Intestinal intraepithelial lymphocyte-enterocyte crosstalk regulates production of bactericidal angiogenin 4 by Paneth cells upon microbial challenge

Antimicrobial proteins influence intestinal microbial ecology and limit proliferation of pathogens, yet the regulation of their expression has only been partially elucidated. Here, we have identified a putative pathway involving epithelial cells and intestinal intraepithelial lymphocytes (iIELs) that leads to antimicrobial protein (AMP) production by Paneth cells. Mice lacking γδ iIELs (TCRδ(-/-)) express significantly reduced levels of the AMP angiogenin 4 (Ang4). These mice were also unable to up-regulate Ang4 production following oral challenge by Salmonella, leading to higher levels of mucosal invasion compared to their wild type counterparts during the first 2 hours post-challenge. The transfer of γδ iIELs from wild type (WT) mice to TCRδ(-/-) mice restored Ang4 production and Salmonella invasion levels were reduced to those obtained in WT mice. The ability to restore Ang4 production in TCRδ(-/-) mice was shown to be restricted to γδ iIELs expressing Vγ7-encoded TCRs. Using a novel intestinal crypt co-culture system we identified a putative pathway of Ang4 production initiated by exposure to Salmonella, intestinal commensals or microbial antigens that induced intestinal epithelial cells to produce cytokines including IL‑23 in a TLR-mediated manner. Exposure of TCR-Vγ7(+) γδ iIELs to IL-23 promoted IL‑22 production, which triggered Paneth cells to secrete Ang4. These findings identify a novel role for γδ iIELs in mucosal defence through sensing immediate epithelial cell cytokine responses and influencing AMP production. This in turn can contribute to the maintenance of intestinal microbial homeostasis and epithelial barrier function, and limit pathogen invasion

Prenatal exposure to perfluoroalkyl acids and allergic diseases in early childhood

Perfluoroalkyl acids (PFAAs) are persistent organic pollutants that are detected in humans worldwide. Laboratory animal studies have shown that PFAAs are associated with immunotoxic effects. However, epidemiological studies investigating the role of PFAAs, in particular PFAAs with longer chains than perfluorooctanoic acid, are scarce. We investigated associations between prenatal exposure to PFAAs, including long-chain compounds, and infant allergic diseases at 12 and 24 months in a large study population. The participants included mothers and their infants who enrolled in the Hokkaido Study on Environment and Children's Health 2003-2009. Eleven PFAAs were measured in maternal plasma taken at 28-32 weeks of gestation using ultra-performance liquid chromatography coupled to triple quadrupole tandem mass spectrometry. Characteristics of participants and information on infant allergic diseases were obtained from self-administered questionnaires and medical records. At 24 months, the adjusted odds ratio (OR) (first vs. fourth quartiles) for eczema in association with higher maternal perfluorotridecanoic acid (PFTrDA) levels was 0.62 (95% confidence interval (CI) 0.45, 0.86). After stratification by gender, the adjusted ORs in female infants from mothers with higher maternal perfluoroundecanoic acid (PFUnDA) and PFTrDA levels were also statistically significant (PFUnDA: OR = 0.50; 95% CI, 030, 0.81; PFTrDA: OR = 0.39; 95% CI, 0.23, 0.64). Our findings suggest that lower prenatal exposure to PFTrDA may decrease the risk of developing eczema in early childhood, only in female infants. 2014 Elsevier Ltd. All rights reserved

Effects of prenatal exposure to dioxin-like compounds on allergies and infections during infancy

Dioxin-like compounds are endocrine disruptors. The effects of prenatal exposure to environmental levels of dioxins on immune function during infancy have not been clarified, although dioxins induce immunosuppression in offspring of animals. Moreover, human studies have not assessed the effects of gender- or congener-specific differences. The purpose of this study was to investigate the association between dioxin levels in maternal blood and the risk of infection and allergies in infancy. We examined 364 mothers and their infants enrolled in a Hokkaido Study on Environment and Children's Health between 2002 and 2005 in Sapporo, Japan. Relevant information was collected from a baseline questionnaire during pregnancy, medical records at delivery, and a follow-up questionnaire when the child was 18 months of age that assessed development of allergies and infections in infancy. Dioxin-like compound levels in maternal blood were measured with high-resolution gas chromatography/high-resolution mass spectrometry. Relatively higher levels of polychlorinated dibenzofuran were associated with a significantly increased risk of otitis media, especially among male infants (odds ratio=2.5, 95% confidence interval=1.1-5.9). Relatively higher levels of 2,3,4,7,8-pentachlorodibenzofuran were also associated with a significantly increased risk of otitis media (odds ratio=5.3, 95% confidence interval=1.5-19). However, we observed a weak association between dioxin-like compound levels and allergic symptoms in infancy. At environmental levels, prenatal exposure to dioxin-like compounds may alter immune function and increase the risk of infections in infancy, especially among males. The compound 2,3,4,7,8-pentachlorodibenzofuran may be responsible for this

