Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
Epigenetic modifications, such as DNA methylation, due to in utero exposures may play a critical role in early programming for childhood and adult illness. Maternal smoking is a major risk factor for multiple adverse health outcomes in children, but the underlying mechanisms are unclear.
We investigated epigenome-wide methylation in cord blood of newborns in relation to maternal smoking during pregnancy.
We examined maternal plasma cotinine (an objective biomarker of smoking) measured during pregnancy in relation to DNA methylation at 473,844 CpG sites (CpGs) in 1,062 newborn cord blood samples from the Norwegian Mother and Child Cohort Study (MoBa) using the Infinium HumanMethylation450 BeadChip (450K).
We found differential DNA methylation at epigenome-wide statistical significance (p-value
Impaired glucose tolerance and impaired insulin secretion have been reported in families with PAX6 mutations and it is suggested that they result from defective proinsulin processing due to lack of prohormone convertase 1/3, encoded by PCSK1. We investigated whether a common PAX6 variant would mimic these findings and explored in detail its effect on islet function in man.
A PAX6 candidate single nucleotide polymorphism (rs685428) was associated with fasting insulin levels in the Diabetes Genetics Initiative genome-wide association study. We explored its potential association with glucose tolerance and insulin processing and secretion in three Scandinavian cohorts (N?=?8,897 individuals). In addition, insulin secretion and the expression of PAX6 and transcriptional target genes were studied in human pancreatic islets.
rs685428 G allele carriers had lower islet mRNA expression of PAX6 (p?=?0.01) and PCSK1 (p?=?0.001) than AA homozygotes. The G allele was associated with increased fasting insulin (p (replication)?=?0.02, p (all)?=?0.0008) and HOMA-insulin resistance (p (replication)?=?0.02, p (all)?=?0.001) as well as a lower fasting proinsulin/insulin ratio (p (all)?=?0.008) and lower fasting glucagon (p?=?0.04) and gastric inhibitory peptide (GIP) (p?=?0.05) concentrations. Arginine-stimulated (p?=?0.02) insulin secretion was reduced in vivo, which was further reflected by a reduction of glucose- and potassium-stimulated insulin secretion (p?=?0.002 and p?=?0.04, respectively) in human islets in vitro.
A common variant in PAX6 is associated with reduced PAX6 and PCSK1 expression in human islets and reduced insulin response, as well as decreased glucagon and GIP concentrations and decreased insulin sensitivity. These findings emphasise the central role of PAX6 in the regulation of islet function and glucose metabolism in man.
Persistent organohalogen pollutants (POPs) have been suggested to be involved in changing the proportion of ejaculated Y-bearing sperm. The androgen receptor (AR), aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor repressor (AHRR) may modulate the effect of POPs with regard to previously observed sperm Y:X ratio changes. The objective of this study was to investigate whether sperm Y:X ratio changes in subjects exposed to 2,2'4,4'5,5'-hexachlorobiphenyl (CB-153) and dichlorodiphenyl dichloroethene (p,p'-DDE) were modified by polymorphisms in the AR, AHR and AHRR genes. Semen for analysis of Y- and X-bearing sperm by two-colour fluorescence in situ hybridization and blood for leukocyte DNA genotyping and analysis of CB-153 and p,p'-DDE concentrations were obtained from 195 Swedish fishermen. The polymorphic CAG and GGN repeats in the AR and the R554K and P185A single-nucleotide polymorphisms in the AHR and AHRR genes, respectively, were determined by direct sequencing and allele-specific PCR. The effect of p,p'-DDE was modified by CAG or GGN repeat category in relation to the proportion of Y-bearing sperm (P = 0.005 and 0.02 for CAG and GGN, respectively). Moreover, p,p'-DDE, but not CB-153, levels were associated with Y-sperm proportion in men with CAG or = 22 (P = 0.73). This association was even more pronounced in subjects carrying a short CAG repeat in combination with an AHRR G-allele. The association in regard to p,p'-DDE was found for GGN = 23 but not for the GGN 23 subgroups (P = 0.01, 0.44 and 0.99, respectively). In conclusion The endocrine-disrupting action of POPs, in relation to the observed changes in sperm Y:X ratio, may be modulated by the genes involved in sex steroid and dioxin-mediated pathways.
The objective of this study was to estimate the tetracycline resistance level in the modern population of Neisseria gonorrhoeae in the Russian Federation, where this drug was removed from the treatment regimen for gonococcal infections in 2003. A total of 401 isolates collected between 2015 and 2017 were analyzed for genetic markers (chromosomal porB, rpsJ and mtrR gene mutations and the plasmid-located tetM gene) involved in tetracycline resistance. Antibiotic susceptibility testing revealed that 19% of the strains were tetracycline resistant (MIC?>?1?mg/L) and that 10% of the strains had intermediate susceptibility (0.5??8?mg/L). One N. gonorrhoeae isolate was found to carry a defective tetM gene with an AG deletion at position 1239-1240, ? new stop codon was introduced that caused a defect in TetM protein synthesis and decrease in the tetracycline resistance. Phylogenetic trees constructed using N. gonorrhoeae NG-MAST and tetM loci were compared. Complex relationship was observed between the N. gonorrhoeae sequence type and the tetM plasmid type. Partial recovery of N. gonorrhoeae tetracycline susceptibility was observed relative to the proportion of isolates with resistance detected ten years ago (75%). However, the current levels of tetracycline resistance still preclude the renewed use of these drugs for gonococcal infection therapy.