Maternal exposure to pesticides induces perturbations in the gut microbiota and blood-brain barrier of dams and the progeny, prevented by a prebiotic.

Exposure to pesticide residues during the first 1000 days of life can disrupt body homeostasis and contribute to chronic metabolic diseases. Perinatal chlorpyrifos (CPF) exposure alters gut microbiota (GM) balance, potentially affecting offspring's health. Given the GM influence on brain function, the primary aim is to determine if pesticide-induced dysbiosis (microbial imbalance) affects indirectly other organs, such as the blood-brain barrier (BBB). The secondary objective is to evaluate the prebiotics protective effects, particularly inulin in promoting microbial balance (symbiosis), in both mothers and offspring. A total of 15 or more female rats were divided in 4 groups: control, oral CPF-exposed (1 mg/kg/day), exposed to inulin (10 g/L), and co-exposed to CPF and inulin from pre-gestation until weaning of pups. Samples from intestines, spleen, liver, and brain microvessels underwent microbiological and biomolecular analyses. Bacterial culture assessed GM composition of living bacteria and their translocation to non-intestinal organs. RT qPCR and Western blotting detected gene expression and protein levels of tight junction markers in brain microvessels. CPF exposure caused gut dysbiosis in offspring, with decreased Lactobacillus and Bifidobacterium and increased Escherichia coli (p < 0.01) leading to bacterial translocation to the spleen and liver. CPF also decreased tight junction's gene expression levels (50 to 60% decrease of CLDN3, p < 0.05). In contrast, inulin partially mitigated these adverse effects and restored gene expression to control levels. Our findings demonstrate a causal link between GM alterations and BBB integrity disruptions. The protective effects of inulin suggest potential therapeutic strategies to counteract pesticide-induced dysbiosis.

Impact of Perinatal Coexposure to Chlorpyrifos and a High-Fat Diet on Kisspeptin and GnRHR Presence and Reproductive Organs.

Emerging evidence has indicated the involvement of extrahypothalamic Kisspeptin and GnRHR in reproductive function. In this study, we evaluate if maternal exposure to the pesticide chlorpyrifos (CPF) and/or a high-fat diet (HFD) has an impact on the expression of Kisspeptin and GnRHR in the reproductive organs of rats' offspring. A total of 16 pregnant rats are divided into four groups: a control group (n = 4), CPF group (4 rats exposed daily to 1/mg/kg/day), HFD group (4 rats randomly fed a 5.25 kcal/g HFD), and coexposed group (4 rats exposed to CPF and HDF). At postnatal development postnatal day (PND) 60, male and female offspring were sacrificed. The reproductive organs (ovary and testis) were removed, and histological and immunohistological analysis and in silico quantification (TissueGnostics software 6.0.1.102, TissueFAXS, HistoQuest) were applied to investigate the impact of different treatments on Kisspeptin and GnRHR expression in reproductive organs. The main outcomes of the study showed a significant decrease in rat offspring's body weight in the CPF group from PND30 and PND60 (p < 0.05 and p < 0.01, respectively). Histological analysis showed a significant increase in the atretic follicle and abnormal testis structure with germ cell desquamation in the CPF-exposed group. The immunodetection quantification of protein shows a significant decrease in GnRHR and Kisspeptin in the HFD and CPF exposed groups, respectively, in testis rat offspring. Perinatal exposure to CPF and HFD exposure affect the reproduction function of rat offspring.

Perigestational exposure of a combination of a high-fat diet and pesticide impacts the metabolic and microbiotic status of dams and pups; a preventive strategy based on prebiotics.

PURPOSE: Metabolic changes during the perinatal period are known to promote obesity and type-2 diabetes in adulthood via perturbation of the microbiota. The risk factors for metabolic disorders include a high-fat diet (HFD) and exposure to pesticide residues. The objective of the present study was to evaluate the effects of perigestational exposure to a HFD and chlorpyrifos (CPF) on glycemia, lipid profiles, and microbial populations in Wistar dams and their female offspring. We also tested a preventive strategy based on treatment with the prebiotic inulin. METHODS: From 4 months before gestation to the end of the lactation period, six groups of dams were exposed to either a standard diet, a HFD alone, CPF alone, a combination of a HFD and CPF, and/or inulin supplementation. All female offspring were fed a standard diet from weaning to adulthood. We measured the impacts of these exposures on glycemia, the lipid profile, and the microbiota (composition, metabolite production, and translocation into tissues). RESULTS: HFD exposure and CPF + HFD co-exposure induced dysmetabolism and an imbalance in the gut flora in both the dams and the female offspring. Inulin mitigated the impact of exposure to a HFD alone but not that of CPF + HFD co-exposure. CONCLUSION: Our results provide a better understanding of the complex interactions between environmental pollutants and diet in early life, including in the context of metabolic diseases.

