Biomarker Candidates of Habitual Food Intake in a Swedish Cohort of Pregnant and Lactating Women and Their Infants.

Circulating food metabolites could improve dietary assessments by complementing traditional methods. Here, biomarker candidates of food intake were identified in plasma samples from pregnancy (gestational week 29, N = 579), delivery (mothers, N = 532; infants, N = 348), and four months postpartum (mothers, N = 477; breastfed infants, N = 193) and associated to food intake assessed with semi-quantitative food frequency questionnaires. Families from the Swedish birth cohort Nutritional impact on Immunological maturation during Childhood in relation to the Environment (NICE) were included. Samples were analyzed using untargeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomics. Both exposure and outcome were standardized, and relationships were investigated using a linear regression analysis. The intake of fruits and berries and fruit juice were both positively related to proline betaine levels during pregnancy (fruits and berries, ß = 0.23, FDR < 0.001; fruit juice, ß = 0.27, FDR < 0.001), at delivery (fruit juice, infants: ß = 0.19, FDR = 0.028), and postpartum (fruits and berries, mothers: ß = 0.27, FDR < 0.001, infants: ß = 0.29, FDR < 0.001; fruit juice, mothers: ß = 0.37, FDR < 0.001). Lutein levels were positively related to vegetable intake during pregnancy (ß = 0.23, FDR < 0.001) and delivery (mothers: ß = 0.24, FDR < 0.001; newborns: ß = 0.18, FDR = 0.014) and CMPF with fatty fish intake postpartum (mothers: ß = 0.20, FDR < 0.001). No clear relationships were observed with the expected food sources of the remaining metabolites (acetylcarnitine, choline, indole-3-lactic acid, pipecolic acid). Our study suggests that plasma lutein could be useful as a more general food group intake biomarker for vegetables and fruits during pregnancy and delivery. Also, our results suggest the application of proline betaine as an intake biomarker of citrus fruit during gestation and lactation.

Short-chain fatty acids (SCFA) in infants' plasma and corresponding mother's milk and plasma in relation to subsequent sensitisation and atopic disease.

BACKGROUND: Short-chain fatty acids (SCFAs) in intestinal contents may influence immune function, while less is known about SCFAs in blood plasma. The aims were to investigate the relation between infants' and maternal plasma SCFAs, as well as SCFAs in mother's milk, and relate SCFA concentrations in infant plasma to subsequent sensitisation and atopic disease. METHODS: Infant plasma (N = 148) and corresponding mother's milk and plasma were collected four months postpartum. Nine SCFA (formic, acetic, propionic, isobutyric, butyric, succinic, valeric, isovaleric, and caproic acid) were analysed by UPLC-MS. At 12 months of age, atopic disease was diagnosed by a pediatric allergologist, and sensitisation was measured by skin prick test. All families participated in the Swedish birth cohort NICE (Nutritional impact on Immunological maturation during Childhood in relation to the Environment). FINDINGS: Infants with sensitisation, atopic eczema, or food allergy had significantly lower concentrations of five, three, and two SCFAs, respectively, in plasma at four months. Logistic regressions models showed significant negative associations between formic, succinic, and caproic acid and sensitisation [ORadj (95% CI) per SD: 0.41 (0.19-0.91); 0.19 (0.05-0.75); 0.25 (0.09-0.66)], and between acetic acid and atopic eczema [0.42 (0.18-0.95)], after adjusting for maternal allergy. Infants' and maternal plasma SCFA concentrations correlated strongly, while milk SCFA concentrations were unrelated to both. Butyric and caproic acid concentrations were enriched around 100-fold, and iso-butyric and valeric acid around 3-5-fold in mother's milk, while other SCFAs were less prevalent in milk than in plasma. INTERPRETATION: Butyric and caproic acid might be actively transported into breast milk to meet the needs of the infant, although mechanistic studies are needed to confirm this. The negative associations between certain SCFAs on sensitisation and atopic disease adds to prior evidence regarding their immunoregulatory potential. FUNDING: Swedish Research Council (Nr. 2013-3145, 2019-0137 and 2023-02217 to A-S.S.), Swedish Research Council for Health, Working Life and Welfare FORTE, Nr 2018-00485 to A.W.), The Swedish Asthma and Allergy Association's Research Fund (2020-0020 to A.S.).

Associations of the placental metabolome with immune maturation up to one year of age in the Swedish NICE-cohort.

