Titanium dioxide exposure during gestation is critical to worsen DSS-induced colitis

Abstract Inflammatory bowel diseases (IBD) are characterized by disrupted intestinal barrier function and impaired tolerance to the gut microbiota. In mammals, early life is crucial for gut development and the establishment of a homeostatic state between mucosal immune system and microbiota. Although the etiology of IBD remains unclear, both genetic and environmental factors are implicated. Among environmental factors, perinatal exposure to food additives such as titanium dioxide particles (TiO 2 , i.e. E171) has been shown to impair intestinal barrier and worsen colitis in offspring. We aimed to assess the importance of the gestational period versus the lactational one on the detrimental effects of TiO 2 exposure on intestinal barrier function and colitis severity. To compare the effects of E171 exposure during gestation or lactation on intestinal homeostasis in offspring, dams were exposed to E171 (9 mg/kg body weight/day) in drinking water throughout gestation, lactation or both periods. These consequences were monitored both at basal state and during colitis. Colitis was induced in male and female offspring by exposing them to drinking water containing 3% DSS for 5 days, and mice were sacrificed 2 days later. Colonic permeability was assessed in Ussing chamber. The microbiota was analyzed by sequencing the 16S rRNA gene. Colonic inflammation was monitored by measuring fecal biomarkers, including IgA and IgG. The severity of colitis was also monitored through macroscopic assessment of colonic inflammation. In basal condition, perinatal exposure to E171 during both gestation and lactation increased fecal IgG in male and female offspring. Histologically, E171 exposure during lactation in males induced villus elongation and colonic crypt shortening, while gestational exposure increased goblet‑cell numbers; in females, gestational exposure also increased goblet‑cell numbers and decreased colonic crypt length. Colonic permeability to FD4 kDa was increased only in male after exposure to E171 during both gestation and lactation. TiO₂ exposure in males during lactation and both periods increased microbiota richness, but not diversity, compared to controls. DSS-induced colitis increased macroscopic inflammation scores. Those scores were even higher when male and female were perinatally exposed to E171 during gestation and both gestation and lactation but not lactation alone. In conclusion, our data demonstrated that gestation is a more critical period than lactation for aggravation of colitis induced by perinatal exposure to E171. In addition, our results shown that male mice offspring were more sensitive to the deleterious impact of E171 than female. This result is of particular interest for public health dietary recommendations, especially for pregnant women and TiO2 regulation.