Prolonged tamoxifen‐enriched diet is associated with cardiomyopathy and nutritional frailty in mice.

Tamoxifen (TAM) is required for gene recombination in the inducible Cre/lox system. The TAM‐enriched diet is considered safe, with negligible impact on animal wellbeing. However, studies reporting the long‐term effects of the TAM diet and its potential impact on experimental outcomes are scarce. We conducted a longitudinal study on mice exposed to a 4‐week dietary TAM citrate supplementation. Several parameters were recorded, such as body weight, body composition, mortality, and cardiac function. The collagen1a2 (Col1a2) transgenic mouse was used to assess TAM‐induced recombination in vivo in cardiac fibroblasts followed by myocardial infarction (MI). The impact of TAM on the MI outcome was also evaluated. The recombination efficiency and cytotoxic effect of the TAM active metabolite, 4‐hydroxy‐tamoxifen (4‐OHT), were assessed in vitro. Mice exposed to a TAM diet showed body weight loss and a 10% increase in mortality (P = 0.045). The TAM diet decreased cardiac function and induced cardiac remodeling, indicated by decreased fractional shortening from 32.23% to 19.23% (P = 0.001) and left ventricular (LV) wall thinning. All measured parameters were reversed to normal when mice were returned to a normal diet. Infarcted Col1a2‐CreER mice on the TAM regimen showed gene recombination in fibroblasts, but it was associated with a substantial increase in mortality post‐surgery (2.5‐fold) compared to the controls. In vitro, 4‐OHT induced gene editing in fibroblasts; however, cell growth arrest and cytotoxicity were observed at high concentrations. In conclusion, prolonged exposure to the TAM diet can be detrimental and necessitates careful model selection and interpretation of the results. What is the central question of this study?Tamoxifen is used to induce Cre‐mediated gene editing, but high doses used in intraperitoneal injection can be toxic and tamoxifen‐enriched food has emerged as an alternative: what is the impact of long‐term exposure to the tamoxifen diet in mice?What is the main finding and its importance?Prolonged exposure to the tamoxifen diet induced severe weight loss, weakness, and impaired cardiac function. Mice exposed to long‐term tamoxifen‐enriched diet are more likely to succumb to further interventions. Investigators planning to use inducible mouse models should be aware of the potential problems that can be avoided with careful experimental design. [ABSTRACT FROM AUTHOR]