ToxSci Advance Access published online on June 15, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi223
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1 Department of Biology, Saint Mary's University, Halifax, Nova Scotia, Canada, B3H 3C3
* To whom correspondence should be addressed. In vitro and in vivo studies have shown that building-associated Penicillium spores and spore extracts can induce significant inflammatory responses in lung cells and animal models of lung disease. However, because spores and spore extracts comprise mixtures of bioactive constituents often including toxins, it is impossible to resolve which constituent mediates inflammatory responses. This study examined dose-response (0.5 nM, 2.5 nM, 5.0 nM, 12.5 nM/g body weight (BW) animal) and time-course (3, 6, 24 and 48hr post instillation (PI)) relationships associated with inflammatory and cytotoxic responses in mouse lungs intratracheally instilled with pure brevianamide A, mycophenolic acid and roquefortine C. High doses (5.0 nM and/or 12.5 nM/g BW animal) of brevianamide A and mycophenolic acid, the dominant metabolites of P. brevicompactum and roquefortine C, the dominant metabolite of P. chrysogenum, induced significant inflammatory responses within 6 h PI manifest as differentially elevated macrophage, neutrophil, MIP-2, TNF and IL-6 concentrations in the bronchioalveolar lavage fluid (BALF) of intratracheally exposed mice. Macrophage and neutrophil numbers were maximal at 24 h PI; responses of the other inflammatory markers were maximal at 6 h PI. Except for macrophage numbers in mycophenolic acid treatment animals, cells exhibited significant dose dependent-like responses; for the chemo-/cytokine markers, dose dependency was lacking except for MIP-2 concentration in brevianamide A treatment animals. It was also found that brevianamide A induced cytotoxicity manifest as significantly increased LDH concentration in mouse BALF, at concentrations of 12.5 nM/g BW animal and at 6 and 24 hr PI. Albumin concentrations, measured as a non-specific marker of vascular leakage, were significantly elevated in the BALF of mice treated with 12.5 nM/g nM brevianamide A/animal from 6 to 24 hr PI and in
Received March 12, 2005
Accepted June 4, 2005
Respiratory Toxicology
Inflammatory and cytotoxic responses in mouse lungs exposed to purified toxins from building isolated Penicillium brevicompactum Dierckx and P. chrysogenum Thom
2 Department of Chemistry, Carleton University, Ottawa, Ontario, Canada K1S 5B6
Thomas G. Rand, E-mail: tgrand{at}eastlink.ca
Abstract 
5.0 nM/g mycophenolic acid-treated animals at 6 to 24 hr PI. These results suggest that these three toxins from Penicillium species common on damp materials in residential housing provoke compound-specific toxic responses with different toxicokinetics. Moreover, that these toxins can stimulate significant inflammatory responses in vivo might help explain some of the indoor effects associated with Penicillium spore exposures in indoor environments.
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