Impact of COVID-19 Lockdown on Children's Health in North Africa.

OBJECTIVES: Lockdown measures have been adopted in many countries around the world to control the spread of COVID-19. These measures induced long confinement period that may have had an unintended negative impact on children's life behaviors and health. This study aimed to investigate the impact of behaviors related to COVID-19 confinement on body weight/BMI changes in children from Constantine, Algeria. METHODS: This was a cross-sectional survey based on children aged 5 to 12 years dwelling in any province of Constantine. Parents of children completed an online-distributed questionnaire at two time points (between April and May and anther time between 11th July and 10th august 2020). The questionnaire assessed sociodemographic information, anthropometric data, physical activity, dietary, eating habits, and other factors related to children's lifestyle before and during lockdown. Paired before and during lockdown comparison for each lifestyle multiple statistic tests were performed to assess associations among before and during lockdown data. RESULTS: 275 questionnaires were completed (59.7%). Mean self-reported weight and BMI significantly increased by 1.43 kg and 0.84 kg/meter 2, respectively. Among the examined variables, increased unhealthy food consumption, snacks, number of daily meals taken, low physical activity and increased sedentary behaviors were significantly correlated with higher body weight gain (P < 0.005). These behaviors may not only have a significant impact on the development of childhood obesity but also on the deterioration of the mental state of the children surveyed. CONCLUSION: Restrictive measures during the COVID-19 lockdown, and home confinement, school closure makes children more vulnerable to environmental risks. Results from this study highlight the risk associated with a shift in eating habits, increased dietary intake, decreased physical activity, increased sedentary behaviors, and their impact in exacerbating the gain in body weight and BMI.

Chronic Perigestational Exposure to Chlorpyrifos Induces Perturbations in Gut Bacteria and Glucose and Lipid Markers in Female Rats and Their Offspring.

An increasing burden of evidence is pointing toward pesticides as risk factors for chronic disorders such as obesity and type 2 diabetes, leading to metabolic syndrome. Our objective was to assess the impact of chlorpyrifos (CPF) on metabolic and bacteriologic markers. Female rats were exposed before and during gestation and during lactation to CPF (1 mg/kg/day). Outcomes such as weight, glucose and lipid profiles, as well as disturbances in selected gut bacterial levels, were measured in both the dams (at the end of the lactation period) and in their female offspring at early adulthood (60 days of age). The results show that the weight of CPF dams were lower compared to the other groups, accompanied by an imbalance in blood glucose and lipid markers, and selected gut bacteria. Intra-uterine growth retardation, as well as metabolic disturbances and perturbation of selected gut bacteria, were also observed in their offspring, indicating both a direct effect on the dams and an indirect effect of CPF on the female offspring. Co-treatment with inulin (a prebiotic) prevented some of the outcomes of the pesticide. Further investigations could help better understand if those perturbations mimic or potentiate nutritional risk factors for metabolic syndrome through high fat diet.

Effect of daily co-exposure to inulin and chlorpyrifos on selected microbiota endpoints in the SHIME® model.

The intestinal microbiota has a key role in human health via the interaction with the somatic and immune cells in the digestive tract environment. Food, through matrix effect, nutrient and non-nutrient molecules, is a key regulator of microbiota diversity. As a food contaminant, the pesticide chlorpyrifos (CPF) has an effect on the composition of the intestinal microbiota and induces perturbation of microbiota. Prebiotics (and notably inulin) are known for their ability to promote an equilibrium of the microbiota that favours saccharolytic bacteria. The SHIME® dynamic in vitro model of the human intestine was exposed to CPF and inulin concomitantly for 30 days, in order to assess variations in both the bacterial populations and their metabolites. Various analyses of the microbiota (notably temporal temperature gradient gel electrophoresis) revealed a protective effect of the prebiotic through inhibition of the enterobacterial (E. coli) population. Bifidobacteria were only temporarily inhibited at D15 and recovered at D30. Although other potentially beneficial populations (lactobacilli) were not greatly modified, their activity and that of the saccharolytic bacteria in general were highlighted by an increase in levels of short-chain fatty acids and more specifically butyrate. Given the known role of host-microbiota communication, CPF's impact on the body's homeostasis remains to be determined.

Programming of intestinal homeostasis in male rat offspring after maternal exposure to chlorpyrifos and/or to a high fat diet.

