Phthalate levels in prenatal and postnatal bedroom dust in the SELMA study.

Phthalates are common in polyvinyl chloride (PVC) plastics and numerous consumer goods in our homes from which they can migrate and adhere to indoor dust particles. It is known that indoor dust exposure contribute to human phthalate intake; however, there is a lack of large studies with a repeated-measure design investigating how phthalate levels in indoor dust may vary over time in people's homes. This study investigated levels of seven phthalates and one alternative plasticiser di-iso-nonyl-cyclohexane-di-carboxylate (DiNCH) in bedroom dust collected prenatally around week 25 during pregnancy and postnatally at six months after birth, from 496 Swedish homes. Prenatal and postnatal phthalate levels were compared using correlation and season-adjusted general linear regression models. Over the nine-month period, levels of six out of seven phthalates were associated as indicated by a positive Pearson correlation (0.18 < r < 0.50, P < .001) and Lin's concordance correlation between matched prenatal and postnatal dust samples. Compared to prenatal levels, the season-adjusted postnatal levels decreased for five phthalates, whilst di-ethyl-hexyl phthalate (DEHP), di-2-propylheptyl phthalate (DPHP) and DiNCH increased. The results suggest that families with higher phthalate levels in bedroom dust during pregnancy are likely to remain among those with higher levels in the infancy period. However, all average phthalate levels changed over this specific nine-month period suggesting that available phthalate sources or their use were altered between the dust collections. Changes in home characteristics, family lifestyle, and phthalate replacement trends may contribute to explain the differences.

Indoor phthalate exposure and contributions to total intake among pregnant women in the SELMA study.

Phthalates are widely used in consumer products. Exposure to phthalates can lead to adverse health effects in humans, with early-life exposure being of particular concern. Phthalate exposure occurs mainly through ingestion, inhalation, and dermal absorption. However, our understanding of the relative importance of different exposure routes is incomplete. This study estimated the intake of five phthalates from the residential indoor environment for 455 Swedish pregnant women in the SELMA study using phthalate mass fraction in indoor dust and compares these to total daily phthalate intakes back-calculated from phthalate metabolite concentrations in the women's urine. Steady-state models were used to estimate indoor air phthalate concentrations from dust measurements. Intakes from residential dust and air made meaningful contributions to total daily intakes of more volatile di-ethyl phthalate (DEP), di-n-butyl phthalate (DnBP), and di-iso-butyl phthalate (DiBP) (11% of total DEP intake and 28% of total DnBP and DiBP intake combined). Dermal absorption from air was the dominant pathway contributing to the indoor environmental exposure. Residential exposure to less volatile phthalates made minor contributions to total intake. These results suggest that reducing the presence of low molecular weight phthalates in the residential indoor environment can meaningfully reduce phthalate intake among pregnant women.

Prenatal phthalate exposure and early childhood wheeze in the SELMA study.

BACKGROUND: Prenatal maternal phthalate exposure has been associated with wheeze and asthma in children, but results are inconclusive. Previous studies typically assessed exposure in late pregnancy, included only a small number of old phthalates, and assessed outcomes in children aged 5 years or older. OBJECTIVE: We explored associations between 1st trimester prenatal maternal exposure to a wider range of phthalates and wheeze in early childhood. METHODS: First trimester concentrations of 14 metabolites from 8 phthalates and one alternative plasticizer were quantified in first-morning void urine from 1148 mothers in the Swedish SELMA study. Associations between log-transformed metabolite concentrations and parental reported ever wheeze among 24-month-old children were investigated with logistic regression models adjusted for parental asthma/rhinitis, sex of child, maternal education, smoking, and creatinine. RESULTS: Metabolites of replacement phthalates di-iso-decyl phthalate (DiDP) and di-2-propylheptyl phthalate (DPHP) were associated with increased risk for wheeze (aOR 1.47, 95% CI 1.08-2.01 and aOR 1.49, 95% CI 1.04-2.15, respectively). The associations with DiDP and DPHP were stronger among children whose parents did not have asthma or rhinitis. In this group, wheeze was also associated with metabolites of butyl-benzyl phthalate (BBzP) and di-iso-nonyl phthalate (DiNP). SIGNIFICANCE: Maternal phthalate exposure during early pregnancy may be a risk factor for wheeze in early childhood, especially among children whose parents do not have asthma or rhinitis symptoms.

