title: Evaluation of the genotoxicity of clomiphene citrate.
abstract: Clomiphene citrate (CC) is a selective estrogen-receptor modulator that is primarily used to enhance follicular development in women receiving in vitro fertilization (IVF) treatment. Although some studies suggested large increases in ovarian cancer risk related to fertility medications, this association has not been confirmed in other studies. Whether there could be a residual, small risk is still an open question. It is known that genomic instability and multiple genetic changes may be required in carcinogenesis. Genomic instability such as single-base changes, chromosomal rearrangements or aneuploidy may accelerate this process. Genomic instability is not only central to carcinogenesis, but it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy. For these reasons, this study was planned to examine genotoxic effects of CC in human lymphocytes by use of the chromosome aberration (CA) assay, the micronucleus (MN) test, the comet assay, and the test for bacterial mutagenicity in Salmonella typhimurium strains TA98 and TA100 (Ames test). Concentrations of 0.40, 0.80, 1.60, and 3.20μg/ml of CC significantly increased the frequency of chromosomal aberrations (p<0.01 and p<0.001) and micronuclei (p<0.05, p<0.01 and p<0.001) in cultured human lymphocytes, and of DNA damage (tail length, p<0.05, except 0.80μg/ml) in isolated lymphocytes compared with their respective controls. The highest CC concentration at 24h and highest two concentrations after the 48-h treatment significantly decreased the mitotic index. The Ames test showed that the concentrations of CC used in this study induced neither base-pair substitutions nor frame-shift mutations in S. typhimurium strains TA98 and TA100.
authors.affiliation: Ankara University, Faculty of Health Sciences, 06190 Ankara, Turkey. Electronic address: syilmaz@health.ankara.edu.tr.
authors.forename: Serkan
authors.initials: S
authors.lastname: Yilmaz
authors.affiliation: Gazi University, Science Faculty, Department of Biology, 06500 Ankara, Turkey.
authors.forename: Fatma
authors.initials: F
authors.lastname: Unal
authors.affiliation: Gazi University, Vocational School of Health Services, Gölbaşı, Ankara, Turkey.
authors.forename: Ebru
authors.initials: E
authors.lastname: Yilmaz
authors.affiliation: Gazi University, Science Faculty, Department of Biology, 06500 Ankara, Turkey.
authors.forename: Deniz
authors.initials: D
authors.lastname: Yüzbaşioğlu
authors.affiliation: Ankara University, Faculty of Health Sciences, 06190 Ankara, Turkey.
authors.forename: Sibel
authors.initials: S
authors.lastname: Erkal İlhan
mesh_terms: D000328:Adult; D002869:Chromosome Aberrations; D002996:Clomiphene / Q000633:toxicity*; D004249:DNA Damage; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000648:ultrastructure; D048629:Micronuclei, Chromosome-Defective; D009152:Mutagenicity Tests; D020845:Selective Estrogen Receptor Modulators / Q000633:toxicity*
chemical_list: D020845:Selective Estrogen Receptor Modulators; D002996:Clomiphene
keywords: Ames; Clomiphene citrate; Genotoxicity; Human lymphocytes