This article is from the WSSF 2012 AFRMA Rat & Mouse Tales news-magazine.

By Karen Robbins and Carmen Jane Booth, D.V.M., Ph.D.

TERMS:

Vaginal atresia – imperforation or occlusion of the vaginal cavity.

Imperforation – the condition of being abnormally occluded or closed; lacking a normal opening.

Occlusion – to be obstructed from any cause

Perineum – area between the vaginal opening and the anus.

Prolapse – to fall out of place

Hermaphrodite – has gonadal tissue (ovary and testis) of both male and female, can be mixed ovary and testis or have one ovary and one testis. The external genitalia can be ambiguous; genetically can be XY or XX.

Pseudohermaphrodite – has external genitalia of one sex, and the gonadal tissue of the other; genetically can be XXY, XY, XX.

Mucometra – uterus filled up with mucoid (mucous) fluid

Hydrometra – uterus filled up with fluid

Mice with vaginal atresia are females that are lacking the vaginal opening and have swellings in the perineum area that look like testicles. They can also have a swollen abdomen when they are older due to fluid (water, or mucoid) buildup in the uterus. These female mice are mistakenly called hermaphrodites and thought to be males by many fanciers; they are not capable of reproducing. This is also referred to as imperforation or occlusion of the vagina; also called colpatresia.

*In females, pelvic organ prolapse has a similar perineal bulge but these mice are capable of reproducing. In males, herniation of abdominal contents into the scrotum can have a similar perineal bulge/swelling but these mice are capable of reproducing as long as the testes are not compromised.

Intersexes are animals where elements of both genders are present at the same time. When this occurs, the animal has a genetic defect. In all mammals, during embryogenesis, the gonads, internal and external reproductive organs differentiate into either male or female under the control of different genes. All mammals will develop into females regardless of genotype (XX, XY) unless specific genes on the Y chromosome are both present and functioning normally. Male animals differentiate into males early and females late during embryogenesis.

The specific genes responsible for testis-determining factor (TDF) are located on the short arm of the Y chromosome that induce the embryonic gonadal tissue to become a testis. Without TDF, the embryonic gonad will develop into an ovary.

Next, there are the accessary glands and ducts. In the embryo for a brief period of time, there are both the mesonephric (Wolffian) and paramesonephric (Mullerian) ducts and tubules present that will form either the male or female accessary glands or ducts respectively. In males, under the influence of hormones (Mullerian inhibiting substance [MIS], dihydrotestosterone [DHT]), produce the fetal testis and TDF, the Wolffian ducts develop into glands (seminal vesicles, prostate, coagulating gland, etc.) and ducts that connect the testis to the urethra as well as drive the differentiation of the external genitalia into the glans penis. At the same times MIS causes regression of the Mullerian ducts.

In contrast, in the female, the role is largely passive. When there is no TDF or MIS, the embryonic gonadal tissue develops into an ovary, and the Mullerian ducts develop into the fallopian tubes, uterus, cervix, and upper part of the vagina. Without the presence of DHT, the mesonephric (Wolffian) ducts regress passively. Again without DHT, the remainder of the vagina and external genitalia (labia, clitoris) develop as female.

Therefore, gender differentiation is very complex and under the influence of different genes and hormones at key points in embryogenesis. If there is any problem in any phase of the process due to genetic mutations, you can end up with either a true or pseudohermaphrodite with ambiguous external genitalia. Further, there can be variable presence of any parts derived from both the Wolffian or Mullerian ducts and tubules.

Where the upper and lower parts of the vagina meet, if there is a problem, the result can be vaginal atresia or imperforate vagina.

There is a great deal written up on this in relation to domestic animals (dogs, cats, horses, cattle, etc.¹).

Everything I could find on hermaphrodites talks about/shows male mice with very small testicles—female parts inside that you wouldn’t know unless you cut them open. If our mice were hermaphrodites (males with female parts), you wouldn’t be able to put them with another male to keep company like the mice we have which are females, or they would be fighting. Also, these mice have nipples (females) where males don’t.

A 4-month-old Reverse Siamese Standard female from 2008 with vaginal atresia. She has a large swelling.

In my experience, of the ones produced here at Karen’s Kritters with vaginal atresia and kept to be friends for males, there have been no health issues and they live long normal lives. Some will get huge swellings, others just large swellings.

