The failure of two major formaldehyde catabolism enzymes (ADH5 and ALDH2) leads to partial synthetic lethality in C57BL/6 mice

Jun Nakamura; Darcy W Holley; Toshihiro Kawamoto; Scott J Bultman

doi:10.1186/s41021-020-00160-4

The failure of two major formaldehyde catabolism enzymes (ADH5 and ALDH2) leads to partial synthetic lethality in C57BL/6 mice

Genes Environ. 2020 Jun 3:42:21. doi: 10.1186/s41021-020-00160-4. eCollection 2020.

Authors

Jun Nakamura^{1

2}, Darcy W Holley³, Toshihiro Kawamoto⁴, Scott J Bultman³

Affiliations

¹ Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
² Laboratory of Laboratory Animal Science, Graduate School of Life and Environmental Biosciences, Osaka Prefecture University, Izumisano, Osaka, Japan.
³ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
⁴ Department of Environmental Health, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan.

Abstract

Background: Exogenous formaldehyde is classified by the IARC as a Category 1 known human carcinogen. Meanwhile, a significant amount of endogenous formaldehyde is produced in the human body; as such, formaldehyde-derived DNA and protein adducts have been detected in animals and humans in the absence of major exogenous formaldehyde exposure. However, the toxicological effects of endogenous formaldehyde on individuals with normal DNA damage repair functions are not well understood. In this study, we attempted to generate C57BL/6 mice deficient in both Adh5 and Aldh2, which encode two major enzymes that metabolize endogenous formaldehyde, in order to understand the effects of endogenous formaldehyde on mice with normal DNA repair function.

Results: Due to deficiencies in both ADH5 and ALDH2, few mice survived past post-natal day 21. In fact, the survival of pups within the first few days after birth was significantly decreased. Remarkably, two Aldh2 ^-/- /Adh5 ^-/- mice survived for 25 days after birth, and we measured their total body weight and organ weights. The body weight of Aldh2 ^-/- /Adh5 ^-/- mice decreased significantly by almost 37% compared to the Aldh2 ^-/- /Adh5 ^+/- and Aldh2 ^-/- /Adh5 ^+/+ mice of the same litter. In addition, the absolute weight of each organ was also significantly reduced.

Conclusion: Mice deficient in both formaldehyde-metabolizing enzymes ADH5 and ALDH2 were found to develop partial synthetic lethality and mortality shortly after birth. This phenotype may be due to the accumulation of endogenous formaldehyde. No serious phenotype has been reported in people with dysfunctional, dominant-negative ALDH2*2 alleles, but it has been reported that they may be highly susceptible to osteoporosis and neurodegenerative diseases. It is important to further investigate these diseases in individuals with ALDH2*2 alleles, including an association with decreased metabolism, and thus accumulation, of formaldehyde.

Keywords: ADH5; ALDH2; Knockout mice; Synthetic lethality; formaldehyde metabolism.