Title : Impacts on gut and adipose tissue of a long-term co-exposure to the pesticide Chlorpyrifos and a high fat diet in male rat offspring
Background/aims: The perinatal period is characterized by a strong plasticity of physiological systems explaining the higher individual sensitivity to environmental factors (foetal programming). An association of junk food and early exposure to pesticide residues seem to be involved in the sharp increase of pathologies such as obesity and metabolic disorders, a real public health concern. This project is aimed at determining if a long term exposure of mothers and offsprings to the pesticide chlorpyrifos (CPF), associated or not to an obesogenic diet after weaning, could alter the body energy balance and promote disorders of intestinal homeostasis and adipose tissue in the offspring.
Methods: Two groups of female rats were exposed during gestation till the end of lactation period to oral CPF (1 mg/kg/day) or its vehicle (organic rapeseed oil; controls). After weaning, male offspring were divided and fed either a high fat diet (HFD) or a conventional pelleted food associated or not with CPF oral administration (4 groups). After 10 weeks, the animals were administered by oral gavage a fluorescent marker (FITC-dextran 4 kDa) 2 hours before sacrifice for assessment of intestinal epithelial permeability. Blood drawings were then performed in order to measure FITC-dextran concentration, metabolic and inflammatory markers. In addition, samples from ileum, colon, mesenteric and gonadic adipose tissues were removed and stored at -80°C until further analysis. We analyzed in tissue samples: myeloperoxidase (MPO) activity, cytokines mRNA expression by PCR, the number of mast cells in the gut wall, muscular layers thickness, the size of mesenteric and gonadic adipocytes by histology, proinflammatory cytokines levels in blood by ELISA.
Results: Rats fed a HFD were characterized by a higher weight gain compared to CPF and control groups while not significant. We found a significant decrease of intestinal permeability in the group co-exposed to CPF and HFD (CPF-HFD) compared to controls, CPF and HFD groups. Blood metabolic markers (glucose, triglycerides, cholesterol, HDL) were found significantly increased in HFD and CPF-HFD groups but not LDL, compared to controls and CPF group. CPF-HFD rats were characterized by a colonic inflammation compared to the other groups, as shown by increased MPO activity levels, IL-1b mRNA expression in colon, IL-1b plasma levels and hypermastocytosis in the gut wall. Ileum and colon longitudinal muscle layers thickness were found enhanced in the CPF group while both muscular layers were thicker in the CPF/HFD group. Adipocytes size was enlarged in the HFD group but was not impacted by CPF alone compared to controls both in mesenteric and gonadic adipose tissues. The co-exposition CPF/HFD had a strong impact by reducing the adipocyte size compared to all other groups in both adipose tissues.
Conclusion: In our rodent model, we identified that early life exposure to CPF and an obesogenic diet later in life during growth and maturation of the organs had strong impacts on tissue homeostasis. In particular, the intestinal disorders observed in the animals simultaneously exposed to CPF and HFD or even each individual factor (intestinal epithelial integrity and inflammation, intestinal development and maturation), and the abnormalities of adipose tissue, may explain the alarming increase in inflammatory and metabolic pathologies in humans over the past several years.
Key words: Chlorpyrifos, high-fat diet, ileum, colon, adipose tissue, mast cells, inflammation