Sanna Lignell

Background: Arsenic is a widespread environmental contaminant with known toxic effects, but its impact on adolescent reproductive development, a critical window for endocrine regulation, remains insufficiently understood. Objectives: We studied associations between arsenic species levels and reproductive development markers in European teenagers, focusing on reproductive hormones, kisspeptin, and pubertal timing. Methods: Harmonized biomonitoring data from five European countries within the Human Biomonitoring for Europe (HBM4EU) initiative included 1,139 teenagers (12–18 years) with data on at least one arsenic species and one reproductive marker. Urinary arsenic species, arsenite [As(III)], arsenate [As(V)], monomethylarsonic acid [MMA], dimethylarsinic acid [DMA], arsenobetaine [AsB], total arsenic [TAS] and toxicologically relevant arsenic [TRA], were measured and normalised for specific gravity. Reproductive markers included serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), sex hormone-binding globulin (SHBG), and total testosterone (TT) in boys, kisspeptin in both sexes, and age at menarche in girls. Associations were estimated using linear regression, adjusting for confounders. Results: In boys, As(V) was positively associated with FSH (geometric mean ratio [GMR] for detectable versus non-detectable As(V): 1.24; 95% CI: 1.02, 1.51). SHBG increased with DMA, TAS, and TRA (GMRs per interquartile fold change [IQFc] in exposure: ~1.09–1.10). A suggestive positive association was observed between As(V) and TT. Kisspeptin levels were 70.0 pg/mL (95% CI: 6.4, 133.6) and 80 pg/mL (95% CI: 18.7, 141.3) higher per IQFc in AsB and TAS sum, respectively. In girls, higher DMA was associated with later menarche (+0.18 years per IQFc; 95% CI: 0.01, 0.36), with a similar trend for TRA, and a suggestive positive association between As(V) and kisspeptin. Conclusions: Arsenic exposure during adolescence was associated with altered hormone levels and later pubertal timing, suggesting endocrine effects at exposure levels relevant to European populations. Continued monitoring and mitigation of arsenic exposure during sensitive developmental periods are warranted.

Background: Sweden expanded its mandatory vitamin D fortification program in 2018 addressing high rates of insufficient vitamin D status and low intake. This study aimed to assess vitamin D status among young children post-expansion, evaluate its determinants, and identify main vitamin D sources and their climate impact. Methods: Dietary intake among 18-month-olds (18mo, n = 1074) and 4-year-olds (4yo, n = 746) were obtained from the Swedish national survey Riksmaten Young Children 2021-24 based on two non-consecutive 24-hour food records. Intake of vitamin D from drops (µg/d) was also recorded. Individual vitamin D intakes were adjusted using the Multiple Source Method to reflect habitual intake. Blood concentrations of 25-hydroxyvitamin D (25OHD) were provided for a subset (18mo, n = 281; 4yo, n = 270). Climate impact was expressed as greenhouse gas emissions (GHGEs) in carbon dioxide equivalents (CO₂ eq), using life cycle assessment data from the Research Institutes of Sweden. Associations between 25OHD and plausible determinants were analyzed with linear regression. Results: 16% of 18mo and 61% of 4yo had total vitamin D intakes (including diet and drops) below the average requirement, 7.5 µg/d. None were deficient (25OHD < 30 nmol/l), and 7% of 18mo and 4% of 4yo were insufficient (< 50 nmol/l). 25OHD was positively associated with dietary vitamin D intake and vitamin D from drops, and inversely associated with blood sampling during winter and parents’ birth country (≥ 1 parent born outside Nordics). Main vitamin D sources for 18mo were vitamin D drops and fortified foods: dairy, porridge and cereal drinks; and for 4yo, fortified dairy and fat spreads. Dairy was a large contributor to diet-related GHGEs (18mo: 10%, 4yo: 16%), whereas fortified fat spreads and plant-based dairy alternatives were effective sources of vitamin D, providing the highest vitamin D concentrations per kg CO₂ eq. Conclusions: A high proportion of young children in Sweden are vitamin D sufficient, with dietary vitamin D intake, vitamin D drops, and blood sampling season being major determinants. Fortified dairy is an important dietary source of vitamin D, but a shift to fortified plant-based alternatives would reduce diet-related climate impact and should be explored in future research.

