Route of Arsenic Exposure Differentially Impacts the Expression of Genes Involved in Gut-Mucosa-Associated Immune Responses and Gastrointestinal Permeability

Abstract

First-pass metabolism alters arsenic biotransformation and its immunomodulatory activities. This study aims to determine the mRNA expression of intestinal-immunity- and permeability-associated genes, levels of cytokine/chemokines and levels of immunoglobulin isotypes when CD-1 mice were exposed to a single dose of intravenous (IV) sodium arsenite (50 µg/kg body weight (BW)) and to compare these responses to exposure via oral gavage (OG) (50 µg/kg BW). Samples were collected at 1, 4, 24 and 48 h post IV exposure and 24 and 48 h post OG. Sodium arsenite IV exposure led to a transient modulation of mRNA expression and protein levels of immunity-related genes involved in inflammation/apoptotic pathways and production of cytokines/chemokines, whereas it also led to downregulated expression of genes encoding tight junction, focal adhesion, and gap junction proteins, which are responsible for maintaining cell permeability. Oral exposure perturbed fewer cell-permeability-related genes at 24 and 48 h post exposure. At 24 h post exposure, OG decreased IgA and IgG2b levels; however, IV exposure significantly increased IgG2b, IgG3 and IgA in ileal tissue. Earlier, we showed significant downregulation of mRNA expression of genes involved in the immune-related pathways during OG in the intestinal mucosa of the same animals. Cumulatively, these results provide evidence that the exposure route of a xenobiotic can differentially impact the intestinal responses due to the impact of first-pass metabolism.

Guardians at the Gate: Immune System in Gastrointestinal Diseases

“…Recent research has elucidated the mechanisms underlying leaky gut syndrome, including the dysregulation of tight junction proteins, mucosal inflammation, and dysbiosis of the gut microbiota [ 26 ], yet the external agents triggering leaky gut syndrome are not completely understood. Several studies show that environmental toxins such as arsenic can be an important modulator of gut-mucosa-associated immune responses and gastrointestinal permeability [ 27 ], opening up potential approaches to restore intestinal homeostasis.…”