Phthalate levels in indoor dust and associations to croup in the SELMA study.

Phthalates are ubiquitous indoor pollutants which have been associated with child airway disease although results are inconclusive. This study examined associations between phthalate levels in residential indoor dust and croup during infancy. Settled indoor dust was collected in 482 homes of 6-month-old infants in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study and analysed for seven phthalates and one phthalate replacement using gas chromatography tandem mass spectrometry. The incidence of parental reported croup at 12 months was 6.4% for girls and 13.4% for boys. Associations between phthalate dust levels and croup were analysed by logistic regression adjusted for potential confounders. We found significant associations between di-ethyl phthalate (DEP) and di-ethyl-hexyl phthalate (DEHP) in residential dust and parental reported croup (adjusted odds ratio (aOR) = 1.71; 95% CI: 1.08-2.73 and 2.07; 1.00-4.30, respectively). Stratified results for boys showed significant associations between DEP and butyl-benzyl phthalate (BBzP) in dust and infant croup (aOR = 1.86; 95% CI: 1.04-3.34 and 2.02; 1.04-3.90, respectively). Results for girls had questionable statistical power due to few cases. Our results suggest that exposure to phthalates in dust is a risk factor for airway inflammatory responses in infant children.

Convergent evidence for 2',3'-cyclic nucleotide 3'-phosphodiesterase as a possible susceptibility gene for schizophrenia.

CONTEXT: Convergent data make 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) a candidate gene for schizophrenia. Reduced expression has been reported in the schizophrenic brain. The CNP gene maps to a region to which we have reported linkage to schizophrenia. Mice in which the CNP gene has been knocked out display central nervous system pathological characteristics reminiscent of some features observed in schizophrenia. 2',3'-Cyclic nucleotide 3'-phosphodiesterase is used as a marker of myelin-forming cells and is detectable in cells of oligodendrocyte lineage throughout life. Because CNP is thought to be important for oligodendrocyte function, altered expression has been interpreted as supportive of the hypothesis that altered oligodendrocyte function may be an etiological factor in schizophrenia. However, it is unclear whether the observed changes in the schizophrenic brain are primary or secondary. OBJECTIVES: To determine if CNP expression is influenced by DNA polymorphisms and to verify if these polymorphisms are associated with schizophrenia. DESIGN: Allele-specific messenger RNA expression assay and genetic association studies. SETTING: Unrelated subjects were ascertained from secondary psychiatric inpatient and outpatient services. PARTICIPANTS: We used brain tissue from 60 anonymous individuals with no known psychiatric disorder; a case-control sample of 708 white individuals from the United Kingdom meeting DSM-IV criteria for schizophrenia matched for age, sex, and ethnicity to 711 blood donor controls; and a pedigree with DNA from 6 affected siblings and 1 parent, showing evidence for linkage to CNP. MAIN OUTCOME MEASURES: Association between allele and gene expression. Association between allele and schizophrenia. RESULTS: The exonic single nucleotide polymorphism rs2070106 was associated with CNP expression (P<.001). Compatible with underexpression of CNP messenger RNA in schizophrenia, the lower-expressing A allele was significantly associated with schizophrenia (P = .04) in the case-control sample. All affected individuals in the linked pedigree were homozygous for the lower-expression allele, providing independent support for the association (P = .03). CONCLUSIONS: Our data support the hypothesis that reduced CNP expression in the schizophrenic brain is relevant to disease etiology and therefore provide support for the general hypothesis that altered oligodendrocyte function is an etiological factor in schizophrenia.

No evidence for association between polymorphisms in GRM3 and schizophrenia.

BACKGROUND: Three studies have previously reported data that were interpreted by the authors as supportive of association between schizophrenia and polymorphisms in the gene encoding the metabotropic glutamate receptor GRM3. METHODS: In a bid to examine this hypothesis, we examined seven SNPs spanning GRM3 in a UK case-control sample (schizophrenic cases n = 674, controls n = 716). These included all SNPs previously reported to be associated, alone or in haplotypes, with schizophrenia in European or European American samples. RESULTS: Our data showed no evidence for association with single markers, or 2, 3, 4 and 5 marker haplotypes, nor did any specific haplotypes show evidence for association according to previously observed patterns. CONCLUSION: Examination of our own data and those of other groups leads us to conclude that at present, GRM3 should not be viewed as a gene for which there is replicated evidence for association with schizophrenia.