INTRODUCTION: Allergies and other immune-mediated diseases are thought to result from incomplete maturation of the immune system early in life. We previously showed that infants' metabolites at birth were associated with immune cell subtypes during infancy. The placenta supplies the fetus with nutrients, but may also provide immune maturation signals. OBJECTIVES: To examine the relationship between metabolites in placental villous tissue and immune maturation during the first year of life and infant and maternal characteristics (gestational length, birth weight, sex, parity, maternal age, and BMI). METHODS: Untargeted metabolomics was measured using Liquid Chromatography-Mass Spectrometry. Subpopulations of T and B cells were measured using flow cytometry at birth, 48 h, one, four, and 12 months. Random forest analysis was used to link the metabolomics data with the T and B cell sub populations as well as infant and maternal characteristics. RESULTS: Modest associations (Q2 = 0.2-0.3) were found between the placental metabolome and kappa-deleting recombination excision circles (KREC) at birth and naïve B cells and memory T cells at 12 months. Weak associations were observed between the placental metabolome and sex and parity. Still, most metabolite features of interest were of low intensity compared to associations previously found in cord blood, suggesting that underlying metabolites were not of placental origin. CONCLUSION: Our results indicate that metabolomic measurements of the placenta may not effectively recognize metabolites important for immune maturation.

Toxic metals and essential trace elements in placenta and their relation to placental function.

INTRODUCTION: Placental function is essential for fetal development, but it may be susceptible to malnutrition and environmental stressors. OBJECTIVE: To assess the impact of toxic and essential trace elements in placenta on placental function. METHODS: Toxic metals (cadmium, lead, mercury, cobalt) and essential elements (copper, manganese, zinc, selenium) were measured in placenta of 406 pregnant women in northern Sweden using ICP-MS. Placental weight and birth weight were obtained from hospital records and fetoplacental weight ratio was used to estimate placental efficiency. Placental relative telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) were determined by quantitative PCR (n = 285). Single exposure-outcome associations were evaluated using linear or spline regression, and joint associations and interactions with Bayesian kernel machine regression (BKMR), all adjusted for sex, maternal smoking, and age or BMI. RESULTS: Median cadmium, mercury, lead, cobalt, copper, manganese, zinc, and selenium concentrations in placenta were 3.2, 1.8, 4.3, 2.3, 1058, 66, 10626, and 166 µg/kg, respectively. In the adjusted regression, selenium (>147 µg/kg) was inversely associated with placental weight (B: -158; 95 % CI: -246, -71, per doubling), as was lead at low selenium (B: -23.6; 95 % CI: -43.2, -4.0, per doubling). Manganese was positively associated with placental weight (B: 41; 95 % CI: 5.9, 77, per doubling) and inversely associated with placental efficiency (B: -0.01; 95 % CI: -0.019, -0.004, per doubling). Cobalt was inversely associated with mtDNAcn (B: -11; 95 % CI: -20, -0.018, per doubling), whereas all essential elements were positively associated with mtDNAcn, individually and joint. CONCLUSION: Among the toxic metals, lead appeared to negatively impact placental weight and cobalt decreased placental mtDNAcn. Joint essential element concentrations increased placental mtDNAcn. Manganese also appeared to increase placental weight, but not birth weight. The inverse association of selenium with placental weight may reflect increased transport of selenium to the fetus in late gestation.

Associations of gestational and early-life exposure to toxic metals and fluoride with a diagnosis of food allergy or atopic eczema at 1 year of age.

Studies have indicated that early-life exposure to toxic metals and fluoride affects the immune system, but evidence regarding their role in allergic disease development is scarce. We aimed to evaluate the relations of exposure to such compounds in 482 pregnant women and their infants (4 months of age) with food allergy and atopic eczema diagnosed by a paediatric allergologist at 1 year of age within the Swedish birth-cohort NICE (Nutritional impact on Immunological maturation during Childhood in relation to the Environment). Urinary cadmium and erythrocyte cadmium, lead, and mercury concentrations were measured by inductively coupled plasma mass spectrometry (ICP-MS), urinary inorganic arsenic metabolites by ICP-MS after separation by ion exchange chromatography, and urinary fluoride by an ion-selective electrode. The prevalence of food allergy and atopic eczema was 8 and 7%, respectively. Gestational urinary cadmium, reflecting chronic exposure, was associated with increased odds of infant food allergy (OR [95% CI]: 1.34 [1.09, 1.66] per IQR [0.08 µg/L]). Both gestational and infant urinary fluoride were associated, albeit at a statistically non-significant level, with increased atopic eczema odds (1.48 [0.98, 2.25], 1.36 [0.95, 1.95], per doubling, respectively). By contrast, gestational and infant erythrocyte lead was associated with decreased odds of atopic eczema (0.48 [0.26, 0.87] per IQR [6.6 µg/kg] and 0.38 [0.16, 0.91] per IQR [5.94 µg/kg], respectively), and infant lead with decreased odds of food allergy (0.39 [0.16, 0.93] per IQR [5.94 µg/kg]). Multivariable adjustment had marginal impact on the estimates above. After additional adjustment for fish intake biomarkers, the methylmercury associated atopic-eczema odds were considerably increased (1.29 [0.80, 2.06] per IQR [1.36 µg/kg]). In conclusion, our results indicate that gestational cadmium exposure might be associated with food allergy at 1 year of age and, possibly, early-life exposure to fluoride with atopic eczema. Further prospective and mechanistic studies are needed to establish causality.

