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American Journal of Clinical Nutrition, Vol. 70, No. 4, 502-508, October 1999
© 1999 American Society for Clinical Nutrition

Original Research Communications

Ovariectomy increases squamous metaplasia of the uterine horns and survival of SENCAR mice fed a vitamin A–deficient diet1,2,3

Roshini M Ponnamperuma, Susan M Kirchhof, Lisa Trifiletti and Luigi M De Luca

1 From the Differentiation Control Section, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institutes of Health, Bethesda, MD; and ROW Sciences, Inc, Gaithersburg, MD.

2 Presented in part at the Norman Kretchmer Memorial Symposium: The Effects of Nutrients on Gene Expression, held as part of Experimental Biology 96 in Washington, DC.

3 Address reprint requests to LM De Luca, NIH Building 37, Room 3A-17, 37 Convent Drive, Bethesda, MD 20892-4255.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Retinoic acid is necessary for the growth and differentiation of organisms and exerts its molecular actions by binding to specific nuclear receptors that belong to the thyroid-steroid hormone receptor superfamily. Steroids and retinoids control the differentiation of the female reproductive epithelia: estrogen maintains the squamous differentiation of vaginal and ectocervical epithelia, whereas retinoic acid maintains the simple columnar endocervical and uterine epithelia. These lining epithelia transform into a squamous metaplastic phenotype in vitamin A–deficient animals. Furthermore, mortality due to vitamin A deficiency is usually attributed to infection resulting in part from dysfunction of the protective epithelia.

Objective: Our objective was to test the hypothesis that estrogen depletion might change the squamous metaplastic response to vitamin A deficiency and affect animal survival.

Design: We used female SENCAR mice maintained on a purified vitamin A–deficient diet containing either 0 or 3 µg retinoic acid/g diet. Mice were either ovariectomized or intact. Squamous cells arising in the normally simple columnar epithelium of the endocervix and uterine cavity were monitored by keratin 5 expression with immunohistochemistry.

Results: Ovariectomy did not change the time to onset of vitamin A deficiency. It increased the number of squamous metaplastic cells and prolonged survival in mice consuming a vitamin A–deficient diet by as much as 40%.

Conclusions: Factors other than epithelial differentiation per se control survival outcome of vitamin A–deficient mice. The results also show a significant increase in longevity of vitamin A– deficient mice when ovariectomized.

Key Words: Retinoic acid • estrogen • female reproductive epithelium • ovariectomy • survival • vitamin A deficiency • differentiation • mice


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pioneering efforts (1–4) in nutritional biochemistry defined the essential function of vitamin A and its derivatives (the retinoids) in maintenance of normal adult epithelial differentiation in adult organisms. Deficiency of dietary vitamin A was shown to cause alterations in epithelial differentiation, particularly in mucus-secreting epithelia of the simple and pseudostratified phenotypes. Invariably, squamous metaplastic foci form in these epithelia of vitamin A–deficient animals (4). These foci, initially composed of a few squamous cells, eventually expand to replace normal epithelium. Thus, vitamin A deficiency induces the proliferation of squamous cells and shedding of mucous cells (4). Dietary retinoic acid permits the replacement of squamous metaplastic cells by mucus-secreting cells and, thus, reestablishes normal epithelial morphology and function (4).

These phenotypic alterations are schematically illustrated in Figure 1Go. Single, sparse keratin (K) 5–positive squamous cells (Figure 1Go, panel 8, top arrow) as well as foci of these cells (lower arrow) arise in basal position in the uterine epithelium of mice fed a vitamin A–deficient diet for 15 wk from birth. The squamous, K5-positive cells are normally absent from the uterine epithelium (Figure 1Go, panel 7), which is made up of columnar cells expressing keratin 8 (K8; not shown). With progression of vitamin A deficiency, the basal-like K5-positive cells come to occupy the entirety of the basal membrane and lift the K8-positive columnar cells to the lumen (Figure 1Go, panels 3, 4, and 8, lower arrow). Eventually, severe vitamin A deficiency leads to complete replacement of the K8-expressing simple columnar epithelium of the uterus by a squamous, keratinizing, K5-expressing epithelium (Figure 1Go, panel 9). This squamous metaplastic path of differentiation can also be induced by chemical or viral carcinogens and represents an early change that precedes the formation of neoplastic lesions.