Strong evidence for association between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia in 488 parent-offspring trios from Bulgaria.

BACKGROUND: The gene encoding the dystrobrevin binding protein (DTNBP1) has been implicated in the pathogenesis of schizophrenia by several association studies. We tried to replicate these findings in a sample of 488 parent-proband trios recruited in Bulgaria. Probands had a diagnosis of schizophrenia (n = 441) or schizoaffective disorder (n = 47). METHODS: We genotyped eight single nucleotide polymorphisms within the gene, four of which had been reported in previous studies, and four identified as informative by our group through direct screening of the gene and genotyping in a sample of cases and control subjects. RESULTS: A significant excess of transmissions was observed for two of the markers, p1635 and p1757, (p =.0009 and.0013, respectively). Analysis of two-, three-, and four-marker haplotypes produced numerous positive results, with six (4% of the total combinations) at p <.001. CONCLUSIONS: These results provide strong support for DTNBP1 as a susceptibility gene for schizophrenia; however, different haplotypes seem to be associated in different studies.

Support for RGS4 as a susceptibility gene for schizophrenia.

BACKGROUND: The gene encoding the regulator of G-protein signaling 4 has recently been associated with susceptibility to schizophrenia. This finding is particularly interesting, because it was replicated within the same study and also because there are functional, positional, and expression data to support the regulator of G-protein signaling 4 as a schizophrenia candidate gene. Although the original report was highly suggestive, a limitation was that the study was conducted on rather small samples. METHODS: We have examined a large case (n = 709) control (n = 710) sample for association between schizophrenia using four markers investigated in the earlier study, denoted single nucleotide polymorphisms 1, 4, 7, and 18. RESULTS: We were able to replicate the associations with single nucleotide polymorphisms 4 and 18 that had previously been reported individually and have also identified significant association with haplotypes constructed from single nucleotide polymorphisms 1 and 4. CONCLUSIONS: Our data give modest support for the hypothesis that the regulator of G-protein signaling 4 is a susceptibility gene for schizophrenia.

Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia.

There is now strong evidence that Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. NRG1 mediates some of its effects through the tyrosine kinase receptor erbB4, and analysis of gene knock-out animals suggests that the functional interaction of NRG1 and erbB4 mediates behaviors that may model some aspects of the schizophrenia phenotype in mice. Given these findings, we have sought evidence for association between schizophrenia and erbB4. Mutation screening of erbB4 in 14 DSMIV schizophrenics revealed 15 SNPs, none of which were nonsynonymous. Analysis of the allele frequencies of each SNP in pools of 368 DSMIV schizophrenics and 368 controls provided modest evidence for association with two of the SNPs, although individual genotyping in an extended sample of 680 cases did not confirm this. However, we did find evidence for a significant interaction between the NRG1 "Icelandic" schizophrenia risk haplotype and erbB4 (P = 0.019). The NRG1 and erbB4 interacting marker was further genotyped in an independent sample of 290 cases and 634 controls from Dublin. Interaction between NRG1 and erbB4 remained significant in the combined sample of 970 cases and 1,341 controls, OR = 2.98 (CI: 1.16-7.64), P = 0.01, although it only showed a trend in the Dublin sample alone (P = 0.11, two tailed). Our data require independent replication, but tentatively suggest that NRG1 may mediate its effects on schizophrenia susceptibility through functional interaction with erbB4, and that genetic interaction between variants at the two loci increases susceptibility to schizophrenia.

Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression.

The DTNBP1 gene, encoding dysbindin, is now generally considered to be a susceptibility gene for schizophrenia. However, the confidence with which this hypothesis can be held has to be tempered by the poor reproducibility between studies in terms of the exact nature of the associated haplotypes, by the failure so far to identify any specific susceptibility variants and by the absence of any demonstrated function associated with any of the risk haplotypes. In the present study, we show that a defined schizophrenia risk haplotype tags one or more cis-acting variants that results in a relative reduction in DTNBP1 mRNA expression in human cerebral cortex. Subsidiary analyses suggest that risk haplotypes identified in other sample groups of white European ancestry also index lower DTNBP1 expression, whereas putative 'protective' haplotypes index high DTNBP1 expression. Our data indicate that variation in the DTNBP1 gene confers susceptibility to schizophrenia through reduced expression, and that this, therefore, represents a primary aetiological mechanism in the disorder.