Prenatal exposure to perfluoroalkyl acids and prevalence of infectious diseases up to 4 years of age

Perfluoroalkyl acids (PFAAs) are synthetic chemicals with ability to repel oils and water, and have been widely used in many industrial and household applications such as adhesives and water-and stain-repellent surfaces to nonstick coatings. Animal studies have shown that PFAAs have immunotoxic effects. However, few epidemiological studies have investigated the effects of PFAAs on infectious diseases occurrence. We examined the relationship between prenatal exposure to PFAAs and prevalence of infectious diseases up to 4 years of life. A total of 1558 mother-child pairs, who were enrolled in the Hokkaido Study on Environment and Children's Health, were included in this data analysis. Eleven PFAAs were measured in maternal plasma taken at 28-32 weeks of gestation using ultra-performance liquid chromatography coupled to triple quadrupole tandem mass spectrometry. Participant characteristics were obtained from medical birth records and self-administered questionnaires during pregnancy and after delivery. Physicians' diagnosis of common infectious diseases including otitis media, pneumonia, respiratory syncytial virus infection, and varicella up to 4 years were extracted from the mother-reported questionnaires. The number of children who developed infectious diseases up to 4 years of age was as follows: otitis media, 649 (41.4%); pneumonia, 287 (18.4%); respiratory syncytial virus infection, 197 (12.6%); varicella 589 (37.8%). A total of 1046 (67.1%) children had at least one of the diseases defined as total infectious diseases. After adjusting for appropriate confounders, PFOS levels in the highest quartile were associated with increased odds ratios (ORs) of total infectious diseases (Q4 vs. Q1 OR: 1.61; 95% CI: 1.18, 2.21; p for trend = 0.008) in all children. In addition, perfluorohexane sulfonate (PFHxS) was associated with a higher risk of total infectious diseases only among girls (Q4 vs. Q1 OR: 1.55, 95% CI: 0.976, 2.45; p for trend = 0.045). We found no association between infectious diseases and other examined PFAAs. Our findings suggest that prenatal exposure to PFOS and PFHxS may associated with infectious diseases occurrence in early life. Therefore, prenatal exposure to PFAAs may be immunotoxic for the immune system in offspring

Determinants and Temporal Trends of Perfluoroalkyl Substances in Pregnant Women : The Hokkaido Study on Environment and Children's Health

Perfluoroalkyl substances (PFAS) are persistent bio-accumulative chemicals that impact the health of pregnant women and their children. PFAS derive from environmental and consumer products, which depend on human lifestyle, socioeconomic characteristics, and time variation. Here, we aimed to explore the temporal trends of PFAS in pregnant women and the characteristics related to maternal PFAS concentration. Our study is part of the Hokkaido Study on Environment and Children's Health, the Hokkaido large-scale cohort that recruited pregnant women between 2003 and 2011. Blood samples were acquired from pregnant women during the third trimester to measure PFAS and cotinine concentrations. Maternal basic information was collected with a baseline structured questionnaire. Eleven PFAS were measured from 2123 samples with ultra-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry. Eight PFAS were above 80% detection rate and were included in the final analysis. We used multivariable linear regression to analyze the association of pregnant women characteristics with the levels of eight PFAS. The temporal trend of PFAS was observed in two periods (August 2003 to January 2006 and February 2006 to July 2012). The concentration of perfluorooctane sulfonate (PFOS) significantly decreased from August 2003 to January 2006 and from February 2006 to July 2012. The concentrations of perfluorododecanoic acid (PFDoDA), perfluoroundecanoic acid (PFUnDA), and perfluorotridecanoic acid (PFTrDA) increased significantly between August 2003 and January 2006, whereas they decreased significantly between February 2006 and July 2012. Women with pre-pregnancy body mass index (BMI) >25 kg/m2 had lower PFUnDA, PFDoDA, and PFTrDA levels than did those with normal BMI (18.5-24.9 kg/m2). Pregnant women, who were active smokers (cotinine > 11.49 ng/mL), had higher PFOS than the non-smokers (cotinine < 0.22 ng/mL). Lower levels of PFHxS, PFOS, PFOA, PFNA, and PFDA were observed in women, who had given birth to more than one child. There were also significant positive associations between PFAS levels and annual income or maternal education. PFAS levels varied in women with higher pre-pregnancy BMI, active smoking status, higher education level and annual income. The causes of the individual PFAS differences should be explored in an independent study