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  		FIGURE 1. Progression of squamous metaplasia due to vitamin A deficiency. Left: Artist's rendition (Reproduced with permission from reference 4) of a simple columnar epithelium (panel 1), as normally found in the endocervix and uterine canal, as it progresses through stages of tissue transformation (metaplasia) to become first pseudostratified (panel 2) and then stratified squamous (panels 3 and 4), and eventually stratified epidermoid and keratinizing (panel 5). Right: Top drawing shows a point (squamocolumnar junction) where the squamous stratified epithelium of the ectocervix and vagina (left portion of panel 6) abuts the simple columnar epithelium of the endocervix and uterus (right portion of panel 6). The stratified epithelium of the mouse ectocervix shows a strong reaction with anti-keratin 5 (K5) antibody (left portion of panel 7). The simple columnar epithelium of the endocervix is K5-negative under normal conditions (panel 7, right); however, it is gradually populated with K5-positive cells, showing up first as basal cells (panel 8, top arrow). At this stage the epithelium resembles the pseudostratified epithelium normally found in trachea (and shown schematically in panel 2). With progression of vitamin A deficiency, the basal K5-positive cells occupy larger areas of the basement membrane, thereby marking the transition from a pseudostratified to a stratified epithelium (panel 8, lower arrow). Eventual loss of the columnar cells and total replacement of the initially simple columnar epithelium with a stratified squamous keratinizing epithelium occurs in extreme vitamin A deficiency, as illustrated in panel 9 (low power). Note that the endocervical lumen is now filled with keratin filaments (arrows).

 
In contrast with retinoic acid, estrogen induces the formation of the stratified squamous epithelium of the ectocervix and vagina during estrous. Estrogen depletion, on the other hand, causes simplification of the stratified squamous K5-positive epithelium to an epithelium with just 2–3 cell layers (5). In this study, we tested the hypothesis that the absence of estrogen might change the time to onset of squamous metaplasia.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Preparation of ovariectomized and intact mice
Inbred SENCAR dams who were 2 wk pregnant were obtained from the National Cancer Institute facility in Frederick, MD (Frederick Research Development Center and Animal Production). They were provided a rodent diet (TD 8604; Harlan Teklad, Madison, WI). At parturition, the dams and litters were placed in 2 groups. One group was fed a vitamin A–deficient rodent diet, which we will call the RA- diet (TD 69523; Harlan Teklad), a highly purified research diet containing no sources or precursors of vitamin A. The other group was fed the vitamin A–deficient rodent diet plus retinoic acid as the sole source of vitamin A at 3 µg retinoic acid/g diet, which we will call the RA+ diet, (TD 87373; Harlan Teklad). The experimental procedures were conducted in accordance with the ethical guidelines of the National Institutes of Health.

At age 3 wk, the female pups were selected for this study. At age 4 wk, half of the female pups from each dietary group were anesthetized with pentobarbital and their ovaries were removed bilaterally. This procedure created 4 experimental groups of 25 mice each: 1) intact mice fed the RA- diet, 2) ovariectomized mice fed the RA- diet, 3) intact mice fed the RA+ diet, and 4) ovariectomized mice fed the RA+ diet. This experimental protocol was repeated to prepare animals for survival and tissue collection studies. Daily cage-side observations were performed, including checks for mortality, moribundity, and conditions of skin, eyes, mucous membranes, respiratory system, autonomic and central nervous systems, and somatomotor and behavior patterns.

Immunohistochemistry
At time points corresponding to 12–30 wk of age, unless otherwise stated, animals were killed and the reproductive tracts, including the vagina, cervix, uterine horns, and ovaries (if present) were excised and fixed in 70% ethanol at 4°C. Tissues were sent to American HistoLab (Gaithersburg, MD) for paraffin embedding and sectioning (horizontal sections were cut 5-µm thick to include the entire length of the reproductive tract).

