Persistent organic pollutants (POPs) have been associated with a wide range of adverse health effects. Our case-control study was performed to explore the association between placental levels of selected POPs and risks for neural tube defects (NTDs) in a Chinese population with a high prevalence of NTDs. Cases included 80 fetuses or newborns with NTDs, whereas the controls were 50 healthy, nonmalformed newborn infants. Placental concentrations of polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides, polychlorinated biphenyls, and polybrominated diphenyl ethers were analyzed by gas chromatography-mass spectrometry. The medians of PAHs, o,p′-isomers of dichlorodiphenyltrichloroethane (DDT) and metabolites, α-and γ-hexachlorocyclohexane (HCH), and α-endosulfan were significantly higher in case placentas than in controls. PAH concentrations above the median were associated with a 4.52-fold [95% confidence interval (CI), 2.10-9.74) increased risk for any NTDs, and 5.84-(95% CI, 2.28-14.96) and 3.71-fold (95% CI, 1.57-8.79) increased risks for anencephaly and spina bifida, respectively. A dose-response relationship was observed between PAH levels and the risk of NTDs, with odds ratios for the second, third, and fourth quartiles, compared with the first, of 1.77-(95% CI, 0.66-4.76), 3.83-(95% CI, 1.37-10.75), and 11.67-fold (95% CI, 3.28-41.49), respectively. A dose-response relationship was observed for anencephaly and spina bifida subtypes. Similar results were observed for o,p′-DDT and metabolites, α-HCH, γ-HCH, and α-endosulfan, whereas no dose-response relationship was observed for the last two pollutants. Elevated placental concentrations of PAHs, o,p′-DDT and metabolites, and α-HCH were associated with increased risks of NTDs in this population.congenital abnormalities | indoor air pollution

Background: Folic acid taken in early pregnancy reduces risks for delivering offspring with several congenital anomalies. The mechanism by which folic acid reduces risk is unknown. Investigations into genetic variation that influences transport and metabolism of folate will help fill this data gap. We focused on 118 SNPs involved in folate transport and metabolism.

The authors describe a 6-year-old girl with developmental delay, psychomotor regression, seizures, mental retardation, and autistic features associated with low CSF levels of 5-methyltetrahydrofolate, the biologically active form of folates in CSF and blood. Folate and B12 levels were normal in peripheral tissues, suggesting cerebral folate deficiency. Treatment with folinic acid corrected CSF abnormalities and improved motor skills.

BackgroundAn increasing number of long noncoding RNAs (lncRNAs) have been identified recently. Different from all the others that function in cis to regulate local gene expression, the newly identified HOTAIR is located between HoxC11 and HoxC12 in the human genome and regulates HoxD expression in multiple tissues. Like the well-characterised lncRNA Xist, HOTAIR binds to polycomb proteins to methylate histones at multiple HoxD loci, but unlike Xist, many details of its structure and function, as well as the trans regulation, remain unclear. Moreover, HOTAIR is involved in the aberrant regulation of gene expression in cancer.ResultsTo identify conserved domains in HOTAIR and study the phylogenetic distribution of this lncRNA, we searched the genomes of 10 mammalian and 3 non-mammalian vertebrates for matches to its 6 exons and the two conserved domains within the 1800 bp exon6 using Infernal. There was just one high-scoring hit for each mammal, but many low-scoring hits were found in both mammals and non-mammalian vertebrates. These hits and their flanking genes in four placental mammals and platypus were examined to determine whether HOTAIR contained elements shared by other lncRNAs. Several of the hits were within unknown transcripts or ncRNAs, many were within introns of, or antisense to, protein-coding genes, and conservation of the flanking genes was observed only between human and chimpanzee. Phylogenetic analysis revealed discrete evolutionary dynamics for orthologous sequences of HOTAIR exons. Exon1 at the 5' end and a domain in exon6 near the 3' end, which contain domains that bind to multiple proteins, have evolved faster in primates than in other mammals. Structures were predicted for exon1, two domains of exon6 and the full HOTAIR sequence. The sequence and structure of two fragments, in exon1 and the domain B of exon6 respectively, were identified to robustly occur in predicted structures of exon1, domain B of exon6 and the full HOTAIR in mammals.ConclusionsHOTAIR exists in mammals, has poorly conserved sequences and considerably conserved structures, and has evolved faster than nearby HoxC genes. Exons of HOTAIR show distinct evolutionary features, and a 239 bp domain in the 1804 bp exon6 is especially conserved. These features, together with the absence of some exons and sequences in mouse, rat and kangaroo, suggest ab initio generation of HOTAIR in marsupials. Structure prediction identifies two fragments in the 5' end exon1 and the 3' end domain B of exon6, with sequence and structure invariably occurring in various predicted structures of exon1, the domain B of exon6 and the full HOTAIR.

