Leibniz Institute of Environmental Medicine

Plasticizers like di-(2-ethylhexyl) phthalate (DEHP) are commonly used in medical devices to enhance plastic flexibility. DEHP is classified as a CMR1b substance due to its adverse effects on reproduction and fertility, and it has been linked to neurodevelopmental disorders such as ADHD, autism spectrum disorder, and learning disabilities. While DEHP is scheduled for phase-out by 2030, data on the developmental neurotoxicity (DNT) of alternative plasticizers remain scarce. We evaluated the DNT potential of DEHP and three alternative plasticizers: di-(2-ethylhexyl) terephthalate (DEHT), di-(2-ethylhexyl) adipate (DEHA), and tris-(2-ethylhexyl) trimellitate (TOTM), aiming to identify safer substitutes, particularly for neonates in neonatal intensive care units (NICUs). The human Neurosphere Assay was used to assess plasticizer effects on seven key neurodevelopmental processes: neural progenitor cell (NPC) proliferation, migration of radial glia, neurons, and oligodendrocytes, neurite outgrowth, and differentiation of neurons and oligodendrocytes. Concentration-response analyses provided benchmark concentrations (BMCs) and lowest observed adverse effect concentrations (LOAECs). Gene expression profiling provided mechanistic insights, and toxicity was ranked using the most sensitive endpoint (MSE) and ToxPi Tool. DEHP and TOTM showed the highest DNT potential, with NPC proliferation as the MSE. DEHT impacted oligodendrocyte differentiation, while no BMC was determined for DEHA within the tested concentrations. Considering an exposure scenario in NICUs, the estimated neonatal DEHP plasma levels exceeded the LOAEC for NPC proliferation, raising concerns for DNT. Overall, DEHA emerged as the least hazardous alternative for neurodevelopment, highlighting the value of combined human-relevant in vitro phenomics and human biomonitoring for DNT hazard evaluation.

In 2013, the European Union Common Agricultural Policy introduced a set of compulsory greening measures in its subsidies scheme in order to achieve environmental goals. We analyse the impact of this reform, and particularly the definition of Ecological Focus Areas (EFA), on bird diversity in France. We match bird observations from the French Breeding Bird Survey (BBS) to parcel level information on agricultural land use and type of crops. We exploit the heterogeneous exposure of bird observation sites to the reform depending on their ex-ante extent of arable area in a continuous difference-in-differences approach. We find evidence of an increase in overall bird abundance after 2015 in sites with a higher ex-ante proportion of arable land, driven by a small number of generalist species, and no impact on species richness and phylogenetic diversity. A decomposition by diet type suggests that vertebrate eaters were positively impacted by the reform. By contrast, cropland species experienced the most dramatic decline after 2015 in sites with a higher share of arable area. Estimations of the dynamic effects of the reform suggest that the observed positive effects of the reform on bird abundance were limited to the first two years after its implementation. Based on observational data, our findings confirm previous concerns regarding the effectiveness of the 2013 reform in preserving biodiversity.

This cross-sectional study examined a Lifestyle Risk Factor Index (LSRI) in relation to adiposity measures including visceral adipose tissue (VAT) in the German National Cohort (NAKO). Based on self-reports at baseline among 30,920 of > 205,000 NAKO eligible participants with magnetic resonance imaging (MRI) scans, one point each for not smoking, adhering to ≥ 3/7 diet recommendations, consuming ≤ 1 (women)/≤ 2 (men) alcoholic drinks/day, and ≥ 150 min/week physical activity was assigned. VAT volume, obtained from whole-body MRI at 3T, was analyzed by deep learning-based image segmentation. General linear models estimated adjusted geometric mean adiposity measures by LSRI and stratified analyses by sex and BMI. Of 18,508 participants aged 48.2 ± 12.2 years, the respective proportions for 0/1, 2, 3, and 4 LSRI points were 7%, 24%, 51%, and 18%. Participants with LSRI scores of 4 versus 0/1 had lower adjusted geometric mean volumes of VAT (2.3; 95% CI 2.2, 2.3 vs. 3.0; 95% CI 2.9, 3.1 L). These differences were slightly attenuated after adding BMI. This association was weaker for individuals with obesity than normal/overweight. A combination of lifestyle factors appears to be associated with lower VAT volume, but an elevated BMI may have a greater influence on VAT accumulation than lifestyle behaviors alone.

