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The relationship between pesticide exposures and metabolomics biomarkers is not well understood. We examined the changes in the serum metabolome (early biomarkers) and the metabolic pathways associated with various pesticide exposure scenarios (OPE: overall exposure, PEM: exposure in months, PEY: exposure in years, and PEU: reported specific pesticides use) using data from the Northern Finland Birth Cohort 1966 31-year cross-sectional examination. We utilized questionnaire data on pesticide exposures and serum samples for nuclear magnetic resonance (NMR)-based metabolomics analyses. For exposures and metabolites associations, participants size varied between 2,361 and 5,035. To investigate associations between metabolomics biomarkers and exposure to pesticide scenarios compared to those who reported no exposures multivariable regression analyses stratified by sex and adjustment with covariates (season of pesticide use, socioeconomic position (SEP), alcohol consumption, BMI, and latitude of residence) were performed. Multiple testing by Benjamini-Hochberg false discovery rate (FDR) correction applied. Pesticide exposures differed by sex, season of pesticide use, alcohol, SEP, latitude of residence. Our results showed that all pesticide exposure scenarios were negatively associated with decreased HDL concentrations across all lipoprotein subclasses in women. OPE, PEY, and PEU were associated with decreased branched-chain amino acid concentrations in men and decreased albumin concentrations in women. OPE, PEY and PEU were also associated with changes in glycolysis metabolites and ketone bodies in both sexes. Specific pesticides exposure was negatively associated with sphingolipids and inflammatory biomarkers in men. In women, OPE, PEM, and PEU were associated with decreased apolipoprotein A1 and increased apolipoprotein B/apolipoprotein A1 ratio. Our findings suggest that identification of early biomarkers of disease risk related to pesticide exposures can inform strat

The ubiquitous presence of legacy and emerging persistent organic pollutants (POPs) in the environmental matrices poses a potential hazard to the humans and creating public health concerns. The present study aimed to evaluate dioxins, dioxin-like polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and chlorinated paraffins (CPs) concentrations in serum of women (postpartum, pregnant and non-pregnant) from Northern Norway to better understand their exposure and contamination status as well as temporal trends across 2007–2009 (MISA 1) to 2019 (MISA 2). Sixty-two blood samples from the MISA 1 cohort and 38 samples from MISA 2 were randomly selected in this study (n = 100). Ninety samples from postpartum (MISA 1) and pregnant women (MISA 2) were randomly combined into 9 pools, with 9–11 individual samples contributing to each pool keeping the groups of pregnant and postpartum women. Remaining 10 samples from non-pregnant women (MISA 2) were allocated into separate group. Geometric mean, minimum and maximum were used to describe the serum concentrations of pooled POPs in MISA cohort. Mann-Whitney U test and independent sample t-test were applied for trend analysis of blood levels of POPs between MISA 1 and MISA 2. We found the serum concentrations of selected POPs in this study to be at lower range. Serum concentrations of dibenzo-p-dioxins (PCDDs) (p = 0.010), polychlorinated dibenzofurans (PCDFs) (p = 0.002), dioxins-like PCBs (p = 0.001), hexachlorobenzene (HCB) (p < 0.001) and p,p’-dichlorodiphenyldichloroethylene (p,p’-DDE) (p = 0.002) were decreased between the studied time. In contrast, the serum concentrations of medium chain chlorinated paraffins showed an increasing trend between 2007 and 2009 and 2019 (p = 0.019). Our findings report a particular concern of emerging contaminant medium chain chlorinated paraffin exposure to humans. Future observational studies with repeated measurements of chlorinated paraffins in general populations worldwide an

Background Occupational exposure to pesticides has been reported among general population worldwide. However, little is known about the associations between non-occupational exposure to pesticides, and biological markers of health and their response by sex. Objectives We aimed to assess the associations between non-occupational overall pesticide exposure, length of exposure and specific pesticides reported with 35 biological markers of health representing cardiometabolic, haematological, lung function, sex hormones, liver and kidney function profiles, and vitamin D in Finnish cohort. Methods 31-year cross-sectional examination of the Northern Finland Birth Cohort 1966 provided blood samples for biomarker measurements in 1997–1998. Number of subjects varied between 2361 and 5037 for given exposures and certain outcome associations. Multivariable regression analyses were performed to examine associations between overall pesticide exposure (OPE), length of pesticide exposure in months (PEM), in years (PEY), and specific pesticides use (PEU) or not with cardiometabolic [SBP, DBP, TC, LDL, HDL, triglycerides, fasting glucose, insulin, HOMA-IR, HOMA-B, HOMA-S, hs-CRP], hematological [WBC, RBC, Hb, HCT, MCV, MCH, MCHC, platelets], lung function (FVC, FEV1), sex hormones [luteinizing hormone (LH), testosterone (TT), sex-hormone binding globulin (SHBG)], liver and kidney function profiles [total protein, albumin, globulin, ALP, ALT, GGT, urea, creatinine], and vitamin D adjusting for sex, BMI, socioeconomic position (SEP) and season of pesticide use. Results This cohort study on up to 5037 adults with non-occupational OPE, PEM, PEY and PEU differed by sex and SEP. In regression analyses, all the exposures were positively associated with total cholesterol and low-density lipoprotein cholesterol, and PEU was negatively associated with high-density lipoprotein cholesterol in females. OPE and PEM were positively associated with haematocrit in females and PEU with platelets in ma

Activation of pregnane X receptor (PXR) elevates circulating 4β-hydroxycholesterol (4βHC), an agonist of liver X receptor (LXR). PXR may also regulate 25-hydroxycholesterol and 27-hydroxycholesterol. Our aim was to elucidate the roles of PXR and oxysterols in the regulation of cholesterol transporters. We measured oxysterols in serum of volunteers dosed with PXR agonist rifampicin 600 mg/day versus placebo for a week and analyzed the expression of cholesterol transporters in mononuclear cells. The effect of 4βHC on the transport of cholesterol and the expression of cholesterol transporters was studied in human primary monocyte-derived macrophages and foam cells in vitro. The expression of cholesterol transporters was measured also in rat tissues after dosing with a PXR agonist. The levels of 4βHC were elevated, while 25-hydroxycholesterol and 27-hydroxycholesterol remained unchanged in volunteers dosed with rifampicin. The expression of ATP binding cassette transporter A1 (ABCA1) was induced in human mononuclear cells in vivo. The influx of cholesterol was repressed by 4βHC, as was the expression of influx transporter lectin-like oxidized LDL receptor-1 in vitro. The cholesterol efflux and the expression of efflux transporters ABCA1 and ABCG1 were induced. The expression of inducible degrader of the LDL receptor was induced. In rats, PXR agonist increased circulating 4βHC and expression of LXR targets in peripheral tissues, especially ABCA1 and ABCG1 in heart. In conclusion, PXR activation-elevated 4βHC is a signaling molecule that represses cholesterol influx and induces efflux. The PXR-4βHC-LXR pathway could link the hepatic xenobiotic exposure and the regulation of cholesterol transport in peripheral tissues., Funding Agencies:Academy of Finland 286743 276747Duodecim Society of Oulu Finnish Medical Foundation Finnish Foundation for Cardiovascular Research Northern Finland Health Care Support Foundation Diabetes Research Foundation