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.

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.

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.

Impacts of prolonged chlorpyrifos exposure on locomotion and slow-and fast- twitch skeletal muscles contractility in rats.

AIM: Investigate the effect of dietary exposure to chlorpyrifos on locomotion and contraction of soleus andextensor digitorum longus (edl) involved in locomotion. Methods: Rats were fed diets containing 1 or 5 mg kg-1 of chlorpyrifos for six weeks. Locomotion has been assessed weekly using beam walking and beam balance tests. Soleus and edl were removed to study contractile properties, myofibrillar protein content and myosin heavy chain isoforms. RESULTS: Animals treated with 5 mg kg-1 chlorpyrifos had a decrease body weight. An increase by 28% and 24% in latency time assessed by beam walking test and a decrease by 9% and 13% in the beam balance time was reported after 6 weeks of 1 and 5 chlorpyrifos exposure respectively. The contractile properties in soleus showed an increase in twitch amplitude by 25% and 63% in 1 and 5 doses respectively, without modification in the contraction time and half relaxation time. edl treated with 1 mg kg-1 showed a decrease by 35%, 42% and 22% in twitch amplitude, contraction time and half relaxation time respectively. edl treated with 5 mg kg-1 showed an increase of 23% in twitch amplitude without modification of the other parameters. These changes were associated with modification of myofibrillar protein content in all treated groups. Myosin heavy chain isoforms were altered in both skeletal muscles treated with 1 mg kg-1. CONCLUSION: Exposure to chlorpyrifos can alter the locomotion and produce physiological changes in a dose and muscle type related manner.

Impact of chronic exposure to the pesticide chlorpyrifos on respiratory parameters and sleep apnea in juvenile and adult rats.

The widely used organophosphorus pesticide chlorpyrifos (CPF) is often detected in food. CPF inhibits acetylcholinesterase and can modify muscle contractility and respiratory patterns. We studied the effects of chronic exposure to CPF on respiratory parameters and diaphragm contractility in 21- and 60-days old rats. Pregnant rats were exposed to oral CPF (1 or 5 mg/ kg /day: CPF-1 or CPF-5 groups vs vehicle: controls) from gestation onset up to weaning of the pups that were individually gavaged (CPF or vehicle) thereafter. Two developmental time points were studied: weaning (day 21) and adulthood (day 60). Whole-body plethysmography was used to score breathing patterns and apnea index during sleep. Then, diaphragm strips were dissected for the assessment of contractility and acetylcholinesterase activity. Results showed that the sleep apnea index was higher in CPF-exposed rats than in controls. In adult rats, the expiratory time and tidal volume were higher in CPF-exposed animals than in controls. At both ages, the diaphragm's amplitude of contraction and fatigability index were higher in the CPF-5 group, due to lower acetylcholinesterase activity. We conclude that chronic exposure to CPF is associated with higher sleep apnea index and diaphragm contractility, and modifies respiratory patterns in sleeping juvenile and adult rats.