduação em Endocrinologia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Brazil; Instituto de Ciências Farmacêuticas, Universidade Federal do Rio de Janeiro, Centro Multidisciplinar UFRJ Macaé, Brazil.; Universidade Federal do Rio de Janeiro, Centro Multidisciplinar UFRJ Macaé, Instituto de Ciências Farmacêuticas, Av. Aluizio da Silva Gomes, 50- Novo Cavaleiros, Macaé, 27930-560 Rio de Janeiro, RJ, Brazil.; Centre de Recherche du CHU de Québec, Axe Neurosciences, Québec, QC, Canada.; Laboratório de Endocrinologia Experimental- LEEx, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Brazil; Programa de Pós-graduação em Endocrinologia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Brazil; Programa de Pós-graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Brazil.; Grupo de Pesquisa em Fisiologia Eritróide - GPFisEri, Universidade Federal do Rio de Janeiro, Campus Macaé, Brazil; Programa de Pós-graduação em Endocrinologia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Brazil; Instituto de Ciências Farmacêuticas, Universidade Federal do Rio de Janeiro, Centro Multidisciplinar UFRJ Macaé, Brazil. Electronic address: [email protected].

DOI: 10.1016/j.tiv.2024.105832

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https://medlineplus.gov/sicklecelldisease.html

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Full Text Sources:

https://linkinghub.elsevier.com/retrieve/pii/S0887...

MeSH Terms: Humans, Anemia, Sickle Cell, Hemoglobin, Sickle, Polymerization, Erythrocytes, Diethylhexyl Phthalate, Computer Simulation