Assessing ototoxicity due to chronic lead and cadmium intake with and without noise exposure in the mature mouse

ABSTRACT

Exposure to heavy metals may lead to hearing impairment. However, experimental studies have not explored this issue with and without noise exposure in mature animals with environmentally relevant doses. The aim of this study was to investigate ototoxicity produced by lead (Pb) and cadmium (Cd) and noise, singly and in combination, in the adult CBA/CaJ mouse. Metals were delivered via drinking water (0.03 mM, 1 mM, and 3 mM Pb; or 30, 100, and 300 μM Cd) for 12 weeks, resulting in environmentally- and occupationally relevant mean (± standard deviations) blood levels of Pb (2.89 ± 0.44, 38.5 ± 4.9, and 60.1 ± 6.6 μg/dl, respectively) and Cd (1.3 ± 0.23, 6.37 ± 0.87, 27.2 ± 4.1 μg/L, respectively). Metal treatment was also combined with a noise exposure consisting of a 105 dB broadband (2–20 kHz) stimulus for 2 hr or a sham exposure. Auditory performance was determined by comparing auditory brainstem responses (ABR) and distortion product otoacoustic emissions (DPOAE) at baseline and after 11 weeks of metal treatment. Metal-exposed animals did not develop significant auditory deficits and did not exhibit morphological damage to cochlear hair cells. In contrast, noise-exposed animals, including those exposed to combinations of metals and noise, demonstrated significant hair cell loss, reduced DPOAE amplitudes, and ABR threshold shifts of 42.2 ± 13 dB at 32 kHz (105 dB noise alone). No significant potentiation or synergistic effects were found in groups exposed to multiple agents. This study establishes a highly reproducible adult mouse model that may be used to evaluate a variety of environmental exposure mixtures.

Acknowledgments

The authors would like to acknowledge Ann Kendall, Sue DeRemer, Karin Halsey, and Diane Prieskorn for valuable guidance and mentorship. Additionally, this project could not have taken place without Chrystina James, Katarina Klimpel, Krittika Mittal, and Kan Sun and their assistance on this project.

Disclosure

The authors declare no conflicts of interest related to this research.

Additional information

Funding

This work was supported by grants from the National Institute for Deafness and Communication Disorders at the National Institutes of Health [R03DC013378, R01-DC010412, R01-DC011294, P30-DC05188], a Rackham Merit Fellowship, and a University of Michigan – Environmental Toxicology and Epidemiology Program grant funded through the National Institute of Environmental Health Sciences [P30ES017885].