Lactoferrin Gene Polymorphisms and DES Response

Differential Expression and Estrogen Response of Lactoferrin Gene in the Female Reproductive Tract of Mouse, Rat, and Hamster

2017 Study Abstract

Lactoferrin, an iron-binding glycoprotein, kills bacteria and modulates inflammatory and immune responses. Presence of lactoferrin in the female reproductive tract suggests that the protein may be part of the mucosal immune system and act as the first line of defense against pathogenic organisms. We have discovered that lactoferrin is a major estrogen-inducible protein in the uterus of immature mice and is up-regulated by physiological levels of estrogen during proestrous in mature mice.

In the present study, we examined lactoferrin gene expression and its response to estrogen stimulation in the female reproductive tract of several strains of immature mouse, rat, and hamster. The lactoferrin expression in the cycling adult female rat was also evaluated. Lactoferrin gene polymorphism exists among the different mouse strains. In the three inbred mouse strains studied, lactoferrin gene expression is stimulated by estrogen in the immature uterus, although it is less robust than in the outbred CD-1 mouse. We found that the lactoferrin gene is constitutively expressed in the epithelium of the vagina and the isthmus oviduct; however, it is estrogen inducible in the uterus of immature mice and rats. Furthermore, lactoferrin is elevated in the uterine epithelium of the mature rat during the proestrous and estrous stages of the estrous cycle. Estrogen stimulation of lactoferrin gene expression in the reproductive tract of an immature hamster is limited to the vaginal epithelium. The present study demonstrates differential expression and estrogen responsiveness of the lactoferrin gene in different regions of the female rodent reproductive tract and variation among the rodent species studied.

Lactoferrin Gene Polymorphisms and Estrogen Response among Different Mouse Strains

High levels of lactoferrin were found in the uterine fluid and uterine epithelium of CD-1 mice after DES treatment. Lower levels of lactoferrin were measured in the uterine fluid of DES-treated inbred strains, and less intense immunostaining of the uterine epithelium was found as well. To semiquantify the lactoferrin expression in the uterus of different strains of mice, we scored three regions of the uterus (top; near the oviduct, middle, and bottom; and near the vagina) with arbitrary numbers (0 = negative, 1 = weak, 2 = moderate, 3 = strong, and 4 = intense), and the data were analyzed by both ANOVA and the Dunnett test. The mean ± SEM and the significant differences between DES-treated and untreated mice are presented in Figure 3B. We found that DES induced an intense immunostaining of the lactoferrin in CD-1 mice along the entire epithelial of the uterus and glands; however, we also found variability of lactoferrin staining along the uterine epithelium in the inbred strains. The bottom part of the uterus exhibited stronger lactoferrin immunostaining than the top part of the uterus.

A wide range of genetic variability exists among the different mouse strains and their response to the synthetic estrogen DES. The lactoferrin gene in the three inbred strains examined (SJL, SM, and SWR) showed similar patterns of EcoRI and BamHI restriction enzyme polymorphisms that differ from the outbred CD-1 mouse. These immature inbred mice responded to estrogen stimulation and increased lactoferrin gene expression in the uterus; however, their responses were less robust than those of CD-1 mice. Among the three inbred strains, SWR was more resistant to estrogen stimulation. It has less fluid accumulated in the uterine lumen and a lower level of lactoferrin expression in the epithelium after DES treatment. Interestingly, the lactoferrin detected in the oviduct was also low in the SWR strain. Both SWR and SLJ strains were highly susceptible to infection as compared to other strains. It will be interesting to know whether lactoferrin expression in the neutrophils and other surface mucosa epithelium of these two strains of inbred mice is also low. Nonetheless, the present findings demonstrated that the lactoferrin gene in the uterus of mice is estrogen inducible and likely occurs through the well-characterized estrogen response element (ERE) of the gene regardless of gene polymorphisms. Methylation pattern surrounding the ERE and the presence of estrogen receptor-related receptor could play an important role in determining the estrogen response of the lactoferrin gene in these inbred strains of mice.

Sources and more information
  • Differential Expression and Estrogen Response of Lactoferrin Gene in the Female Reproductive Tract of Mouse, Rat, and Hamster, Biology of Reproduction, Oxford Academic doi.org/10.1095/biolreprod.101.002089, November 2002.
  • Western blot detection of lactoferrin in the uterine fluid from various strains of mice after DES treatment featured image credit figure/60527324/bire-67-05-16-f03.
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