Integrative investigation of hematotoxic effects induced by low doses of lead, cadmium, mercury and arsenic mixture: In vivo and in silico approach

Katarina Živančević; Jovana Živanović; Katarina Baralić; Dragica Božić; Đurđica Marić; Dragana Vukelić; Evica Antonijević Miljaković; Aleksandra Buha Djordjevic; Marijana Ćurčić; Zorica Bulat; Biljana Antonijević; Danijela Đukić-Ćosić

doi:10.1016/j.scitotenv.2024.172608

Integrative investigation of hematotoxic effects induced by low doses of lead, cadmium, mercury and arsenic mixture: In vivo and in silico approach

Sci Total Environ. 2024 Apr 21:930:172608. doi: 10.1016/j.scitotenv.2024.172608. Online ahead of print.

Affiliations

¹ Department of Toxicology "Akademik Danilo Soldatović", Toxicological Risk Assessment Center, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia; University of Belgrade - Faculty of Biology, Institute of Physiology and Biochemistry "Ivan Djaja", Department of General Physiology and Biophysics, Center for Laser Microscopy, Studentski trg 16, 11158 Belgrade, Serbia. Electronic address: kzivancevic@pharmacy.bg.ac.rs.
² Department of Toxicology "Akademik Danilo Soldatović", Toxicological Risk Assessment Center, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia.

PMID: 38653421
DOI: 10.1016/j.scitotenv.2024.172608

Abstract

The effect of the lead (Pb), cadmium (Cd), mercury (Hg) and arsenic (As) mixture (MIX) on hematotoxicity development was investigated trough combined approach. In vivo subacute study (28 days) was performed on rats (5 per group): a control group and five groups orally exposed to increasing metal(loid) mixture doses, MIX 1- MIX 5 (mg/kg bw./day) (Pb: 0.003, 0.01, 0.1, 0.3, 1; Cd: 0.01, 0.03, 0.3, 0.9, 3; Hg: 0.0002, 0.0006, 0.006, 0.018, 0.06; As: 0.002, 0.006, 0.06, 0.18, 0.6). Blood was taken for analysis of hematological parameters and serum iron (Fe) analysis. MIX treatment increased thrombocyte/platelet count and MCHC and decreased Hb, HCT, MCV and MCH values compared to control, indicating the development of anemia and thrombocytosis. BMDIs with the narrowest width were identified for MCH [pg] (6.030E-03 - 1.287E-01 mg Pb/kg bw./day; 2.010E-02 - 4.290E-01 mg Cd/kg bw./day; 4.020E-04 - 8.580E-03 mg Hg/kg bw./day; 4.020E-03 - 8.580E-02 mg As/kg bw./day). In silico analysis showed target genes connected with MIX and the development of: anemia - ACHE, GSR, PARP1, TNF; thrombocytosis - JAK2, CALR, MPL, THPO; hematological diseases - FAS and ALAD. The main extracted pathways for anemia were related to apoptosis and oxidative stress; for thrombocytosis were signaling pathways of Jak-STAT and TPO. Changes in miRNAs and transcription factors enabled the mode of action (MoA) development based on the obtained results, contributing to mechanistic understanding and hematological risk related to MIX exposure.

Keywords: Benchmark modelling; Hematotoxicity; Mode of action; Toxic metal(loid)s mixture.