<title>Abstract</title> Allergies have been linked to immune dysfunction, genetics, and environmental factors. However, environmental exposures are often highly correlated similar to genetic predictors making the cumulative assessment of exposures difficult. Here, we aim to investigate the relative contribution of genetic variants as well as different individual and environmental factors on the presence or absence of allergies in a cohort of elderly German women by using genetic risk scores (GRS) and exposomal risk scores. The weights of the risk scores were obtained through bootstrapped and cross-validated ridge regression. We used the novel cross leverage scores to select genetic variants for GRS. We characterized the relative contributions of the risk scores to presence of allergies such as atopic dermatitis, asthma, or allergic rhinitis using McFadden’s Pseudo R-squared. Overall, our model was able to explain 11.13% of the variance of being diagnosed with allergies. The GRS had the highest relative contribution at 3.80%, followed by the meteorological risk score with 1.13%. This method can easily be adapted to other diseases and can facilitate health risk assessments of exposomal factors. In addition, the results may aid policy-making, for example, by regulating specific sources of exposure. <bold>Word Count</bold> : 190

Abstract Environmental factors shape organismal health through complex interactions known as the exposome. However, the interactions between chemical and non-chemical exposome factors remain largely unclear. Here, a dopaminergic reporter strain of Caenorhabditis elegans and a field isolated rhabditid nematode were used in a behavioral arena to assess natural variation in locomotory behavior in response to silica nanoparticles as a chemical exposome factor, and ambient temperature conditions (15 °C, 20 °C, and 25 °C) as non-chemical factors. Our results reveal that in the C. elegans strain lower temperature (15 °C) mitigates silica-induced locomotion deficits, while higher temperature (25 °C) exacerbates neurotoxicity, suggesting a temperature-dependent response. Notably, the wild rhabditid isolate showed distinct behavioral responses compared to the laboratory strain, highlighting the importance of species-specific ecological backgrounds in toxicological studies. This study provides a conceptual basis for integrating environmental factors and natural diversity into exposome research: Phenotype exposome maps, as presented here, broaden the identification of ecotoxicological hazards of nanomaterials across species. Author summary Incorporating wild rhabditid species with unknown genotypes into neurotoxicology research broadens the traditional model-organism framework by extending beyond C. elegans to encompass a wider range of naturally occurring neuronal and behavioral variation. This phenotype-driven approach enables the detection of both conserved and species-specific responses to neurotoxicants, independent of prior genomic knowledge. Observed differences in locomotor behavior across nematode species may reflect underlying diversity in neural architecture or compensatory mechanisms, offering insights into the functional plasticity of nervous systems. By adopting a comparative perspective grounded in the ecological context, this strategy enhances the environmental relevance of neurotoxicity studies and promotes more inclusive ecological risk assessment through the use of field isolated nematodes in controlled laboratory settings. Synopsis Wild nematodes and C. elegans differ in pollutant responses, highlighting the need for broader toxicology models. Highlights We report comparative testing of Caenorhabditis elegans and a wild rhabditid isolate in a behavioral arena. C. elegans and the wild isolate were assessed under multiple exposome conditions: silica nanoparticles and ambient temperatures (15–25 °C). Field isolated rhabditid nematodes showed distinct behavioral responses to chemical and temperature exposures compared to C. elegans. This study highlights the importance of including wild nematode isolates alongside C. elegans for ecological hazard identification of emerging pollutants like silica nanoparticles. We culture wild nematode isolates under standardized laboratory conditions to probe the limits of C. elegans as a toxicology model and enhance its real-world relevance.