Biomarkers of seafood intake during pregnancy - Pollutants versus fatty acids and micronutrients.

Intake of fish and seafood during pregnancy may have certain beneficial effects on fetal development, but measurement of intake using questionnaires is unreliable. Here, we assessed several candidate biomarkers of seafood intake, including long-chain omega 3 fatty acids (n-3 LCPUFA), selenium, iodine, methylmercury, and different arsenic compounds, in 549 pregnant women (gestational week 29) in the prospective birth cohort NICE (Nutritional impact on Immunological maturation during Childhood in relation to the Environment). Proportions of the fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) in erythrocytes were measured using gas chromatography with flame ionization detector. Selenium was measured in blood plasma and erythrocytes, mercury and arsenic in erythrocytes, and iodine and several arsenic compounds in urine, using inductively coupled plasma mass spectrometry, arsenic compounds after first being separated by ion exchange high-performance liquid chromatography (HPLC). Each biomarker was related to intake of total seafood and to intake of fatty and lean fish, and shellfish in third trimester, estimated from a semi-quantitative food frequency questionnaire filled out in gestational week 34. The pregnant women reported a median total seafood intake of 184 g/week (5th-95th percentiles: 34-465 g/week). This intake correlated most strongly with erythrocyte mercury concentrations (rho = 0.49, p < 0.001), consisting essentially of methylmercury, followed by total arsenic in erythrocytes (rho = 0.34, p < 0.001), and arsenobetaine in urine (rho = 0.33, p < 0.001), the main form of urinary arsenic. These biomarkers correlated well with intake of both fatty fish, lean fish, and shellfish. Erythrocyte DHA and plasma selenium correlated, although weakly, mainly with fatty fish (rho = 0.25 and 0.22, respectively, both p < 0.001). In conclusion, elevated concentrations of erythrocyte mercury and urinary arsenobetaine can be useful indicators of seafood intake, more so than the n-3 LCPUFAs. However, the relative importance of the biomarkers may differ depending on the type and amount of seafood consumed.

Frequent Occurrence of Perianal Disease and Granuloma Formation in Patients with Crohn's Disease and Coexistent Orofacial Granulomatosis.

BACKGROUND: Orofacial granulomatosis (OFG) is an inflammatory disorder of the perioral region and oral cavity. Crohn's disease (CD) in conjunction with OFG (CD-OFG), has been suggested to constitute a phenotype of CD with distinct features at diagnosis. AIMS: The aim of this project was to investigate whether the distinct phenotypic features of CD-OFG persist in the years following the initial diagnosis of CD. METHODS: Clinical data were extracted from medical records covering the first 5 years post-diagnosis for a cohort of patients with CD-OFG, and were compared to those of references with CD without OFG. RESULTS: The clinical characteristics of our cohort of patients with CD-OFG (N = 25) were evaluated in comparison to references with CD without OFG (ratio 1:2). Five years post-diagnosis, more patients with CD-OFG had a phenotype with perianal disease (cumulative incidence: 16/25, 64% vs 13/50, 26%, P = 0.002) and intestinal granulomas (cumulative incidence: 22/25, 88% vs 24/50, 48%, P = 0.0009) than patients in the CD reference group. The patients with CD-OFG were also more likely to have undergone perianal surgery (12/25, 48% vs 4/50, 8%, P = 0.0002). At the end of the observation period, more of the patients with CD-OFG were receiving combination therapy, i.e., immunomodulators and tumor necrosis factor antagonists, than those in the CD reference group (9/25, 36% vs 5/50, 10%, P = 0.01). CONCLUSION: The results support the notion that CD in conjunction with OFG represents a specific phenotype of CD that is characterized by frequent perianal disease, pronounced intestinal granuloma formation and a need for extensive therapy.