Sections were stained immunohistochemically by using the avidin and biotinylated horse radish peroxidase macromolecular complex technique (6). Sections were deparaffinized in xylene and hydrated by bathing them in 100%, then 95%, then 80%, and then 70% ethanol. Sections were incubated in 0.6% hydrogen peroxide in methanol to block endogenous peroxidases and then incubated with normal goat serum (Rabbit IgG Vectastain ABC Peroxidase Kit, Elite Series; Vector Laboratories, Burlingame, CA). Normal goat serum was diluted 20 µL to 1.0 mL of 0.1% bovine serum albumin in phosphate-buffered saline (BSA-PBS) to block nonspecific binding. Next, sections were incubated at 4°C for 18 h with the primary antibody, a polyclonal rabbit antibody against mouse K5 (MK 5 antibody; Berkeley Antibody Company, Richmond, CA) at a dilution of 1:5000 in 0.1% BSA-PBS. Sections were then incubated for 30 min at room temperature with the secondary antibody, a biotinylated goat antibody against rabbit immunoglobulins (Vector Laboratories) diluted in 0.1% BSA-PBS at 5 µL biotinylated antibody + 20 µL normal serum in 1.0 mL total volume. Next, sections were incubated for 60 min at room temperature with the avidin-biotinylated peroxidase complex (Vector Laboratories). The sections were then stained with a developing solution consisting of diaminobenzidine and tris buffer, pH 7.2, and counterstained with contrast (methyl) green (Kirkegaard and Perry Laboratories, Inc, Gaithersburg, MD). Coverslips were mounted with Permount (Fisher Scientific, Fairlawn, NJ) and sections were viewed under a light microscope.

Sections were evaluated for the presence of squamous metaplastic lesions, indicated by positive K5 staining of epithelial cells in the uterine horns. Lesions were quantified by examining the sections under light microscope and determining the number of K5-positive cells per field and in the entire section of the uterine horns (usually between 11 and 32 fields) under 100x magnification.

Statistical analysis
Results were analyzed statistically by one-way analysis of variance and independent sample t tests with SPSS 6.1 for Windows (SPSS, Inc, Chicago). Percentage survival was plotted and analyzed by using ORIGIN 4.0 (Microcal Software, Inc, North Hampton, MA).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Ovariectomy increased survival of vitamin A–deficient mice
Percentage survival (percentage of mice alive at a given time) and total survival (number of mice alive at a given time) are plotted in Figure 2Go. In mice consuming the RA- diet, ovariectomy increased median survival time, ie, the time at which 50% of mice were alive, from 14 to 19.5 wk. This represents an increase in median survival time of {approx}40% ({alpha} = 0.01, P < 0.001). Note that 73% of the ovariectomized mice consuming the RA- diet were alive at 18 wk, when all the mice in the RA- diet group were dead. Survival curves for mice consuming the RA+ diet, whether ovariectomized or intact, were virtually identical, showing close to 100% survival for the 2 groups. The survival curves for mice who consumed the RA- diet, whether ovariectomized or intact, were similar in profile, showing first a gradual decline, followed by a more rapid decrease.




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  		FIGURE 2. Ovariectomy prolongs survival time (percentage survival and total survival) of vitamin A–deficient SENCAR mice. RA+, fed retinoic acid–containing diet; RA-, fed vitamin A–deficient diet.

 
Ovariectomy and squamous metaplasia due to vitamin A deficiency
Separate and parallel groups of mice prepared by the same protocols as for Figure 2Go were used for the immunohistochemistry studies. Representative results of the occurrence of squamous metaplasia of the uterine epithelium of the uterine horns, as shown by the presence of K5-positive cells (brown) using immunohistochemical analysis, are shown in Figure 3Go. Lesions appeared in both groups of mice consuming the RA- diet starting at 12 wk of age. The number of squamous metaplastic cells was higher (4–5-fold) in the ovariectomized group consuming the RA- diet at all ages. Note that, even though 73% of the ovariectomized mice consuming the RA- diet were still alive at 18 wk (Figure 2Go), similarly prepared mice had extensive squamous metaplasia at this time (see Figure 3DGo). Some of these mice lived <=50 wk.