We aimed to assess the exposure to multiple environmental indicators and compare the spatial variation across participants of the German National Cohort (NAKO) to lay the foundation for health analyses. We collected highly resolved German-wide data to capture the following environmental drivers: urbanisation by population density; outdoor air pollution by particulate matter (PM2.5), nitrogen dioxide (NO2), ozone; road traffic noise; meteorology by air temperature, relative humidity; and the built environment by greenspace and land cover. All assessed exposures were assigned to the NAKO participants based on their baseline residential addresses. The NAKO study regions ranged from highly urbanised areas (Berlin, Hamburg) to rural regions (Neubrandenburg). This large variation is reflected in the individual environmental exposures at the place of residence. In 2019, annual PM2.5 and NO2 levels ranged from 6.0 to 14.6 and 3.7-33.6μg/m3, respectively. Annual mean air temperature ranged between 7.8 and 12.7°C. Noise data was available for a subset of urban residents (22 %), of which 42 % fell into the lowest and 1.8 % into the highest category of Lden 55-59 and Lden >75dB(A), respectively. Greenspace also showed considerable differences (Normalised Difference Vegetation Index between 0.08 and 0.84). Spearman correlation was moderate to high within the different exposure groups, but mostly low to moderate between the groups. For the first time, a comprehensive population-based dataset with high quality environmental indicators is available for the whole of Germany. Expanding the database by adding innovative indicators such as light pollution, walkability, biodiversity as well as contextual socioeconomic factors will further increase its usefulness for science and public health.

BackgroundUsing data from the largest German cohort study, we aimed to investigate sex differences in the relationship of socioeconomic position (SEP) with cardiovascular disease (CVD), CVD risk factors, and estimated CVD risk.Methods and ResultsA total of 204 780 (50.5% women) participants from the baseline examination of the population‐based NAKO (German National Cohort) were included. Logistic, multinomial, and linear regression models were used to estimate sex‐specific odds ratios (ORs) and β coefficients with 95% CIs of CVD, CVD risk factors, and very high‐risk score (Systemic Coronary Risk Estimation‐2) for CVD associated with SEP. Women‐to‐men ratios of ORs (RORs) with 95% CIs were estimated. In women compared with men, low versus high SEP (educational attainment and relative income) was more strongly associated with myocardial infarction, hypertension, obesity, overweight, elevated blood pressure, antihypertensive medication, and current alcohol consumption, but less strongly with current and former smoking. In women with the lowest versus highest educational level, the OR for a very high 10‐year CVD risk was 3.61 (95% CI, 2.88–4.53) compared with 1.72 (95% CI, 1.51–1.96) in men. The women‐to‐men ROR was 2.33 (95% CI, 1.78–3.05). For the comparison of low versus high relative income, the odds of having a very high 10‐year CVD risk was 2.55 (95% CI, 2.04–3.18) in women and 2.25 (95% CI, 2.08–2.42) in men (women‐to‐men ROR, 1.31 [95% CI, 1.05–1.63]).ConclusionsIn women and men, there was an inverse relationship between indicators of SEP and the likelihood of having several CVD risk factors and a very high 10‐year CVD risk. This association was stronger in women, suggesting that CVD risk is more strongly influenced by SEP in women compared with men.

Systemic sclerosis is a rare autoimmune and fibrotic disease, often manifesting in the skin. The aryl hydrocarbon receptor is critical for skin homeostasis; however, its role in fibrosis is not well understood. We investigated the crosstalk between TGFβ, AHR, and Wnt/β-catenin signaling. Human dermal fibroblasts and HaCaT keratinocytes, both wild-type and AHR-deficient, were cultured in mono- and co-cultures. Cells were treated with TGFβ and the AHR agonist FICZ. Collagen type I and MMP1 were quantified, Wnt/β-catenin genes analyzed, migration assessed, and proteome profiling performed. AHR deletion reduced Wnt/β-catenin gene expression and abrogated TGFβ-induced collagen production. Co-cultures showed AHR-dependent regulation of immune-related genes, and scratch closure was also AHR-dependent. The study demonstrates a context-dependent role of AHR in skin fibrosis and its interaction with TGFβ and Wnt/β-catenin signaling.