Staphylococcus aureus sequence type (ST) 45, ST30, and ST15 in the gut microbiota of healthy infants - persistence and population counts in relation to ST and virulence gene carriage.

Staphylococcus aureus colonizes the anterior nares, and also the gut, particularly in infants. S. aureus is divided into lineages, termed clonal complexes (CCs), which comprise closely related sequence types (STs). While CC30 and CC45 predominate among nasal commensals, their prevalence among gut-colonizing S. aureus is unknown. Here, 67 gut commensal S. aureus strains from 49 healthy Swedish infants (aged 3 days to 12 months) were subjected to multi-locus sequence typing. The STs of these strains were related to their virulence gene profiles, time of persistence in the microbiota, and fecal population counts. Three STs predominated: ST45 (22% of the strains); ST15 (21%); and ST30 (18%). In a logistic regression, ST45 strains showed higher fecal population counts than the others, independent of virulence gene carriage. The lower fecal counts of ST15 were linked to the carriage of fib genes (encoding fibrinogen-binding proteins), while those of ST30 were linked to fib and sea (enterotoxin A) carriage. While only 11% of the ST15 and ST30 strains were acquired after 2 months of age, this was true of 53% of the ST45 strains (p = 0.008), indicating that the former may be less fit for establishment in a more mature microbiota. None of the ST45 strains was transient (persisting < 3 weeks), and persistent ST45 strains colonized for significantly longer periods than persistent strains of other STs (mean, 34 vs 22 weeks, p = 0.04). Our results suggest that ST45 strains are well-adapted for commensal gut colonization in infants, reflecting yet-unidentified traits of these strains.

Association of maternal urinary fluoride concentrations during pregnancy with size at birth and the potential mediation effect by maternal thyroid hormones: The Swedish NICE birth cohort.

BACKGROUND: Observational studies have indicated that elevated maternal fluoride exposure during pregnancy may impair child neurodevelopment but a potential impact on birth outcomes is understudied. OBJECTIVES: To evaluate the impact of gestational fluoride exposure on birth outcomes (birth size and gestational age at birth) and to assess the potential mediating role of maternal thyroid hormones. METHODS: We studied 583 mother-child dyads in the NICE cohort in northern Sweden. Maternal fluoride exposure was assessed by measuring urinary concentrations at late pregnancy (median: 29th gestational week) using an ion selective electrode. Plasma levels of free and total thyroxine (fT4, tT4) and triiodothyronine (fT3, tT3), and thyroid stimulating hormone (TSH) were measured with electrochemiluminescence immunoassays. The infant's weight, length, head circumference, and gestational age at birth were extracted from hospital records. RESULTS: Median urinary fluoride concentration was 0.71 mg/L (5th-95th percentile 0.31-1.9 mg/L; specific gravity adjusted). In multivariable-adjusted regression models, every 1 mg/L increase of maternal urinary fluoride was associated with a mean increase in birth weight by 84 g (95%CI: 30, 138), length by 0.41 cm (95%CI: 0.18, 0.65), head circumference by 0.3 cm (95%CI: 0.1, 0.4), and with increased odds of being born large for gestational age (OR = 1.39, 95%CI: 1.03, 1.89). Every 1 mg/L increase of maternal urinary fluoride was also associated with a mean increase of the plasma fT3:fT4 ratio (B = 0.007, 95%CI: 0.000, 0.014), but not with the hormones or TSH. In mediation analyses, the maternal fT3:fT4 ratio did not explain the urinary fluoride-birth size relationships. DISCUSSION: Gestational urinary fluoride concentrations were associated with increased size at birth and even with increased odds of being born large for gestational age. The fluoride-related associations with increased size at birth were not explained by changes in maternal thyroid hormone levels.

Assessment of Joint Impact of Iodine, Selenium, and Zinc Status on Women's Third-Trimester Plasma Thyroid Hormone Concentrations.