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  		FIGURE 3. Immunohistochemical analysis of squamous metaplastic lesions, as evidenced by keratin (K) 5 staining in sections of the uterine horns of SENCAR mice, distal to the bifurcation. A: Intact mouse fed diet with retinoic acid, age 50 wk (note the absence of K5-positive cells and the single layer of columnar cells). B: Intact mouse fed diet without retinoic acid, age 17 wk (note K5-positive squamous metaplastic lesions). C: Ovariectomized mouse fed diet with retinoic acid, age 50 wk (note similarity to A, with absence of K5-positive cells). D: Ovariectomized mouse fed diet without retinoic acid, age 50 wk (low magnification; notice extensive keratinization and total replacement of K5-negative columnar cells with K5-positive squamous cells).

 
Next, we quantified the extent of squamous metaplasia observed, both by number of K5-positive squamous cells per microscopic field as well as per entire tissue section, cut to include the full length of the reproductive tract with the uterine horns up to the ovary, at a magnification of 100x. Squamous metaplasia was only observed in the RA- diet groups, whether ovariectomized or intact (Tables 1Go and 2). More importantly, the data in the tables emphasize the significant difference in occurrence of squamous metaplastic cells between the RA- diet groups; on average, the ovariectomized mice had about 5 times the average number of K5-positive cells per section (1894) as did the intact mice (369). A similar ratio was found for the average number of K5-positive cells per field (84 compared with 20 squamous metaplastic cells/field; P = 0.005, {alpha} = 0.05).


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  		TABLE 1. Lack of squamous metaplastic cells in reproductive tract sections of female SENCAR mice fed a retinoic acid–containing diet (RA+) with or without ovariectomy1
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our interest in this study arose from the consideration that both steroid hormones and retinoid vitamins are required to maintain morphology and function of the reproductive organs. Our previous work emphasized that the absence of dietary retinoids transforms the lining epithelium of the uterus from simple columnar to squamous keratinizing cells. This phenotype is similar to that of the ectocervical and vaginal epithelia adjoining the simple columnar epithelium of the endocervix and uterus at the squamocolumnar junction (Figure 1Go, panel 6). Although retinoid deficiency renders the uterine epithelium similar in morphology to the vaginal epithelium in estrous, steroid deficiency makes the vaginal epithelium resemble the uterine epithelium under conditions of normal vitamin A intake. At the molecular level, this was made evident by our studies of keratin expression patterns (7). Keratins typical of squamous cells, such as K5 (basal and suprabasal expression), K1 and K10 (mostly suprabasal), and K6 and K13 (suprabasal), are expressed in the squamous epithelia of the ectocervix and vagina and abut the simple columnar epithelium of the endocervical and uterine canal, which expresses K8 (7). The transformation (squamous metaplasia) of these simple columnar epithelia causes shedding of the K8-expressing columnar cells and replaces them with K5- (and K1-, K6-, and K13-) expressing squamous cells. This metaplastic transformation also causes the expression of cornifin {alpha}, normally only found in suprabasal squamous cells in the metaplastic epithelium of the uterus (8). Conversely, cornifin {alpha} expression was greatly diminished in estrogen deficiency induced by ovariectomy and up-regulated by estrogen supplementation of ovariectomized mice because the hormone increases stratification of this squamous epithelium (8). All of this indicated that there are diverse and perhaps antagonistic actions of steroids and retinoids involved in the maintenance of epithelial morphology and the function of the female reproductive epithelium.

We observed that, in mice consuming an RA- diet, ovariectomy increased maximum survival time by 40%. No difference was observed between ovariectomized and intact mice consuming RA+ diets within the 50 wk of the study. Although ovariectomy increased the survival time of mice consuming the RA- diet, it increased rather than decreased the amount of squamous metaplastic lesions in the uterine horns. This leads us to conclude that, in our experimental system, squamous metaplasia is not a major factor in mortality. To our knowledge, this is the first time that ovariectomy has been shown to lengthen the survival time of vitamin A–deficient mice.

