Corinne Lencina

Food intolerance at adulthood after perinatal exposure to the endocrine disruptor bisphenol A

The food contaminant bisphenol A (BPA) is pointed out as a risk factor in development of food allergy and food intolerance, two adverse food reactions increasing worldwide. We evaluated the consequences of perinatal exposure to low doses of BPA on immune‐specific response to the food antigen ovalbumin (OVA) at adulthood. Perinatal exposure to BPA (0.5, 5, or 50 μg/kg/d) from 15th day of gravidity to pups weaning resulted in an increase of anti‐OVA IgG titers at all BPA dosages in OVA‐tolerized rats, and at 5 μg/kg/d in OVA‐immunized rats compared to control rats treated with vehicle. In BPA‐treated and OVA‐tolerized rats, increased anti‐OVA IgG titers were associated with higher IFNγ secretion by the spleen. This result is in accordance with the increase of activated CD4+CD44high CD62Llow T lymphocytes observed in spleen of BPA‐exposed rats compared to controls. Finally, when BPA‐treated OVA‐tolerized rats were orally challenged with OVA, colonic inflammation occurred, with neutrophil infiltration, increased IFNγ, and decreased TGFβ. We show that perinatal exposure to BPA altered oral tolerance and immunization to dietary antigens (OVA). In summary, the naive immune system of neonate is vulnerable to low doses of BPA that trigger food intolerance later in life.—Menard, S., Guzylack‐Piriou, L., Leveque, M., Braniste, V., Lencina, C., Naturel, M., Moussa, L., Sekkal, S., Harkat, C., Gaultier, E., Theodorou, V., Houdeau, E., Food intolerance at adulthood after perinatal exposure to the endocrine disruptor bisphenol A. FASEB J. 28, 4893–4900 (2014). www.fasebj.org

Perinatal Exposure to a Low Dose of Bisphenol A Impaired Systemic Cellular Immune Response and Predisposes Young Rats to Intestinal Parasitic Infection

Perinatal exposure to the food contaminant bisphenol A (BPA) in rats induces long lasting adverse effects on intestinal immune homeostasis. This study was aimed at examining the immune response to dietary antigens and the clearance of parasites in young rats at the end of perinatal exposure to a low dose of BPA. Female rats were fed with BPA [5 µg/kg of body weight/day] or vehicle from gestational day 15 to pup weaning. Juvenile female offspring (day (D)25) were used to analyze immune cell populations, humoral and cellular responses after oral tolerance or immunization protocol to ovalbumin (OVA), and susceptibility to infection by the intestinal nematode Nippostrongylus brasiliensis (N. brasiliensis). Anti-OVA IgG titers following either oral tolerance or immunization were not affected after BPA perinatal exposure, while a sharp decrease in OVA-induced IFNγ secretion occurred in spleen and mesenteric lymph nodes (MLN) of OVA-immunized rats. These results are consistent with a decreased number of helper T cells, regulatory T cells and dendritic cells in spleen and MLN of BPA-exposed rats. The lack of cellular response to antigens questioned the ability of BPA-exposed rats to clear intestinal infections. A 1.5-fold increase in N. brasiliensis living larvae was observed in the intestine of BPA-exposed rats compared to controls due to an inappropriate Th1/Th2 cytokine production in infected jejunal tissues. These results show that perinatal BPA exposure impairs cellular response to food antigens, and increases susceptibility to intestinal parasitic infection in the juveniles. This emphasized the maturing immune system during perinatal period highly sensitive to low dose exposure to BPA, altering innate and adaptative immune response capacities in early life.

A Low Dose of Fermented Soy Germ Alleviates Gut Barrier Injury, Hyperalgesia and Faecal Protease Activity in a Rat Model of Inflammatory Bowel Disease