BACKGROUND: Iodine is essential for synthesizing thyroid hormones, but other micronutrients are also required for optimal thyroid function. However, there is a lack of data on combined micronutrient status in relation to thyroid hormones in pregnancy. OBJECTIVES: We aimed to assess the joint associations of iodine, selenium, and zinc status with plasma concentrations of thyroid hormones and thyroid-stimulating hormone (TSH) in pregnancy. METHODS: We included 531 pregnant women (aged 22-40 y) participating in a Swedish birth cohort who provided blood and spot urine samples in gestational weeks 27-33 (mean: 29). Associations of urinary iodine concentration (UIC), plasma selenium concentration, and plasma zinc concentration (measured by inductively coupled plasma mass spectrometry) with plasma hormone concentrations [total and free thyroxine (tT4, fT4), total and free triiodothyronine (tT3, fT3), and TSH] were explored with Bayesian kernel machine regression (BKMR; n = 516; outliers excluded) and multivariable-adjusted linear regression (n = 531; splined for nonlinear associations). RESULTS: Median (IQR) micronutrient concentrations were 112 µg/L (80-156 µg/L) for UIC, 67 µg/L (58-76 µg/L) for plasma selenium, and 973 µg/L (842-1127 µg/L) for plasma zinc; the former 2 median values were below recommended concentrations (150 µg/L and 70 µg/L, respectively). Mean ± SD TSH concentration was 1.7 ± 0.87 mIU/L, with 98% < 4 mIU/L. BKMR showed a positive trend of joint micronutrient concentrations in relation to TSH. Plasma zinc was most influential for all hormones but tT3, for which plasma selenium was most influential. In adjusted linear regression models, zinc was positively associated with tT4, tT3, and TSH, and <1200 µg/L also with fT4 and fT3. Selenium was inversely associated with fT3, and <85 µg/L with tT3. CONCLUSIONS: Pregnant women's plasma TSH concentrations in the early third trimester increased with increasing joint status of iodine, selenium, and zinc. Zinc and selenium were more influential than iodine for the hormone concentrations. Multiple micronutrients need consideration in future studies of thyroid hormone status.

Differences between Arterial and Venous Umbilical Cord Plasma Metabolome and Association with Parity.

Umbilical cord blood is frequently used in health monitoring of the neonate. Results may be affected by the proportion of arterial and venous cord blood, the venous blood coming from the mother to supply oxygen and nutrients to the infant, and the arterial carrying waste products from the fetus. Here, we sampled arterial and venous umbilical cords separately from 48 newly delivered infants and examined plasma metabolomes using GC-MS/MS metabolomics. We investigated differences in metabolomes between arterial and venous blood and their associations with gestational length, birth weight, sex, and whether the baby was the first born or not, as well as maternal age and BMI. Using multilevel random forest analysis, a classification rate of 79% was achieved for arteriovenous differences (p = 0.004). Several monosaccharides had higher concentrations in the arterial cord plasma while amino acids were higher in venous plasma, suggesting that the main differences in the measured arterial and venous plasma metabolomes are related to amino acid and energy metabolism. Venous cord plasma metabolites related to energy metabolism were positively associated with parity (77% classification rate, p = 0.004) while arterial cord plasma metabolites were not. This underlines the importance of defining cord blood type for metabolomic studies.

Maternal characteristics and pregnancy outcomes in the NICE birth cohort: an assessment of self-selection bias.

BACKGROUND: Prospective birth cohorts are essential for identifying associations between exposures and outcomes. However, voluntary participation introduces a potential bias due to self selection since the persons that chose to participate may differ in background characteristics and behaviors. OBJECTIVES: To investigate potential bias due to self-selection in the Nutritional impact on Immunological maturation during Childhood in relation to the Environment (NICE) birth cohort in northern Sweden. METHODS: Women in the NICE birth cohort (N = 621) were compared to nonparticipating pregnant women in Norrbotten County in northern Sweden who were eligible for participation (N = 4976) regarding maternal characteristics and lifestyle. Maternal characteristics and pregnancy outcomes were compared between the groups and associations between exposures (smoking, folic acid, BMI, parity, education) and pregnancy outcomes (birth weight and gestational age) were analyzed by linear regression analyses, examining any interaction with the group. RESULTS: NICE participants were more highly educated, older and more likely to cohabit than the non-participants. They more often took folic acid and multivitamin supplements and less often smoked during early pregnancy. Pregnancy outcomes (mode of delivery, gestational age at delivery, birth weight and APGAR score) did, however, not differ significantly between participants and non-participants. Smoking, BMI, education and parity affected gestational age and birth weight, but the associations were of similar magnitude in participants and non-participants, with no significant effect on the group. CONCLUSION: Self-selection to the NICE study was evident in some factors related to lifestyle and socioeconomic characteristics but did not appear to skew pregnancy outcomes or alter well-known effects of certain lifestyle parameters on pregnancy outcomes.

Low Concentration of Fecal Valeric Acid at 1 Year of Age Is Linked with Eczema and Food Allergy at 13 Years of Age: Findings from a Swedish Birth Cohort.

