Accumulation of molybdenum in major organs following repeated oral administration of bis‐choline tetrathiomolybdate in the Sprague Dawley rat

• Published in: Journal of applied toxicology 2022-11, Vol.42 (11), p.1807-1821
• Main Authors: Foster, John R., Billimoria, Kharmen, Castillo Busto, M. Estela, Strekopytov, Stanislav, Goenaga‐Infante, Heidi, Morley, Timothy J.
• Format: Article
• Language: English
• Subjects: Accumulation; adrenal gland; Adrenal glands; Biomonitoring; bis‐choline tetrathiomolybdate; brain; Choline; Diet; Dosage; Hematology; Histopathology; Inductively coupled plasma; kidney; Kidneys; Laser ablation; laser ablation inductively coupled plasma time‐of‐flight mass spectrometry; liver; Mass spectrometry; Mass spectroscopy; Molybdenum; Molybdenum compounds; Oral administration; rat; spleen; testes; Tissues; Toxicity; Trace elements; Trace elements (nutrients)
• ISSN: 0260-437X; 1099-1263
• DOI: 10.1002/jat.4358

Molybdenum is an essential dietary trace element required for several critical enzyme systems. High intake is associated with toxicity in ruminants and animal studies. The proposed therapeutic use of molybdenum‐based drugs poses a potential risk for accumulation through chronic administration of therapeutic doses of this element. The current experiment was designed to study the effect of daily dosing of a molybdenum compound, bis‐choline tetrathiomolybdate (TTM), in Sprague Dawley rats using laser ablation inductively coupled plasma time‐of‐flight mass spectrometry (LA‐ICP‐ToF‐MS) and two dosing levels of TTM for up to 3 months. To investigate if molybdenum accumulation was associated with tissue toxicity, histopathology, haematology and clinical biochemistry markers of toxicity were incorporated into the study design. There were no behavioural signs of toxicity to the rats, and no clinical or anatomic pathology was associated with treatment. The current data did show a progressive accumulation of molybdenum within the adrenal gland, kidneys, liver, spleen, brain and testes. Although this was not associated with tissue toxicity within the 3‐month study design, greater exposure over a longer period of time has the potential for producing adverse pathophysiological cellular function. Tissue toxicity, as a result of local excessive accumulation of molybdenum over time, has clear implications for the therapeutic use of molybdenum in humans and demands sensitive monitoring of tissue molybdenum levels to avoid toxicity. The current study highlights the shortcomings of conventional biomonitoring approaches to detect molybdenum accumulation with the goal of avoiding molybdenum‐associated toxicity. Following daily oral dosing of rats with bis‐choline tetrathiomolybdate, molybdenum for 3 months, accumulation was observed in the adrenal gland, kidneys, liver, spleen, brain and testes using laser ablation inductively coupled plasma time‐of‐flight mass spectrometry. Although this accumulation was not associated with adverse histopathology over the period of study, pigment accumulation, corresponding to the presence of molybdenum, was observed in phagocytic cells in all of the affected organs. Because this therapeutic is used in human medicine, it is considered prudent that levels of molybdenum are monitored to avoid potential toxicity following long‐term dosing.