In a recent issue of Science, Wilson et al. (2019) provide direct evidence that the bacterial-produced colibactin alkylates DNA in vivo, resulting in DNA adducts, which mediates its genotoxic effect. ...This work reinforces the role of colibactin-producing bacteria in colon cancer pathogenesis.
In a recent issue of Science, Wilson et al. (2019) provide direct evidence that the bacterial-produced colibactin alkylates DNA in vivo, resulting in DNA adducts, which mediates its genotoxic effect. This work reinforces the role of colibactin-producing bacteria in colon cancer pathogenesis.
Bisphenol (BP)A is an endocrine disruptor (ED) widely used in thermal papers. Regulatory restrictions have been established to prevent risks for human health, leading to BPA substitution by ...structural analogues, like BPS and BPF. We previously demonstrated that oral perinatal exposure to BPA had long-term consequences on immune responses later in life. It appears now essential to enhance our understanding on immune impact of different routes of BP exposure. In this study, we aimed at comparing the impact of mother dermal exposure to BPs on offspring immune system at adulthood. Gravid mice were dermally exposed to BPA, BPS or BPF at 5 or 50 μg/kg of body weight (BW)/day (d) from gestation day 15 to weaning of pups at post-natal day (PND)21. In offspring, BPs dermal impregnation of mothers led to adverse effects on immune response at intestinal and systemic levels that was dependent on the BP, the dose and offspring sex. These findings provide, for the first time, results on long-term consequences of dermal perinatal BPs exposure on immune responses in offspring. This work warns that it is mandatory to consider immune markers, dose exposure as well as sex in risk assessment associated with new BPA's alternatives.
Abstract
Background
Bisphenol A (BPA), one of the highest-volume chemicals produced worldwide, has been identified as an endocrine disruptor. Many peer-reviewing studies have reported adverse effects ...of low dose BPA exposure, particularly during perinatal period (gestation and/or lactation). We previously demonstrated that perinatal oral exposure to BPA (via gavage of mothers during gestation and lactation) has long-term consequences on immune response and intestinal barrier functions. Due to its adverse effects on several developmental and physiological processes, BPA was removed from consumer products and replaced by chemical substitutes such as BPS or BPF, that are structurally similar and not well studied compare to BPA. Here, we aimed to compare perinatal oral exposure to these bisphenols (BPs) at two doses (5 and 50 μg/kg of body weight (BW)/day (d)) on immune response at intestinal and systemic levels in female offspring mice at adulthood (Post Natal Day PND70).
Methods
Pregnant female mice were orally exposed to BPA, BPS or BPF at 5 or 50 μg/kg BW/d from 15th day of gravidity to weaning of pups at Post-Natal Day (PND) 21. Humoral and cellular immune responses of adult offspring (PND70) were analysed at intestinal and systemic levels.
Results
In female offspring, perinatal oral BP exposure led to adverse effects on intestinal and systemic immune response that were dependant of the BP nature (A, S or F) and dose of exposure. Stronger impacts were observed with BPS at the dose of 5 μg/kg BW/d on inflammatory markers in feces associated with an increase of anti-
E. coli
IgG in plasma. BPA and BPF exposure induced prominent changes at low dose in offspring mice, in term of intestinal and systemic immune responses, provoking an intestinal and systemic Th1/Th17 inflammation.
Conclusion
These findings provide, for the first time, results of long-time consequences of BPA, S and F perinatal exposure by oral route on immune response in offspring mice. This work warns that it is mandatory to consider immune markers and dose exposure in risk assessment associated to new BPA’s alternatives.
Epidemiology evidenced the Bisphenol A (BPA), a chemical found in daily consumer products, as an environmental contributor to obesity and type II diabetes (T2D) in Humans. However, the BPA-mediated ...effects supporting these metabolic disorders are still unknown. Knowing that obesity and T2D are associated with low-grade inflammation and gut dysbiosis, we performed a longitudinal study in mice to determine the sequential adverse effects of BPA on immune system and intestinal microbiota that could contribute to the development of metabolic disorders. We observed that perinatal exposure to BPA (50 µg/kg body weight/day) induced intestinal and systemic immune imbalances at PND45, through a decrease of Th1/Th17 cell frequencies in the lamina propria concomitant to an increase of splenic Th1/Th17 immune responses. These early effects are associated with an altered glucose sensitivity, a defect of IgA secretion into faeces and a fall of faecal bifidobacteria relative to control mice. Such BPA-mediated events precede infiltration of pro-inflammatory M1 macrophages in gonadal white adipose tissue appearing with ageing, together with a decreased insulin sensitivity and an increased weight gain. Our findings provide a better understanding of the sequential events provoked by perinatal exposure to BPA that could support metabolic disorder development in later life.