BACKGROUND: Short-chain fatty acids (SCFAs) are abundant bacterial metabolites in the gut, with immunomodulatory properties. Hence, they may influence allergy development. Previous studies have linked fecal SCFA pattern during infancy with allergy. However, the association of SCFAs to allergic outcomes in adolescence is not well established. Here, we examined how the fecal SCFA pattern at 1 year of age related to allergy at 13 years of age. METHODS: Levels of 8 SCFAs in fecal samples collected at 1 year of age from 110 children were quantified using gas chromatography. The same individuals were evaluated at 13 years of age for allergic symptoms, allergy diagnosis and allergy medication by questionnaire, and for sensitization using skin prick test against egg, milk, fish, wheat and soy, cat, dog, horse, birch, and timothy grass. RESULTS: The concentration of fecal valeric acid at 1 year of age was inversely associated with eczema at 13 years of age (OR 0.6, 95% CI: 0.4-1.0, p = 0.049) and showed a trend for inverse association with food allergy at 13 years of age (OR 0.6, 95% CI: 0.4-1.0, p = 0.057). In a sub-group analysis of children with eczema at 1 year of age, a higher concentration of fecal valeric acid was linked with reduced risk of their eczema remaining at 13 years of age (OR 0.2, 95% CI: 0.0-1.5), although this latter analysis did not reach statistical significance (p = 0.12). CONCLUSIONS: Our findings lend further support to the notion of early childhood as a critical period when allergy may be programmed via the gut microbiota. Higher levels of fecal valeric acid may be characteristic of a protective gut microbiota and/or actively contribute to protection from eczema and food allergy.

Proportions of Polyunsaturated Fatty Acids in Umbilical Cord Blood at Birth Are Related to Atopic Eczema Development in the First Year of Life.

Atopic eczema, the most common atopic disease in infants, may pave the way for sensitization and allergy later in childhood. Fatty acids have immune-regulating properties and may regulate skin permeability. Here we examine whether the proportions of fatty acids among the infant and maternal plasma phospholipids at birth were associated with maternal dietary intake during pregnancy and development of atopic eczema during the first year of age in the Nutritional impact on Immunological maturation during Childhood in relation to the Environment (NICE) birth cohort. Dietary data were collected with a semi-quantitative food frequency questionnaire, fatty acids were measured with GC-MS and atopic eczema was diagnosed by a pediatric allergologist at 12 months of age. We found that higher proportions of n-6 PUFAs (including arachidonic acid) but lower proportions of n-3 PUFAs (including DPA) in the infant's phospholipids at birth were associated with an increased risk of atopic eczema at 12 months of age. The n-6 and n-3 PUFAs were related to maternal intake of meat and fish, respectively. Our results suggest that prenatal exposure to unsaturated fatty acids is associated with eczema development in the infant. Maternal diet during pregnancy may partly explain the fatty acid profiles in utero.

Thyroid hormones in relation to toxic metal exposure in pregnancy, and potential interactions with iodine and selenium.

BACKGROUND: Several endocrine-disrupting metals may affect thyroid function, but the few available studies of exposure during pregnancy and thyroid hormones are inconclusive. OBJECTIVE: To explore if environmental exposure to cadmium (Cd), lead (Pb), and methylmercury (MeHg) impacts thyroid function in pregnancy, and interacts with iodine and selenium status. METHODS: Women in a Swedish birth cohort provided blood and urine samples in early third trimester. Concentrations of erythrocyte Cd, Pb, and Hg (n = 544), urinary Cd and iodine (n = 542) and plasma selenium (n = 548) were measured using inductively coupled plasma-mass spectrometry.Free and total thyroxine (fT4, tT4) and triiodothyronine (fT3, tT3), and thyroid stimulating hormone (TSH), were measured in plasma (n = 548) with electrochemiluminescence immunoassays. Metal-hormone associations were assessed in regression models, and metal mixture effects and metal-nutrient interactions were explored in Bayesian kernel machine regression (BKMR). RESULTS: In multivariable-adjusted regression models, a doubling of urinary Cd was associated with a mean increase in tT4 of 2.7 nmol/L (95% CI: 0.78, 4.6), and in fT3 and tT3 of 0.06 pmol/L (0.02, 0.10) and 0.09 nmol/L (0.05, 0.13), respectively. A doubling of urinary Cd was associated with a -0.002 (-0.003, -0.001) and -0.03 (-0.05, -0.02) decrease in the fT4:tT4 and fT3:tT3 ratio, respectively. A doubling of erythrocyte Hg (>1 µg/kg) was associated with a decrease in fT3 and tT3 by -0.11 pmol/L (-0.16, -0.05) and -0.11 nmol/L (-0.16, -0.06), respectively, and a -0.013 (-0.02, -0.01) decrease in the fT3:fT4 ratio. BKMR did not indicate any mixture effect of toxic metals or interactions between metals and iodine or selenium in relation to the hormones. CONCLUSION: Our findings suggest that exposure to Cd and Hg, at levels globally prevalent through the diet, may affect thyroid function during pregnancy, independently of iodine and selenium levels. Further studies on potential implications for maternal and child health are warranted.