Triple-negative breast cancer (TNBC) exhibits poor prognosis, with high metastasis and low survival. Long non-coding RNAs (lncRNAs) play critical roles in tumor progression. Here, we identified lncRNA MIR100HG as a pro-oncogene for TNBC progression. Knockdown of MIR100HG decreased cell proliferation and induced cell arrest in the G1 phase, whereas overexpression of MIR100HG significantly increased cell proliferation. Furthermore, MIR100HG regulated the p27 gene to control the cell cycle, and subsequently impacted the progression of TNBC. In analyzing its underlying mechanism, bioinformatics prediction and experimental data demonstrated that MIR100HG participated in the formation of RNA–DNA triplex structures. MIR100HG in The Cancer Genome Atlas (TCGA) and breast cancer cell lines showed higher expression in TNBC than in other tumor types with poor prognosis. In conclusion, our data indicated a novel working pattern of lncRNA in TNBC progression, which may be a potential therapeutic target in such cancers.

Women who consume folic acid in early pregnancy reduced their risks for delivering offspring with neural tube defects (NTDs). The underlying process by which folic acid facilitated this risk reduction is unknown. Investigating genetic variation that influences cellular absorption, transport, and metabolism of folate will help fill this data gap. We focused our studies on a candidate gene that is involved in folate transport, the reduced folate carrier 1 (RFC1). Using data from a California population-based case control interview study (1989-1991 birth cohorts), we investigated whether spina bifida risk was influenced by an interaction between a polymorphism of infant RFC1 at nucleotide 80 (A80G) and maternal periconceptional use of vitamins containing folic acid. Allelic variants of RFC1 were determined by genotyping 133 live-born spina bifida case infants and 188 control infants. The percentages of case infants with the A80/A80, G80/G80, and G80/A80 genotypes were 27.2%, 28.0%, and 44.7%, respectively. The percentages of control infants were similar: 26.1%, 29.3%, and 44.7%. Odds ratios of 1.0 (95% confidence interval 0.5-2.0) for the G80/G80 genotype and 1.1 (0.6-2.0) for the G80/A80 genotype were observed relative to the A80/A80 genotype. Among mothers who did not use vitamins, spina bifida risk was 2.4 (0.8-6.9) for infants with genotype G80/G80 compared to those with A80/A80 genotype. Among mothers who did use vitamins, the risk was 0.5 (0.1-3.1) for infants with the G80/G80 genotype. Although this study did not find an increased spina bifida risk for infants who were heterozygous or homozygous for RFC1 A80G, it did reveal modest evidence for a gene-nutrient interaction between infant homozygosity for the RFC1 G80/G80 genotype and maternal periconceptional intake of vitamins containing folic acid on the risk of spina bifida.

It is generally understood that both genetic and environmental factors contribute to the highly complex etiology of structural birth defects, including neural tube defects, oral clefts and congenital heart defects, by disrupting highly regulated embryonic developmental processes. The intrauterine environment of the developing embryo/fetus is determined by maternal factors such as health/disease status, lifestyle, medication, exposure to environmental teratogens, as well as the maternal genotype. Certain genetic characteristics of the embryo/fetus also predispose it to developmental abnormalities. Epidemiologic and animal studies conducted over the last few decades have suggested that the interplay between genes and environmental factors underlies the etiological heterogeneity of these defects. It is now widely believed that the study of gene-environment interactions will lead to better understanding of the biological mechanisms and pathological processes that contribute to the development of complex birth defects. It is only through such an understanding that more efficient measures will be developed to prevent these severe, costly and often deadly defects. In this review, we attempt to summarize the complex clinical and experimental literature on current hypotheses of interactions between several select environmental factors and those genetic pathways in which they are most likely to have significant modifying effects. These include maternal folate nutritional status, maternal diabetes/obesity-related conditions, and maternal exposure to selected medications and environmental contaminants. Our goal is to highlight the potential gene-environment interactions affecting early embryogenesis that deserve comprehensive study.

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