Mutagenicity of 3-methylcholanthrene, PCB3, and 4-OH-PCB3 in the lung of transgenic BigBlue® rats

Abstract

Recent findings of high levels of predominantly lower chlorinated biphenyls in indoor and outdoor air open the question of possible health consequences. Lower chlorinated biphenyls are more readily metabolized to reactive and potentially harmful intermediates, acting as mutagens and cancer initiators. The goal of this study was to assess the mutagenicity of PCB3 in the lungs of rats. Male BigBlue® 334 Fisher transgenic rats, which carry the bacterial lacI gene as a target of mutagenicity, were given intraperitoneal injections of corn oil, 3-methylcholanthrene (3-MC, positive control), 4-monochlorobiphenyl (PCB3) or its metabolite 4-hydroxy-PCB3 (4-OH-PCB3) weekly for 4 weeks. Lungs tissue was harvested to determine mutant frequencies, mutation spectra, and pathological changes. 3-MC caused a 15-fold increase in mutant frequency and an increase in transversion type mutations; a very early occurrence of this type of mutation in lung tissue was previously identified in Ki-ras oncogenes of lung tumors from 3-MC exposed mice. The 2-fold increase in the mutant frequency after treatment with PCB3 and 4-OH-PCB3 was not statistically significant, but a shift in the mutation spectra, especially with PCB3, and an increase in mutations outside of the hotspot region for spontaneous mutations (bp 1-400), suggest that PCB3 and possibly 4-OH-PCB3 are mutagenic in the rat lung.

Evaluating the mechanistic evidence and key data gaps in assessing the potential carcinogenicity of carbon nanotubes and nanofibers in humans

“…Thus, the focal adenomatous alveolar hyperplasia incidence was two-fold higher than the cancer incidence in the mice exposed to MWCNT only. The mechanism of carcinogenesis induced by MCA is gene mutation (Maddox et al 2008), which differs from that expected for CNTs. MWCNT-7 does not appear to be a strong mutagen, but induces chromosomal aberrations (aneugens and clastogens); it also stimulates cell growth in vivo, and stimulates proliferation of MCA-mutated cells.…”

Exposure to and health effects of volatile PCBs

“…Although those congeners with fewer chlorines are more rapidly metabolized, they generate hydroxylated and other metabolic progeny that exhibit genotoxicity (36) and oxidative stress (29). Maddox et al (37) demonstrated a non-significant two-fold increase in spontaneous mutations induced by PCB 3 (4 monochloro biphenyl) and 4-OH-PCB 3 in rat lung. Xie et al (38) showed that PCB 3 is converted to quinones which are very efficient in inducing gene mutations and chromosomal breaks.…”

Polychlorinated Biphenyls and Polybrominated Biphenyls

“…Seventeen days after the last injection, the frequency and spectrum of mutation in the lacI gene were determined in the liver and lung (Maddox et al, 2008) of males, and in the liver of females (Jacobus et al, 2010). Both PCB-3 and its 4′-OH-metabolite caused a similar, more than twofold, increase in mutation frequency in the liver of male rats; however, only the increase observed with PCB-3 was statistically significant.…”

“…PCB-3 and its 4′-OH-metabolite caused a twofold, but not statistically significant, increase in mutation frequency in the lungs of treated males. However, a shift in the mutation spectra, especially with PCB-3, and an increase in the frequency of mutation outside of the hotspot region for spontaneous mutation of lacI (base pairs 1-400) were observed (Maddox et al, 2008). The genotoxicity profile of metabolites of PCB-3 is summarized in Table 4.7.…”