Physiological and experimental determinants of tamoxifen-induced Atf3 in vagal sensory neurons in mice

Tamoxifen is widely used clinically as an anticancer therapy and is also commonly employed in transgenic mouse models to induce Cre-dependent recombination. Although its toxicity has been documented across multiple cell types, its effects on the gut–brain axis remain unclear. Here, we demonstrate that a single intraperitoneal injection of tamoxifen (150 mg/kg) acutely induces Activating Transcription Factor 3 ( Atf3 ), a marker of cellular stress, in neurons of the nodose ganglion. Tamoxifen-induced Atf3 expression was accompanied by severe gastric enlargement and weight loss. While gastric enlargement and weight loss were resolved within one week, Atf3 expression in the nodose ganglion remained elevated. Interestingly, tamoxifen administration to Nav1.8-Cre-Tomato mice was not associated with overt damage to vagal innervation of the stomach. Notably, the severity of tamoxifen-induced Atf3 expression was attenuated by oral administration (gavage or dietary delivery) and by female sex. Collectively, these findings demonstrate that tamoxifen triggers a lasting cellular stress response in vagal sensory neurons, which can be modulated by various experimental factors.