Modifying effect of the AR gene trinucleotide repeats and SNPs in the AHR and AHRR genes on the association between persistent organohalogen pollutant exposure and human sperm Y:X ratio.
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 < 22 (P < 0.001), but not in those carrying 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 or 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.
Tiido
T
T
Department of Clinical Sciences, Molecular Reproductive Medicine Research Unit, Malmö University Hospital, Sweden. tarmo.tiido@med.lu.se
Rignell-Hydbom
A
A
Jönsson
B A G
BA
Rylander
L
L
Giwercman
A
A
Giwercman
Y Lundberg
YL
D051792:Basic Helix-Loop-Helix Proteins; D041321:Chromosomes, Human, X / Q000187:drug effects*; D041322:Chromosomes, Human, Y / Q000187:drug effects*; D015331:Cohort Studies; D003633:Dichlorodiphenyl Dichloroethylene / Q000633:toxicity; D004781:Environmental Exposure; D004785:Environmental Pollutants / Q000097:blood / Q000633:toxicity*; D005838:Genotype; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000097:blood / Q000633:toxicity*; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D013091:Spermatogenesis / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects* / Q000378:metabolism; D013548:Sweden; D018911:Trinucleotide Repeats
D051792:Basic Helix-Loop-Helix Proteins; D003633:Dichlorodiphenyl Dichloroethylene; D004785:Environmental Pollutants; D006843:Hydrocarbons, Chlorinated; D011078:Polychlorinated Biphenyls; D011944:Receptors, Androgen; D018336:Receptors, Aryl Hydrocarbon; D012097:Repressor Proteins; C111235:AHR protein, human; C492162:AHRR protein, human; C410798:AR protein, human; C014024:2,4,5,2',4',5'-hexachlorobiphenyl