Conditioned flavor aversion and brain Fos expression following exposure to arsenic.

Recent advances in the knowledge of the cellular effects of arsenic have provided insights into the molecular mechanisms of arsenic-associated carcinogenesis, immunotoxicity and cardiovascular disease. In the present experiments we tested the hypothesis that the arrival of arsenic to the gastrointestinal (GI) tract is detected by the gut-brain axis, which includes hindbrain and forebrain nuclei activated by GI stimulation. As a marker of neuronal activation we measured Fos expression using immunohistochemistry. Because Fos expression in these nuclei is closely linked to the development of conditioned flavor aversion (CFA) we also tested the effect of arsenic on CFA. Our experiments indicate that arsenic ingestion is readily detected by the brain, as shown by increased Fos expression after oral administration of arsenic. Furthermore, the vagus nerve, which supplies information from the GI tract to the brain, is not involved in this response because a complete subdiaphragmatic vagotomy did not reduce the effect of arsenic on brain Fos expression, but enhanced this response. In parallel, arsenic ingestion is associated with a robust, dose-dependent CFA, which started at doses as low as 0.1 mg/kg body weight. In summary, these data indicate that arsenic given by oral administration is detected by the brain in low concentrations, and activates specific nuclei, which might trigger behavioral responses, such as CFA.