Temporal trends of perfluoroalkyl acids in plasma samples of pregnant women in Hokkaido, Japan, 2003–2011

Perfluoroalkyl acids (PFAAs) are persistent organic pollutants that are used in a wide range of consumer products. Recent epidemiological studies have shown that prenatal exposure to toxic levels of PFAAs in the environment may adversely affect fetal growth and humoral immune response in infants and children. Here we have characterized levels of prenatal exposure to PFAA between 2003 and 2011 in Hokkaido, Japan, by measuring PFAA concentrations in plasma samples from pregnant women. The study population comprised 150 women who enrolled in a prospective birth cohort study conducted in Hokkaido. Eleven PFAAs were measured in maternal plasma samples using simultaneous analysis by ultra-performance liquid chromatography coupled to triple quadrupole tandem mass spectrometry. At the end of the study, in 2011, age- and parity-adjusted mean concentrations of perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorododecanoic acid (PFDoDA), perfluorotridecanoic acid (PFTrDA), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) were 1.35ng/mL, 1.26ng/mL, 0.66ng/mL, 1.29ng/mL, 0.25ng/mL, 0.33ng/mL, 0.28ng/mL, and 3.86ng/mL, respectively. Whereas PFOS and PFOA concentrations declined 8.4%/y and 3.1%/y, respectively, PFNA and PFDA levels increased 4.7%/y and 2.4%/y, respectively, between 2003 and 2011. PFUnDA, PFDoDA, and PFTrDA were detected in the vast majority of maternal samples, but no significant temporal trend was apparent. Future studies must involve a larger population of pregnant women and their children to determine the effects of prenatal exposure to PFAA on health outcomes in infants and children

Association of perfluorinated chemical exposure in utero with maternal and infant thyroid hormone levels in the Sapporo cohort of Hokkaido Study on the Environment and Children's Health

Objectives: Perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) have been widely used as industrial products, and are persistent organic pollutants due to their chemical stability. Previous studies suggested that PFOS and PFOA might disrupt thyroid hormone (TH) status. Although TH plays an important role in fetal growth during pregnancy, little attention has been paid to the relationships between maternal exposure to perfluorocarbons and TH statuses of mothers and fetuses. We investigated the effects of low levels of environmental PFOS and PFOA on thyroid function of mothers and infants. Methods: Of the eligible subjects in a prospective cohort, 392 mother-infant pairs were selected. Concentration of maternal serum PFOS and PFOA was measured in samples taken during the second and third trimesters or within 1 week of delivery. Blood samples for measuring thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were obtained from mothers at early gestational stage (Median; 11.1 weeks), and from infants between 4 and 7 days of age, respectively. Results: Median concentrations of PFOS and PFOA were 5.2 (95% confidence interval [CI]]: 1.6-12.3) and 1.2 (95% CI: limitation of detection-3.4) ng/mL, respectively. Maternal PFOS levels were inversely correlated with maternal serum TSH and positively associated with infant serum TSH, whereas maternal PFOA showed no significant relationship with TSH or FT4 among mothers and infants. Conclusions: These findings suggest that PFOS may independently affect the secretion and balances of maternal and infant TSH even at low levels of environmental exposure

Effects of prenatal exposure to perfluoroalkyl acids on prevalence of allergic diseases among 4-year-old children

