8245 Estradiol Interacts with the Val66Met Single Nucleotide Polymorphism in the Brain-Derived Neurotrophic Factor Gene to Alter Endometrial Thickness in a Rat Model

Abstract

Abstract Disclosure: S. Moosa: None. E. Kohlmeir: None. S. Kujawa: None. D. Korol: None. A. Prakapenka: None. Brain derived neurotrophic factor (BDNF) is most known for its involvement in cell development, survival, and plasticity in the nervous system. BDNF and its cognate receptors can also be found in non-neural tissue including the ovary and uterus in humans and in animal models, suggesting that BDNF signaling may regulate reproductive functions. Indeed, disruptions in BDNF signaling are associated with health conditions related to the reproductive system, such as endometriosis. Studies show that treatment with estradiol increases expression of uterine BDNF and its cognate receptors, suggesting that estradiol can modulate BDNF signaling and its effects in the reproductive system. A common human functional single nucleotide polymorphism (SNP) in the BDNF gene, Val66Met (rs6265), is thought to decrease activity-dependent release of BDNF, altering BDNF signaling. Using a CRISPR/cas9 rat model of the human Val66Met BDNF SNP, we investigated the interacting role of estradiol and this variation in the BDNF gene on female uterine structure. Middle-aged (11-14-months-old) female rats were either homozygous for the Val allele (Val/Val; control) or the Met allele (Met/Met; BDNF SNP). All rats were ovariectomized and after three weeks randomly assigned to receive subcutaneous treatment of vehicle (sesame oil) or estradiol (17beta-estradiol benzoate) for two consecutive days. Twenty-four hours after the second injection, rats were euthanized and tissue collected, weighed, and placed in fixative. Uterine tissue weights differed significantly by treatment and by genotype such that uterine horns were heavier in estradiol-treated compared to vehicle-treated rats within each genotype and uterine horns were heavier in Met/Met compared to Val/Val rats within each treatment condition. To determine which uterine layer contributed to the weight differences, uterine horns were sectioned and stained with hematoxylin and eosin. Thickness of myometrium, endometrium, and lumen were individually measured. Although there were no treatment and no genotype effects on myometrial thickness, there were significant treatment and genotype effects on endometrial thickness. Of note, the endometrium of estradiol-treated Met/Met rats was thicker compared to vehicle-treated Met/Met rats and compared to estradiol-treated Val/Val rats, suggesting that estradiol and the BDNF gene variation interact to modulate endometrial size. Lumen circumference did not differ between genotypes but did increase with estradiol compared to vehicle treatment within each genotype. Altogether, findings suggest that BDNF genotype affects uterine structure, notably the endometrium. Differences with BDNF gene variation emerged with estradiol exposure, implicating the hormone’s role in modulating BDNF signaling and warranting future research on the interactive effects of estradiol and BDNF genotype on the endometrium. Presentation: 6/2/2024