Segregated responses of mammary gland development and vaginal opening to prepubertal genistein exposure in Bscl2−/− female mice with lipodystrophy

Abstract

Berardinelli-Seip congenital lipodystrophy 2-deficient (Bscl2−/−) mice recapitulate human BSCL2 disease with lipodystrophy. Bscl2-encoded seipin is detected in adipocytes and epithelium of mammary gland. Postnatal mammary gland growth spurt and vaginal opening signify pubertal onset in female mice. Bscl2−/− females have longer and dilated mammary gland ducts at 5-week old and delayed vaginal opening. Prepubertal exposure to 500 ppm genistein diet increases mammary gland area and accelerates vaginal opening in both control and Bscl2−/− females. However, genistein treatment increases ductal length in control but not Bscl2−/− females. Neither prepubertal genistein treatment nor Bscl2-deficiency affects phospho-estrogen receptor α or progesterone receptor expression patterns in 5-week old mammary gland. Interestingly, Bscl2-deficiency specifically reduces estrogen receptor β expression in mammary gland ductal epithelium. In summary, Bscl2−/− females have accelerated postnatal mammary ductal development but delayed vaginal opening; they display segregated responses in mammary gland development and vaginal opening to prepubertal genistein treatment.

Seipin deficiency leads to defective parturition in mice†

“…This speculation was supported by a recent study demonstrating that the development of hypertrophic cardiomyopathy in Bscl2 −/− mice was prevented by the treatment with dapagliflozin, a hypoglycemic sodium-glucose cotransporter 2 inhibitor [16]. We have been studying the functions of seipin in reproductive systems using seipin-deficient Bscl2 −/− mice and identified roles of seipin in mammary gland development, vaginal opening, and spermatogenesis [11,12]. Since seipin deficiency is associated with muscle hypertrophy and diabetes [10,17], diabetes has been associated with impairment of uterine contractility [18], and uterine smooth muscle contractions are critical for parturition, it was hypothesized that seipin deficiency might affect the myometrium to influence parturition.…”

“…Genotyping was done as previously described [11,12]. Since Bscl2 +/+ (WT) and Bscl2 +/− females had comparable fertility, they were used as the genotype control for Bscl2 −/− females.…”

“…Uterine histology was performed as previously described [20,21]. Uterine area and myometrial area in uterine cross sections were measured using ImageJ [11,12,22].…”

“…Quantification of LC3 staining in D18.5 and postpartum day 1 (PPD1) uterine luminal epithelium (LE) was done as follow: LC3 staining in at least three representative LE areas and nearby myometrium areas (same size) from the same section was quantified using ImageJ [11,12,22]. The ratio of average LE staining intensity/average myometrium staining from one section per mouse was counted as one data point.…”

“…Seipin is an integral endoplasmic reticulum (ER) membrane protein encoded by the BSCL2 gene, and seipin deficiency results in lipodystrophy, diabetes, muscle hypertrophy, and male infertility in both humans and mice [9][10][11][12]. The exact signaling/molecular mechanisms of seipin involved in these functions are not fully understood.…”