Associations of maternal and infant metabolomes with immune maturation and allergy development at 12 months in the Swedish NICE-cohort.

Allergic diseases are the most common chronic diseases in childrenin the Western world, but little is know about what factors influence immune maturation and allergy development. We therefore aimed to associate infant and maternal metabolomes to T- and B-cell subpopulations and allergy diagnosis. We performed liquid chromatography-mass spectrometry based untargeted metabolomics on blood plasma from mothers (third trimester, n = 605; delivery, n = 558) and from the umbilical cord (n = 366). The measured metabolomes were associated to T- and B-cell subpopulations up to 4 months after delivery and to doctor´s diagnosed eczema, food allergy and asthma at one year of age using random forest analysis. Maternal and cord plasma at delivery could predict the number of CD24+CD38low memory B-cells (p = 0.033, n = 26 and p = 0.009, n = 22), but future allergy status could not be distinguished from any of the three measured metabolomes. Replication of previous literature findings showed hypoxanthine to be upregulated in the umbilical cord of children with subsequent asthma. This exploratory study suggests foetal immune programming occuring during pregnancy as the metabolomic profiles of mothers and infants at delivery related to infants' B-cell maturation.

Bacterial Carriage of Genes Encoding Fibronectin-Binding Proteins Is Associated with Long-Term Persistence of Staphylococcus aureus in the Nasal and Gut Microbiota of Infants.

Staphylococcus aureus can colonize both the anterior nares and the gastrointestinal tract. However, colonization at these sites in the same individuals has not been studied, and the traits that facilitate colonization and persistence at these sites have not been compared. Samples from the nostrils and feces collected on 9 occasions from 3 days to 3 years of age in 65 infants were cultured; 54 samples yielded S. aureus. The numbers of nasal and fecal S. aureus strains increased rapidly during the first weeks and were similar at 1 month of age (>40% of infants colonized). Thereafter, nasal carriage declined, while fecal carriage remained high during the first year of life. Individual strains were identified, and their colonization patterns were related to their carriage of genes encoding adhesins and superantigenic toxins. Strains retrieved from both the nose and gut (n = 44) of an infant were 4.5 times more likely to colonize long term (≥3 weeks at both sites) than strains found only in the rectum/feces (n = 56) or only in the nose (n = 32) (P ≤ 0.001). Gut colonization was significantly associated with carriage of the fnbA gene, and long-term colonization at either site was associated with carriage of fnbA and fnbB. In summary, gut colonization by S. aureus was more common than nasal carriage by S. aureus in the studied infants. Gut strains may provide a reservoir for invasive disease in vulnerable individuals. Fibronectin-binding adhesins and other virulence factors may facilitate commensal colonization and confer pathogenic potential. IMPORTANCE S. aureus may cause severe infections and frequently colonizes the nose. Nasal carriage of S. aureus increases 3-fold the risk of invasive S. aureus infection. S. aureus is also commonly found in the gut microbiota of infants and young children. However, the relationships between the adhesins and other virulence factors of S. aureus strains and its abilities to colonize the nostrils and gut of infants are not well understood. Our study explores the simultaneous colonization by S. aureus of the nasal and intestinal tracts of newborn infants through 3 years of follow-up. We identify bacterial virulence traits that appear to facilitate persistent colonization of the nose and gut by S. aureus. This expands our current knowledge of the interplay between bacterial commensalism and pathogenicity. Moreover, it may contribute to the development of targeted strategies for combating S. aureus infection.

Circulating proteins associated with allergy development in infants-an exploratory analysis.

