Use of proliferation tests to evaluate the effects of complexing agents on beryllium toxicity

Abstract

Occupational exposure to beryllium may cause chronic beryllium disease (CBD), a granulomatous interstitial pneumonitis caused by a cell-mediated immune response with delayed hypersensitivity initiated by an electrostatic interaction with the MHC class II human leukocyte antigen (HLA). Increased research efforts focus on the development of a CBD treatment by chelation therapy. This work presents an in vitro evaluation of the beneficial effects of beryllium chelation with different organic substrates. We have used a standard beryllium lymphocyte proliferation test (BeLPT) adapted for mouse splenocytes. Three complexing agents, 4,5-dihydroxy-1,3-benzenedisulfonic acid (tiron), nitrilotripropionic acid (NTP) and nitrilotriacetic acid (NTA), were tested using different protocols of the splenocyte proliferation test (SPT). We studied their corrective effect (beryllium pre-exposed splenocytes), their protective effect (ligand pre-exposed splenocytes) and their combined effects at fixed Be:L ratio of 1:2, at fixed Be concentration and at fixed L concentration. We also studied the effect of tiron in preventing splenocyte sensitization to beryllium. All three complexing agents showed a corrective effect and proved efficient in the combined effects, except NTA in the fixed Be:L ratio. Only NTP and tiron showed a significant protection at lower beryllium concentrations, while NTA was not significant. Splenocytes pre-exposed to chelated beryllium did not show sensitization while splenocytes pre-exposed to beryllium were sensitized. We observed a strong correlation between the efficiency of the complexing agent and its affinity towards beryllium. Both tiron and NTP showed a similar affinity towards the beryllium ion that is 10(7) higher than that of NTA.

Electrospray Ionisation Mass Spectrometric (ESI MS) Screening and Characterisation of Beryllium Complexes with Potentially Encapsulating Aminopolycarboxylate and Related Ligands

“…Nevertheless, the few other beryllium-containing ESI MS ions observed in the positive ion mode, although occurring at lower intensity (< 20 %), highlighted the existence of other coordination modes. For instance the full encapsulation of beryllium by a single ligand can be ruled out in the complexes of 1:2 beryllium/ligand stoichiometry observed in species such as [Be(L -H ) 2 plexes in solution, in which the Be 2+ ion is most likely in a tetrahedral coordination mode with a single ligand, in agreement with the related tetradentate nitrilotripropionate (NTP) ligand. [12] Signals corresponding to solvated ions, adducts and other polynuclear hydroxido species well-known to exist in beryllium solutions (especially the beryllium hydroxide trimer) were absent, revealing the ability of these ligands to completely exclude the solvent molecules from binding in the beryllium primary coordination sphere, thereby suppressing the wellknown hydrolytic tendency of Be 2+ .…”

“…One area of major interest in the chemistry of beryllium is its coordination to uniquely designed ligands with the ability to sequester the metal for applications in therapies for exposed individuals . Generally, beryllium poisoning is less common in comparison with intoxication from the heavier metals like Pb, As and Cd for instance.…”

“…Recent experimental results from in vivo animal testing as well as potentiometric titrations have identified nitrilotripropionic acid (NTP, Figure ) as a potentially useful chelating agent for beryllium , . Nitrilotripropionic acid is a tripodal aminopolycarboxylic acid that forms a strong complex with beryllium (log k = 9.24) through binding with a nitrogen atom and oxygen atoms from 3 carboxylate pendant arms, so that the beryllium ion is completely encapsulated in a tetrahedral pocket .…”

“…One area of major interest in the chemistry of beryllium is its coordination to uniquely designed ligands with the ability to sequester the metal for applications in therapies for exposed individuals. [1][2][3][4] Generally, beryllium poisoning is less common in comparison with intoxication from the heavier metals like Pb, As and Cd for instance. However, the absence of a well-defined dose-related toxicity level as well as newly emerging risks of exposure have progressively increased biomedical interest in the toxicology of beryllium.…”

Electrospray‐Ionisation Mass‐Spectrometric (ESI‐MS) Investigation of Beryllium Hydrolysis in Acidic Solutions of Beryllium Sulfate

“…Despite its toxicity, the production and usage of beryllium components has continued unabated, renewing research interest in the chemistry of beryllium and its interactions with ligands of biological interest over the last decade . Of interest to coordination and materials chemists in this area is beryllium's coordination to uniquely designed ligands with the ability to selectively sequester beryllium for applications such as light‐emitting materials, physiological and environmental detection, and therapies for exposed individuals , . In line with this, research in our groups (which has been geared toward understanding a selective binding pocket for beryllium encapsulation) has led us to explore and optimise various solution‐based analytical techniques for the in situ investigation of beryllium compounds .…”