Effect of tamoxifen treatment on global and insulin-like growth factor 2-H19 locus-specific DNA methylation in rat spermatozoa and its association with embryo loss

• Published in: Fertility and sterility Vol. 91; no. 5; pp. 2253 - 2263
• Main Authors: Pathak, Shilpa, Kedia-Mokashi, Neelam, Saxena, Madhurima, D'Souza, Ryan, Maitra, Anurupa, Parte, Priyanka, Gill-Sharma, Manjit, Balasinor, Nafisa
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2009
• Subjects: Animals; CpG Islands - drug effects; DNA - drug effects; DNA - genetics; DNA methylation; DNA Methylation - drug effects; embryo development; Embryo Loss - epidemiology; Embryo Loss - prevention & control; estrogen; Female; genomic imprinting; imprinting control region; Insulin-Like Growth Factor II - genetics; Internal Medicine; Male; Obstetrics and Gynecology; Pregnancy; Rats; Spermatozoa - drug effects; Spermatozoa - physiology; Tamoxifen; Tamoxifen - pharmacology; DNA methylation; imprinting control region; embryo development; estrogen; genomic imprinting; Tamoxifen
• ISSN: 0015-0282; 1556-5653; 1556-5653
• DOI: 10.1016/j.fertnstert.2008.07.1709

To determine the effect of tamoxifen treatment on global and insulin-like growth factor 2-H19 imprinting control region (Igf2-H19 ICR)-specific DNA methylation in rat spermatozoa and analyze its association with postimplantation loss. Experimental prospective study. Animal research and academic research facility. Male and female 75-day-old Holtzman rats. Global and Igf2-H19 ICR-specific DNA methylation was analyzed in an epididymal sperm sample in control and tamoxifen-treated rats at a dose of 0.4 mg tamoxifen/kg/day. DNA methylation status was correlated to postimplantation loss in females mated with tamoxifen-treated males. Global sperm DNA methylation level, methylation status of Igf2-H19 ICR in sperm, postimplantation loss. Tamoxifen treatment significantly reduced methylation at Igf2-H19 ICR in epididymal sperm. However, the global methylation level was not altered. A mating experiment confirmed a significant increase in postimplantation loss upon tamoxifen treatment and showed significant correlation with methylation at Igf2-H19 ICR. Reduced DNA methylation at Igf2-H19 ICR in rat spermatozoa upon tamoxifen treatment indicated a role of estrogen-associated signaling in the acquisition of paternal-specific imprints during spermatogenesis. In addition, association between DNA methylation and postimplantation loss suggests that errors in paternal imprints at Igf2-H19 ICR could affect embryo development.