Alteration of programming of the intestinal wall maturation may be responsible for non-communicable chronic diseases in adulthood. It may originate from prenatal exposure of mothers to deleterious environmental factors such as pesticides or western diet. This work was undertaken to determine whether disturbances of the digestive tract function and of innate immunity of offspring at adulthood could be due to maternal exposure to a pesticide, chlorpyrifos (CPF) and a High Fat Diet (HFD) starting 4 months before gestation and lasting until weaning of offspring. Fifty-one male Wistar rats coming from 4 groups of dams exposed to CPF, HFD, both and control were followed from birth to 8 weeks of age. They were fed standard chow and received no treatment. The maternal pesticide exposure slows down fetal and postnatal weight gain without histological injuries of the gut mucosa. CPF or HFD both induced modifications of tight junctions and mucins genes expressions without inducing an increase in epithelial permeability or an inflammatory state. Co-exposure to both CPF and HFD did not exacerbate the effects observed with each factor separately. Despite the lack of direct contact except through breast milk until weaning, CPF or HFD maternal exposure have demonstrated preliminary gut barrier impacts on offspring.

Perinatal exposure to chlorpyrifos and/or a high-fat diet is associated with liver damage in male rat offspring.

Metabolic impairments in childhood are known to promote the development of type 2 diabetes and/or obesity in adulthood. These impairments may result from perinatal exposure to harmful environmental factors, such as pesticide residues or the consumption of a "western" diet. In the present study, we sought to determine whether an obesogenic profile, metabolic disorders and liver damage in offspring (observed during young adulthood) were related to maternal exposure to the pesticide chlorpyrifos (CPF) and/or a high-fat diet (HFD) starting 4 months before conception and ending at weaning. After the end of exposure, 51 male rat pups were left to develop under normal conditions and were studied in young adulthood. Despite the absence of direct exposure to harmful factors (other than through the dam's milk), maternal exposure to CPF or an HFD was associated with changes in the offspring's metabolic activity in the liver in the offspring. This indirect exposure to CPF was associated with a relative reduction in the expression of genes coding for enzymes involved in lipid or glucose metabolism but did induce histopathological changes in the offspring at adulthood. Maternal exposure to an HFD alone or to CPF alone gave similar results in offspring, changes in the same direction. Exposure of the mother to HFD did not exacerbate CPF effects. Co-exposure to both CPF and HFD did not increase the observed effects compared to each factor taken separately.

Chronic oral exposure to pesticides and their consequences on metabolic regulation: role of the microbiota.

Pesticides have long been used in agriculture and household treatments. Pesticide residues can be found in biological samples for both the agriculture workers through direct exposure but also to the general population by indirect exposure. There is also evidence of pesticide contamination in utero and trans-generational impacts. Whilst acute exposure to pesticides has long been associated with endocrine perturbations, chronic exposure with low doses also increases the prevalence of metabolic disorders such as obesity or type 2 diabetes. Dysmetabolism is a low-grade inflammation disorder and as such the microbiota plays a role in its etiology. It is therefore important to fully understand the role of microbiota on the genesis of subsequent health effects. The digestive tract and mostly microbiota are the first organs of contact after oral exposure. The objective of this review is thus to better understand mechanisms that link pesticide exposure, dysmetabolism and microbiota. One of the key outcomes on the microbiota is the reduced Bacteroidetes and increased Firmicutes phyla, reflecting both pesticide exposure and risk factors of dysmetabolism. Other bacterial genders and metabolic activities are also involved. As for most pathologies impacting microbiota (including inflammatory disorders), the role of prebiotics can be suggested as a prevention strategy and some preliminary evidence reinforces this axis.

Does the perigestational exposure to chlorpyrifos and/or high-fat diet affect respiratory parameters and diaphragmatic muscle contractility in young rats?

The perinatal period is characterized by developmental stages with high sensitivity to environmental factors. Among the risk factors, maternal High-Fat Diet (HFD) consumption and early-life pesticide exposure can induce metabolic disorders at adulthood. We established the effects of perigestational exposure to Chlorpyrifos (CPF) and/or HFD on respiratory parameters, sleep apnea and diaphragm contractility in adult rats. Four groups of female rats were exposed starting from 4 months before gestation till the end of lactation period to CPF (1 mg/kg/day vs. vehicle) with or without HFD. Sleep apnea and respiratory parameters were measured by whole-body plethysmography in male offspring at postnatal day 60. Then diaphragm strips were dissected for the measurement of contractility, acetylcholinesterase (AChE) activity, and gene expression. The perigestational exposure to CPF and/or HFD increased the sleep apnea index but decreased the respiratory frequency. The twitch tension and the fatigability index were also increased, associated with reduced AChE activity and elevated mRNA expression of AChE, ryanodine receptor, and myosin heavy chain isoforms. Therefore, the perigestational exposure to either CPF and/or HFD could program the risks for altered ventilatory parameters and diaphragm contractility in young adult offspring despite the lack of direct contact to CPF and/or HFD.