Human exposure to foodborne inorganic nanoparticles (NPs) is a growing concern. However, identifying potential hazards linked to NP ingestion often requires long-term exposure in animals. Owing these ...constraints, intestinal organoids are a promising alternative to in vivo experiments; as such, an in vitro approach should enable a rapid and reliable assessment of the effects of ingested chemicals on the gut. However, this remains to be validated for inorganic substances. In our study, a transcriptomic analysis and immunofluorescence staining were performed to compare the effects of food-grade TiO
(
-TiO
) on enteroid-derived monolayers (EDMs) from murine intestinal organoids to the known impacts of TiO
on intestinal epithelium. After their ability to respond to a pro-inflammatory cytokine cocktail was validated, EDMs were exposed to 0, 0.1, 1, or 10 µg
-TiO
/mL for 24 h. A dose-related increase of the
,
, and
gene markers of cell differentiation was observed. In addition,
-TiO
induced apoptosis and dose-dependent genotoxicity, while a decreased expression of genes encoding for antimicrobial peptides, and of genes related to tight junction function, was observed. These results validated the use of EDMs as a reliable model for the toxicity testing of foodborne NPs likely to affect the intestinal barrier.
Inflammatory bowel disease patients have a greatly increased risk of developing colitis-associated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for ...neoplasia is unclear. Using three models of CAC, we find that sustained inflammation triggers 8-oxoguanine DNA lesions. Strikingly, antioxidants or iNOS inhibitors reduce 8-oxoguanine and polyps in CAC models. Because the mismatch repair (MMR) system repairs 8-oxoguanine and is frequently defective in colorectal cancer (CRC), we test whether 8-oxoguanine mediates oncogenesis in a Lynch syndrome (MMR-deficient) model. We show that microbiota generates an accumulation of 8-oxoguanine lesions in MMR-deficient colons. Accordingly, we find that 8-oxoguanine is elevated in neoplastic tissue of Lynch syndrome patients compared to matched untransformed tissue or non-Lynch syndrome neoplastic tissue. While antioxidants reduce 8-oxoguanine, they do not reduce CRC in Lynch syndrome models. Hence, microbe-induced oxidative/nitrosative DNA damage play causative roles in inflammatory CRC models, but not in Lynch syndrome models.
The endocrine disruptor and food contaminant bisphenol A (BPA) is frequently present in consumer plastics and can produce several adverse health effects participating in the development of ...inflammatory and autoimmune diseases. Regulatory restrictions have been established to prevent risks for human health, leading to the substitution of BPA by structural analogues, such as bisphenol S (BPS) and F (BPF). In this study, we aimed at comparing the in vitro impact of these bisphenols from 0.05 to 50,000 nM on Th17 differentiation, frequency and function in mouse systemic and intestinal immune T cells and in human blood T cells. This study reports the ability of these bisphenols, at low and environmentally relevant concentration, i.e, 0.05 nM, to increase significantly IL-17 production in mouse T cells but not in human T lymphocytes. The use of an aryl hydrocarbon receptor (AhR) specific inhibitor demonstrated its involvement in this bisphenol-induced IL-17 production. We also observed an increased IL-17 secretion by BPS and BPF, and not by BPA, in mouse naive T cells undergoing in vitro Th17 differentiation. In total, this study emphasizes the link between bisphenol exposures and the susceptibility to develop immune diseases, questioning thus the rational of their use to replace BPA.
•In vitro exposure to bisphenols A, S, F differentially alter IL-17 secretion by mouse T cells.•Such effect occurs at low and environmentally relevant concentrations.•Such effect is partly mediated by aryl hydrocarbon receptor activation.•Effects of bisphenols A, S, F on IL-17 secretion are different in human and mouse T cells.
