In this study we use aggregated weighted scores of environmental effects to study environmental influences on well-being and happiness. To this end, we split a sample of Netherlands Twin Register (NTR) participants into a training (N =4857) and test (N =2077) sample. In the training sample, we use elastic net regression to estimate effect sizes for associations between life satisfaction and two sets of environmental variables: one based on self- report socioenvironmental data, and one based on objective physical environmental data. Based on these effect sizes, we create two poly-environmental scores (PES-S and PES-O, for self-reports and objective data respectively). In the test sample, we perform association analyses between different measures of well-being and the two PESs. We find that the PES-S explains ~36% of the variance in well-being, while the PES-O does not significantly contribute to the model. Variance in other well-being measures (i.e., different life satisfaction domains, subjective happiness, quality of life, flourishing, psychological well-being, self-rated health, depressive problems, and loneliness) are explained to varying extents by the PESs, ranging from 6.36% (self-rated health) to 36.66% (loneliness). These predictive values did not change during the COVID-19 pandemic (N =3214). Validating the PES-S in the UK biobank (N =40,614), we find that the UK biobank PES-S explains about ~12% of the variance in happiness. Lastly, we examine if there is any indication for gene-environment correlation (rGE), the phenomenon where one’s genetic predisposition influences exposure to the environment, by associating the PESs with polygenic scores (PGS) in a sample of Netherlands Twin Register (NTR) and UK Biobank participants. While the PES and PGS were not correlated in the NTR sample, they were correlated in the larger UK biobank sample, indicating the potential presence of rGE. We discuss several limitations pertaining to our dataset, such as a potential influence of common method bias, and reflect on how PESs might be used in future research.
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From PLoS website: In general, dietary antigens are tolerated by the gut associated immune system. Impairment of this so-called oral tolerance is a serious health risk. We have previously shown that activation of the ligand-dependent transcription factor aryl hydrocarbon receptor (AhR) by the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects both oral tolerance and food allergy. In this study, we determine whether a common plant-derived, dietary AhR-ligand modulates oral tolerance as well. We therefore fed mice with indole-3-carbinole (I3C), an AhR ligand that is abundant in cruciferous plants. We show that several I3C metabolites were detectable in the serum after feeding, including the high-affinity ligand 3,3´-diindolylmethane (DIM). I3C feeding robustly induced the AhR-target gene CYP4501A1 in the intestine; I3C feeding also induced the aldh1 gene, whose product catalyzes the formation of retinoic acid (RA), an inducer of regulatory T cells. We then measured parameters indicating oral tolerance and severity of peanut-induced food allergy. In contrast to the tolerance-breaking effect of TCDD, feeding mice with chow containing 2 g/kg I3C lowered the serum anti-ovalbumin IgG1 response in an experimental oral tolerance protocol. Moreover, I3C feeding attenuated symptoms of peanut allergy. In conclusion, the dietary compound I3C can positively influence a vital immune function of the gut.
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Glucocorticoids (GCs) such as prednisolone are potent immunosuppressive drugs but suffer from severe adverse effects, including the induction of insulin resistance. Therefore, development of so-called Selective Glucocorticoid Receptor Modulators (SGRM) is highly desirable. Here we describe a non-steroidal Glucocorticoid Receptor (GR)-selective compound (Org 214007-0) with a binding affinity to GR similar to that of prednisolone. Structural modelling of the GR-Org 214007-0 binding site shows disturbance of the loop between helix 11 and helix 12 of GR, confirmed by partial recruitment of the TIF2-3 peptide. Using various cell lines and primary human cells, we show here that Org 214007-0 acts as a partial GC agonist, since it repressed inflammatory genes and was less effective in induction of metabolic genes. More importantly, in vivo studies in mice indicated that Org 214007-0 retained full efficacy in acute inflammation models as well as in a chronic collagen-induced arthritis (CIA) model. Gene expression profiling of muscle tissue derived from arthritic mice showed a partial activity of Org 214007-0 at an equi-efficacious dosage of prednisolone, with an increased ratio in repression versus induction of genes. Finally, in mice Org 214007-0 did not induce elevated fasting glucose nor the shift in glucose/glycogen balance in the liver seen with an equi-efficacious dose of prednisolone. All together, our data demonstrate that Org 214007-0 is a novel SGRMs with an improved therapeutic index compared to prednisolone. This class of SGRMs can contribute to effective anti-inflammatory therapy with a lower risk for metabolic side effects.