Matrix effects (ME) during LC-ESI-MS analysis are a commonly acknowledged issue for a variety of matrices and analytes. Although sample preparation techniques are steadily evolving to reduce ME, the complexity and variability of the urine matrix remain a challenge, especially for multi-analyte methods. To investigate the extent of ME implications on method performance and quantification, we used stable isotope-labelled standards (SIL-IS) of 11 mycotoxins to evaluate the magnitude and variability of ME in urine samples from two cohorts: Bangladeshi adult women (n = 50) and Swedish children of both sexes (n = 340). Significant ME differences were observed between the two cohorts for eight of the 11 mycotoxins. Additionally, intra-cohort ME variability turned out to be very high with interquartile ranges (IQR) above 15% for 14 out of 22 analyte-cohort combinations. Maximum IQR values were observed for sterigmatocystin in the Bangladeshi cohort (318%), strongly impacting quantitative results obtained with matrix(-matched) calibration. Further experiments on a small German cohort of four subjects, each providing four to five urine samples, revealed high variability of ME within each individual. Factors influencing ME were investigated, showing little to no impact of sex and a moderate impact of age for some analytes in the Swedish cohort. Nonetheless, especially the more polar analytes, showing stronger signal suppression, demonstrated clear correlation of ME with density and creatinine concentration of the urine samples. As a result, urine samples with very high or low density or creatinine values require careful handling in regard to sensitivity or quantification errors when matrix(-matched) calibration without SIL-IS is applied.

Background: Arsenic is a widespread environmental contaminant with known toxic effects, but its impact on adolescent reproductive development, a critical window for endocrine regulation, remains insufficiently understood.Objectives: We studied associations between arsenic species levels and reproductive development markers in European teenagers, focusing on reproductive hormones, kisspeptin, and pubertal timing.Methods: Harmonized biomonitoring data from five European countries within the Human Biomonitoring for Europe (HBM4EU) initiative included 1,139 teenagers (12–18 years) with data on at least one arsenic species and one reproductive marker. Urinary arsenic species, arsenite [As(III)], arsenate [As(V)], monomethylarsonic acid [MMA], dimethylarsinic acid [DMA], arsenobetaine [AsB], total arsenic [TAS] and toxicologically relevant arsenic [TRA], were measured and normalised for specific gravity. Reproductive markers included serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), sex hormone-binding globulin (SHBG), and total testosterone (TT) in boys, kisspeptin in both sexes, and age at menarche in girls. Associations were estimated using linear regression, adjusting for confounders.Results: In boys, As(V) was positively associated with FSH (geometric mean ratio [GMR] for detectable versus non-detectable As(V): 1.24; 95% CI: 1.02, 1.51). SHBG increased with DMA, TAS, and TRA (GMRs per interquartile fold change [IQFc] in exposure: ~1.09–1.10). A suggestive positive association was observed between As(V) and TT. Kisspeptin levels were 70.0 pg/mL (95% CI: 6.4, 133.6) and 80 pg/mL (95% CI: 18.7, 141.3) higher per IQFc in AsB and TAS sum, respectively. In girls, higher DMA was associated with later menarche (+0.18 years per IQFc; 95% CI: 0.01, 0.36), with a similar trend for TRA, and a suggestive positive association between As(V) and kisspeptin.Conclusions: Arsenic exposure during adolescence was associated with altered hormone levels and later pubertal timing, suggesting endocrine effects at exposure levels relevant to European populations. Continued monitoring and mitigation of arsenic exposure during sensitive developmental periods are warranted.

Early puberty has been found to be associated with adverse health outcomes such as metabolic and cardiovascular diseases and hormone-dependent cancers. The decrease in age at menarche observed during the past decades has been linked to an increased exposure to endocrine-disrupting compounds (EDCs). Evidence for the association between PFAS and phthalate exposure and menarche onset, however, is inconsistent. We studied the association between PFAS and phthalate/DINCH exposure and age at menarche using data of 514 teenagers (12 to 18 years) from four aligned studies of the Human Biomonitoring for Europe initiative (HBM4EU): Riksmaten Adolescents 2016–2017 (Sweden), PCB cohort (follow-up; Slovakia), GerES V-sub (Germany), and FLEHS IV (Belgium). PFAS concentrations were measured in blood, and phthalate/DINCH concentrations in urine. We assessed the role of each individual pollutant within the context of the others, by using different multi-pollutant approaches, adjusting for age, age- and sex-standardized body mass index z-score and household educational level. Exposure to di(2-ethylhexyl) phthalate (DEHP), especially mono(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), was associated with an earlier age at menarche, with estimates per interquartile fold change in 5OH-MEHP ranging from −0.34 to −0.12 years in the different models. Findings from this study indicated associations between age at menarche and some specific EDCs at concentrations detected in the general European population, but due to the study design (menarche onset preceded the chemical measurements), caution is needed in the interpretation of causality.