The potent immunomodulatory effect of the endocrine disruptor bisphenol A during development and consequences during life span are of increasing concern. Particular interests have been raised from ...animal studies regarding the risk of developing food intolerance and infection. We aimed to identify immune disorders in mice triggered by perinatal exposure to bisphenol A. Gravid mice were orally exposed to bisphenol (50 μg/kg body weight/day) from day 15 of pregnancy until weaning. Gut barrier function, local and systemic immunity were assessed in adult female offspring. Mice perinatally exposed to bisphenol showed a decrease in ileal lysozyme expression and a fall of fecal antimicrobial activity. In offspring mice exposed to bisphenol, an increase in colonic permeability was observed associated with an increase in interferon-γ level and a drop of colonic IgA
+
cells and fecal IgA production. Interestingly, altered frequency of innate lymphoid cells type 3 occurred in the small intestine, with an increase in IgG response against commensal bacteria in sera. These effects were related to a defect in dendritic cell maturation in the
lamina propria
and spleen. Activated and regulatory T cells were decreased in the
lamina propria
. Furthermore, perinatal exposure to bisphenol promoted a sharp increase in interferon-γ and interleukin-17 production in the intestine and elicited a T helper 17 profile in the spleen. To conclude, perinatal exposure to bisphenol weakens protective and regulatory immune functions in the intestine and at systemic level in adult offspring. The increased susceptibility to inflammatory response is an interesting lead supporting bisphenol-mediated adverse consequences on food reactions and infections.
The increasing prevalence of food sensitivities has been attributed to changes in gut microenvironment; however, ubiquitous environmental triggers such as inorganic nanoparticles (NPs) used as food ...additives have not been thoroughly investigated.
We explored the impact of the NP-structured food-grade silicon dioxide (
) on intestinal immune response involved in oral tolerance (OT) induction and evaluated the consequences of oral chronic exposure to this food-additive using a mouse model of OT to ovalbumin (OVA) and on gluten immunopathology in mice expressing the celiac disease risk gene, HLA-DQ8.
Viability, proliferation, and cytokine production of mesenteric lymph node (MLN) cells were evaluated after exposure to
. C57BL/6J mice and a mouse model of OT to OVA were orally exposed to
or vehicle for 60 d. Fecal lipocalin-2 (Lcn-2), anti-OVA IgG, cytokine production, and immune cell populations were analyzed. Nonobese diabetic (NOD) mice expressing HLA-DQ8 (NOD/DQ8), exposed to
or vehicle, were immunized with gluten and immunopathology was investigated.
MLN cells exposed to
presented less proliferative T cells and lower secretion of interleukin 10 (IL-10) and transforming growth factor beta (
) by T regulatory and
cells compared to control, two factors mediating OT. Mice given
exhibited intestinal Lcn-2 level and interferon gamma (
) secretion, showing inflammation and less production of IL-10 and
. These effects were also observed in OVA-tolerized mice exposed to
, in addition to a breakdown of OT and a lower intestinal frequency of T cells. In NOD/DQ8 mice immunized with gluten, the villus-to-crypt ratio was decreased while the
intraepithelial lymphocyte counts and the Th1 inflammatory response were aggravated after
treatment.
Our results suggest that chronic oral exposure to
blocked oral tolerance induction to OVA, and worsened gluten-induced immunopathology in NOD/DQ8 mice. The results should prompt investigation on the link between
exposure and food sensitivities in humans. https://doi.org/10.1289/EHP12758.
Bisphenol (BP) A, a known food contaminant, is a possible risk factor in the epidemic of non-communicable diseases (NCD) including food intolerance and inflammatory bowel diseases (IBD). Regulatory ...restrictions regarding BPA usage led to BPA removal and replacement by poorly described substitutes, like BPS or BPF (few data on occurrence in food and human samples and biological effect). Oral tolerance protocol to ovalbumin (OVA) in WT mice and Il10−/− mice prone to IBD were used respectively to address immune responses towards food and microbial luminal antigens following BP oral exposure. Both mice models were orally exposed for five weeks to BPA, BPS or BPF at 0.5, 5 and 50 μg/kg of body weight (bw)/day (d). Oral exposure to BPs at low doses (0.5 and 5 μg/kg bw/d) impaired oral tolerance as indicated by higher humoral and pro-inflammatory cellular responses in OVA-tolerized mice. However, only BPF exacerbate colitis in Il10−/− prone mice associated with a defect of fecal IgA and increased secretion of TNF-α in colon. These findings provide a unique comparative study on effects of adult oral exposure to BPs on immune responses and its consequences on NCD related to intestinal luminal antigen development.
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