BACKGROUND: Protein profiles that can predict allergy development in children are lacking and the ideal sampling age is unknown. By applying an exploratory proteomics approach in the prospective FARMFLORA birth cohort, we sought to identify previously unknown circulating proteins in early life that associate to protection or risk for development of allergy up to 8 years of age. METHODS: We analyzed plasma prepared from umbilical cord blood (n = 38) and blood collected at 1 month (n = 42), 4 months (n = 39), 18 months (n = 42), 36 months (n = 42) and 8 years (n = 44) of age. We profiled 230 proteins with a multiplexed assay and evaluated the global structure of the data with principal component analysis (PCA). Protein profiles informative to allergic disease at 18 months, 36 months and/or 8 years were evaluated using Lasso logistic regression and random forest. RESULTS: Two clusters emerged in the PCA analysis that separated samples obtained at birth and at 1 month of age from samples obtained later. Differences between the clusters were mostly driven by abundant plasma proteins. For the prediction of allergy, both Lasso logistic regression and random forest were most informative with samples collected at 1 month of age. A Lasso model with 27 proteins together with farm environment differentiated children who remained healthy from those developing allergy. This protein panel was primarily composed of antigen-presenting MHC class I molecules, interleukins and chemokines. CONCLUSION: Sampled at one month of age, circulating proteins that reflect processes of the immune system may predict the development of allergic disease later in childhood.

Umbilical cord blood metabolome differs in relation to delivery mode, birth order and sex, maternal diet and possibly future allergy development in rural children.

Allergy is one of the most common diseases among young children yet all factors that affect development of allergy remain unclear. In a small cohort of 65 children living in the same rural area of south-west Sweden, we have previously found that maternal factors, including prenatal diet, affect childhood allergy risk, suggesting that in utero conditions may be important for allergy development. Here, we studied if metabolites in the umbilical cord blood of newborns may be related to development of childhood allergy, accounting for key perinatal factors such as mode of delivery, birth order and sex. Available umbilical cord blood plasma samples from 44 of the participants were analysed using gas chromatography-mass spectrometry metabolomics; allergy was diagnosed by specialised paediatricians at ages 18 months, 3 years and 8 years and included eczema, asthma, food allergy and allergic rhinoconjunctivitis. Nineteen cord blood metabolites were related to future allergy diagnosis though there was no clear pattern of up- or downregulation of metabolic pathways. In contrast, perinatal factors birth order, sex and mode of delivery affected several energy and biosynthetic pathways, including glutamate and aspartic acid-histidine metabolism (p = 0.004) and the tricarboxylic acid cycle (p = 0.006) for birth order; branched chain amino acid metabolism (p = 0.0009) and vitamin B6 metabolism (p = 0.01) for sex; and glyoxylate and dicarboxylic acid metabolism (p = 0.005) for mode of delivery. Maternal diet was also related to some of the metabolites associated with allergy. In conclusion, the cord blood metabolome includes individual metabolites that reflect lifestyle, microbial and other factors that may be associated with future allergy diagnosis, and also reflects temporally close events/factors. Larger studies are required to confirm these associations, and perinatal factors such as birth order or siblings must be considered in future cord-blood metabolome studies.

Infant Iodine and Selenium Status in Relation to Maternal Status and Diet During Pregnancy and Lactation.

Iodine and selenium are essential trace elements. Recent studies indicate that pregnant and lactating women often have insufficient intake of iodine and selenium, but the impact on fetal and infant status is unclear. Here, we assessed iodine and selenium status of infants in relation to maternal intake and status of these trace elements in the birth cohort NICE, conducted in northern Sweden (n = 604). Iodine was measured in urine (UIC) in gestational week 29, and in breast milk and infant urine 4 months postpartum, while selenium was measured in maternal plasma and erythrocytes in gestational week 29, and in breast milk and infant erythrocytes 4 months postpartum, in both cases using ICP-MS. Maternal intake was assessed with semi-quantitative food frequency questionnaires in gestational week 34 and at 4 months postpartum. The median intake of iodine and selenium during pregnancy (98 and 40 µg/d, respectively) and lactation (108 and 39 µg/d, respectively) was below recommended intakes, reflected in insufficient status (median UIC of 113 µg/L, median plasma selenium of 65 µg/L). Also, breast milk concentrations (median iodine 77 µg/L, median selenium 9 µg/L) were unlikely to meet infant requirements. Median UIC of the infants was 114 µg/L and median erythrocyte selenium 96 µg/kg, both similar to the maternal concentrations. Infant UIC correlated strongly with breast milk levels (rho = 0.64, p < 0.001). Their erythrocyte selenium correlated with maternal erythrocyte selenium in pregnancy (rho = 0.38, p < 0.001), but not with breast milk selenium, suggesting formation of prenatal reserves. Our results indicate that the transport of iodine and selenium to the fetus and infant is prioritized. Still, it is uncertain whether most infants had sufficient intakes. Further, the results might indicate an involvement of iodine in asthma development during the first year of life, which is essential to follow up. The low maternal and infant dietary intake of both iodine and selenium, especially when the mothers did not use supplements or iodized table salt, suggest a need for a general screening of women and young children.