As for the mechanism of this effect, we could suggest that in the absence of estrogen there is slower use of liver retinoids. However, this notion is unlikely because squamous metaplasia appeared at about the same time in ovariectomized as in intact animals. Furthermore, we know from previous work that this lesion only appears after liver retinol and retinyl ester pools are nearly exhausted (9, 10). An alternative explanation is receptor crosstalk at the DNA level. Although it seems unlikely that the estrogen receptor and retinoid receptors interact under normal physiologic conditions, it is conceivable they may affect each other during ligand imbalance, possibly resulting in increased survival. A third possibility is that steroid depletion alters energy utilization. This would result in significant differences in body weight for the 2 groups. Our measurements indicate that there was a significant (P < 0.0001; n = 20 per group) albeit small difference in body weight: an average of 33.54 and 31.98 g for the ovariectomized and intact groups fed the RA- diet, respectively, ie, a difference of 4.9%. A larger difference (9.5%) was observed for the groups fed the RA+ diet in which the ovariectomized animals weighed, on average, 36.19 g compared with 33.06 g for the intact animals. We think that, although there was a difference in body weight due to ovariectomy, it was small enough that it may not have been the principle reason for the dramatic change in survival.

Finally, we suggest that a likely explanation for the observed difference in survival is a vital, higher-order function of vitamin A other than its role in epithelial differentiation. It was emphasized recently that retinoic acid functions in the brain and in the pituitary gland by regulating the expression of the dopamine receptor D2R gene, which contains a retinoic acid response element (11). Moreover, knockout mice for the D2R gene exhibit a defect in locomotor ability similar to that seen in Parkinson disease. This important finding suggests that functions of retinoic acid that are morphologically "invisible" when the animal is made vitamin A–deficient might be fundamental to survival and perhaps interface with steroid hormone function in as-yet unknown ways.


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  		TABLE 2. Squamous metaplastic cells in reproductive tract sections of female SENCAR mice fed a vitamin A–deficient diet (RA–) with or without ovariectomy1
 

   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
  1. Wolbach SB, Howe PR. Tissue changes following deprivation of fat-soluble A-vitamin. J Exp Med 1925;42:753–78.[Abstract]
  2. De Luca LM, Kosa K, Andreola F. The role of vitamin A in differentiation and skin carcinogenesis. J Nutr Biochem 1997;8:426–37.
  3. Sporn MB, Dunlop NM, Newton DL, Smith JM. Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc 1976;35:1332–8.[Medline]
  4. De Luca LM, Darwiche N, Jones CS, Scita G. Retinoids in differentiation and neoplasia. Sci Med 1995;2:28–37.
  5. Celli G, Darwiche N, De Luca LM. Estrogen induces retinoid receptor expression in mouse cervical epithelia. Exp Cell Res 1996; 226:273–82.[Medline]
  6. Hsu SM, Raine L, Fanger H. A comparative study of the peroxidase-antiperoxidase method and an avidin-biotin complex method for studying polypeptide hormones with radioimmunoassay antibodies. Am J Clin Pathol 1981;75:734–8.[Medline]
  7. Darwiche N, Celli G, Sly L, Lancillotti F, De Luca LM. Retinoid status controls the appearance of reserve cells and keratin expression in mouse cervical epithelium. Cancer Res 1993;53:2287–99.[Abstract/Free Full Text]
  8. Jetten AM, De Luca LM, Nelson K, Schroeder W, Burlingame S, Fujimoto W. Regulation of cornifin {alpha} expression in the vaginal and uterine epithelium by estrogen and retinoic acid. Mol Cell Endocrinol 1996;123:7–15.[Medline]
  9. Shankar S, Creek KE, De Luca LM. The effect of the progression of vitamin A deficiency on glucose, galactose and mannose incorporation into sugar phosphates and sugar nucleotides in hamster liver. J Nutr 1990;120:361–74.
  10. Shankar S, De Luca LM. Retinoic acid supplementation of a vitamin A deficient diet inhibits retinoid loss from hamster liver and serum pools. J Nutr 1988;118:675–80.
  11. Valdenaire O, Maus-Moatti M, Vincent JD, Mallet J, Vernier P. Retinoic acid regulates the developmental expression of dopamine D2 receptor in rat striatal primary cultures. J Neurochem 1998;71:929–36.[Medline]
Received for publication February 10, 1999. Accepted for publication June 9, 1999.




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