Perfluoroalkyl acids (PFAAs) are ubiquitous chemicals extremely resistant and widespread throughout the environment, frequently being detected in human blood samples. Animal studies have revealed that exposure to PFAAs results in immunotoxicity. However, the association between PFAAs, especially long-chain PFAAs, and allergies in humans is not well established. We examined whether prenatal exposure to PFAAs is associated with allergic diseases among 4-year-old children in a large-scale prospective birth cohort in Hokkaido, Japan. In total, 1558 mother-child pairs were included in this study and prenatal levels of eleven PFAAs were measured in maternal plasma samples obtained between 28 and 32 weeks of pregnancy by using ultra-performance liquid chromatography-tandem mass spectrometry. Participant demographic and characteristic information were obtained from self-administered pre- and postnatal questionnaires and medical birth records. Infant allergies were assessed using the Japanese version of the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three questionnaire, which was administered 4 years post-delivery. Symptoms included eczema, wheezing and rhinoconjunctivitis with a prevalence of 19.0%, 18.7%, and 5.4%, respectively. Associations of PFAA quartiles with allergic outcomes were examined using logistic models. Adjusted odds ratios (ORs) in the 4th quartile vs. 1st quartile (Q4 vs. Q1) for total allergic diseases (including at least one allergic outcome) significantly decreased for perfluorododecanoic acid (PFDoDa) (Q4 vs. Q1 OR: 0.621; 95% confidence interval (CI): 0.454, 0.847) andperfluorotridecanoic acid (PFTrDA) (Q4 vs. Q1 OR: 0.712; 95% CI: 0.524, 0.966) in all children. We obtained similar results when examining the association between PFAAs and eczema. The adjusted OR (Q4 vs. Q1) for wheezing in relation to higher maternal PFHxS levels was 0.728 (95% CI: 0.497, 1.06) in all children. In conclusion, prenatal exposure to long-chain PFAAs, such as PFDoDa and PFTrDA may have an immunosuppressive effect on allergic diseases in 4-year-old children

The Association of Prenatal Exposure to Perfluorinated Chemicals with Maternal Essential and Long-Chain Polyunsaturated Fatty Acids during Pregnancy and the Birth Weight of Their Offspring : The Hokkaido Study

Background: Fatty acids (FAs) are essential for fetal growth. Exposure to perfluorinated chemicals (PFCs) may disrupt FA homeostasis, but there are no epidemiological data regarding associations of PFCs and FA concentrations. Objectives: We estimated associations between perfluorooctane sulfonate (PFOS)/perfluorooctanoate (PFOA) concentrations and maternal levels of FAs and triglyceride (TG) and birth size of the offspring. Methods: We analyzed 306 mother-child pairs in this birth cohort between 2002 and 2005 in Japan. The prenatal PFOS and PFOA levels were measured in maternal serum samples by liquid chromatography-tandem mass spectrometry. Maternal blood levels of nine FAs and TG were measured by gas chromatography-mass spectrometry and TG E-Test Wako kits, respectively. Information on infants' birth size was obtained from participant medical records. Results: The median PFOS and PFOA levels were 5.6 and 1.4 ng/mL, respectively. In the fully adjusted model, including maternal age, parity, annual household income, blood sampling period, alcohol consumption, and smoking during pregnancy, PFOS but not PFOA had a negative association with the levels of palmitic, palmitoleic, oleic, linoleic, α-linolenic, and arachidonic acids (p < 0.005) and TG (p- value = 0.016). Female infants weighed 186.6 g less with mothers whose PFOS levels were in the fourth quartile compared with the first quartile (95% CI: -363.4, -9.8). We observed no significant association between maternal levels of PFOS and birth weight of male infants. Conclusions: Our data suggest an inverse association between PFOS exposure and polyunsaturated FA levels in pregnant women. We also found a negative association between maternal PFOS levels and female birth weight

Genetic association of aromatic hydrocarbon receptor (AHR) and cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) polymorphisms with dioxin blood concentrations among pregnant Japanese women

Dioxins are metabolized by cytochrome P450, family 1 (CYP1) via the aromatic hydrocarbon receptor (AHR). We determined whether different blood dioxin concentrations are associated with polymorphisms in AHR (dbSNP ID: rs2066853), AHR repressor (AHRR; rs2292596), CYP1 subfamily A polypeptide 1 (CYP1A1; rs4646903 and rs1048963), CYP1 subfamily A polypeptide 2 (CYP1A2; rs762551), and CYP1 subfamily B polypeptide 1 (CYP1B1; rs1056836) in pregnant Japanese women. These six polymorphisms were detected in 421 healthy pregnant Japanese women. Differences in dioxin exposure concentrations in maternal blood among the genotypes were investigated. Comparisons among the GG, GA, and AA genotypes of AHR showed a significant difference (genotype model: P = 0.016 for the mono-ortho polychlorinated biphenyl concentrations and toxicity equivalence quantities [TEQs]). Second, we found a significant association with the dominant genotype model ([TT + TC] vs. CC: P = 0.048 for the polychlorinated dibenzo-p-dioxin TEQs; P = 0.035 for polychlorinated dibenzofuran TEQs) of CYP1A1 (rs4646903). No significant differences were found among blood dioxin concentrations and polymorphisms in AHRR, CYP1A1 (rs1048963), CYP1A2, and CYP1B1. Thus, polymorphisms in AHR and CYP1A1 (rs4646903) were associated with maternal dioxin concentrations. However, differences in blood dioxin concentrations were relatively low