Pro-inflammatory cytokines like macrophage migration inhibitory factor (MIF), IL-1β and TNF-α predominate in inflammatory bowel diseases (IBD) and TNBS colitis. Increased levels of serine proteases activating protease-activated receptor 2 (PAR-2) are found in the lumen and colonic tissue of IBD patients. PAR-2 activity and pro-inflammatory cytokines impair epithelial barrier, facilitating the uptake of luminal aggressors that perpetuate inflammation and visceral pain. Soy extracts contain phytoestrogens (isoflavones) and serine protease inhibitors namely Bowman-Birk Inhibitors (BBI). Since estrogens exhibit anti-inflammatory and epithelial barrier enhancing properties, and that a BBI concentrate improves ulcerative colitis, we aimed to evaluate if a fermented soy germ extract (FSG) with standardized isoflavone profile and stable BBI content exert cumulative or synergistic protection based on protease inhibition and estrogen receptor (ER)-ligand activity in colitic rats. Female rats received orally for 15 d either vehicle or FSG with or without an ER antagonist ICI 182.780 before TNBS intracolonic instillation. Macroscopic and microscopic damages, myeloperoxidase activity, cytokine levels, intestinal paracellular permeability, visceral sensitivity, faecal proteolytic activity and PAR-2 expression were assessed 24 h, 3 d and 5 d post-TNBS. FSG treatment improved the severity of colitis, by decreasing the TNBS-induced rise in gut permeability, visceral sensitivity, faecal proteolytic activity and PAR-2 expression at all post-TNBS points. All FSG effects were reversed by the ICI 182.780 except the decrease in faecal proteolytic activity and PAR-2 expression. In conclusion, the anti-inflammatory properties of FSG treatment result from two distinct but synergic pathways i.e an ER-ligand and a PAR-2 mediated pathway, providing rationale for potential use as adjuvant therapy in IBD.

Mo1733 Perinatal Exposure to Low Dose of Bisphenol a Alters Immune Cell Differentiation At Systemic and Intestinal Level in Young Offspring Rats

detected in colon tissue was significantly lower in both EBI2 and CH25H knockout mice as compared to wildtype controls (p < 0.01 and p < 0.05). Conclusion: The development of the intestinal lymphoid tissue and the intensity of inflammation in chronic DSS colitis seem to depend on an intact EBI2-7alpha,25-OHC system. These findings may establish EBI2-mediated cell migration as an important step in IBD pathogenesis and development of the gut immune system.

Sa1754 Early Maternal Separation Leads to Abnormal Immune Response Against Commensal Microbiota in Adult Mice

Early maternal separation leads to abnormal immune response against commensal microbita in adult mice. 9. European Mucosal Immunology Group Meeting (EMIG)

Mo1659 Perinatal Exposure to Low Doses of the Food Endocrine Disruptor Bisphenol A Impairs Oral Tolerance and Sensitization in Offspring Rats at Adulthood

Background: The food contaminant Bisphenol A (BPA) is the building plastic monomer widely used in food packaging and epoxy resins lining metal cans. BPA is a xenoestrogen known to disrupt endocrine function, liver metabolism and intestinal barrier function. We have previously shown that BPA exposure in utero and through lactation at the No Observed Adverse Effect Level (NOAEL) (5mg/kg/j) decreased colonic paracellular permeability and enhanced the TNBS-induced colitis severity in adult female offspring. Herein we aimed to address the consequences of perinatal exposure to 1000 time lower than NOAEL dose of BPA (5μg/kg/day) on the upper intestinal immune homeostasis at adulthood. Material and methods: Gravid and breast feeding rats were treated per os from the 15th day of gravidity to pups weaning (D21) with or without BPA [5μg/kg/d]. Paracellular (4kDa dextran-FITC) and transcellular (Horse Radish Peroxidase) jejunal permeability were addressed by Ussing chamber on female adult offspring aged of 45 days. In parallel, effects of BPA perinatal exposure on oral tolerance and systemic immunisation to ovalbumin (OVA) in adult offspring were tested. Anti-OVA IgG titers were measured by ELISA as well as IFNγ secretion after In Vitro stimulation of either spleen ormesenteric lymph nodes cells culture.Results: Perinatal treatment with BPA induced a decrease of jejunal transcellular permeability compared to controls (0.03±0.0045x10-7 vs 0.09±0.02 x10-7 cm/s; p<0.05) but did not affect jejunal paracellular permeability. Furthermore, BPA perinatally treated adult rats exhibited higher anti-OVA IgG titers following either an oral tolerance protocol (162±88.7x103 compared to 6.2±1.9 x103 in controls; p<0.03) or a sensitization with OVA (783±127x103 compared to 433±100 x103 in controls; p<0.03). Enhanced humoral response in perinatally BPA treated adult rats was associated with a higher production of IFNγ by spleen in sensitized rats (628.2±392 compared to 114.9±72 pg/ml in controls) and by mesenteric lymph nodes in tolerized rats (707±325 compared to 54.6±43 pg/ml in controls). Conclusion: Perinatal exposure to low doses of BPA decreased jejunal transcellular permeability and impaired oral tolerance and sensitization to dietary antigen protein in adult offsprings. These results suggest that the perinatal period is a critical window for BPA exposure that may trigger food intolerance in later life.