When I first found this issue, I put down the mom and entire litter and only if I found the male (father) producing it in more than one litter, I then put the male down. After talking with our vet, Dr. Carmen Jane Booth, about this (when I thought we were dealing with hermaphrodites) and her telling me that it (hermaphroditism) is genetic and passed from the fathers as well, I then started tracking it and found this problem (vaginal atresia) does indeed pass down like this. I’ve had males never produce one until their very last litter in old age, others when they are young, so you can’t tell when it might happen from the male’s side. In the females, I’ve had it show up in the first litters, others not until later litters. Some females from the same litter will produce it where their siblings don’t. I had two lines of mice that it originally showed up in and when it was happening in every litter produced, I then cut the entire line from my colony. I have done a couple test breedings of brother x sister siblings (sister had vaginal atresia) to verify it being a recessive trait and it was produced, so it is definitely genetic from both parents. Recently I had it show up in a line that had not had anything for 5 generations that I thought was clean (with these, the first litter from the parents had nothing, but the second and third repeat litters produced one in each litter; out of the females from the first litter that was clean, one didn’t produce any with issues and the other one ate her kids so I don’t know if she would have had any with the problem [bred back to dad on each], so I’m going to do some more test breedings to see if I can salvage this line).

...and a side view of the Reverse Siamese.

. . and another side view of the Reverse Siamese cece, a.k.a. Stone in N.M.C. The swelling looks like testicles.

 

A 9-week-3-day-old Blue Point Himi female (chc dd) with vaginal atresia from 2011.

A side view of a 9-week-3-day-old Blue Point Himi female (chc dd) with vaginal atresia from 2011. It got a little more swollen since this photo. This mouse did get a big belly as an adult like what is talked about in the various articles but lived a normal long life.

...and a side view of the Blue Point Himi.

Of all the litters produced here with vaginal atresia, only one female will show up with the problem in a litter (doesn’t matter how many in the litter). Since this is a recessive trait, it would be possible to get more in a litter if the lines being worked with weren’t having this problem being selected against.

The females with vaginal atresia will look normal until they hit 6 weeks (to the day on most) then suddenly they have a swelling and you think you mis-sexed someone. I’ve had a couple show the problem around 5 weeks but the majority not until 6 weeks. Also, I’ve been able to see the beginnings of the swelling just a couple days prior to it fully developing on a couple of females but normally you don’t know it until the full swelling is there. I just had one produced that had a bit of swelling, then it went away, then a bit of swelling, then nothing, etc., but looking closely she had no hole going inside so she did have the vaginal atresia (this from a new line that had never produced it for the 3 years I’ve had them and they are heavily inbred). I did cut one open once (after the mouse died) to see what the perineum swelling was made of, and it was just fluid which matches what the articles talk about.

These female mice with vaginal atresia have the vaginal opening spot but upon close examination there is no hole going inside. I’ve been trying to eliminate it from my stock as I consider it something that should not be perpetuated (I know a lot of breeders don’t think it is serious and continue to breed lines that have it)—it is very frustrating to get a promising looking litter/females and then this pops up.

An 8 week 6 day Ivory Satin female (cec, a.k.a. B.E. Cream in N.M.C.) showing the vaginal opening (hole going inside).

...and her Reverse Siamese Satin (cece, a.k.a. Stone in N.M.C.) sister with the vaginal opening sealed off. She is the one that had just a bit of swelling off and on since she was 5 weeks 0 days old (she is showing some swelling here).

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Vaginal Atresia in a rat, December 14, 2017

Dec. 14, 2017, Vaginal Atresia in a rat: A 4.5-month-old Russian Blue Berkshire female showing the swelling like testicles.

...and the bottom view of the 4.5-month-old Russian Blue Berkshire female showing the swelling like testicles.

The 4.5-month-old Russian Blue Berkshire female showing no vaginal opening (hole going inside, sealed off).

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References/Further Reading:

1. Color Atlas of Reproductive Patholoy of Domestic Animals, Buergelt CD, 1997, Mosby.

Vaginal Atresia articles specific to mice:

Research articles and photos match with what our mice are

This article describes it perfectly and says that it is hereditary: Pathology of vaginal atresia in BALB/cA-nu/+ and BALB/cA-nu/nu mice by Matsushita S, Matsumoto T. Jikken Dobutsu. 1984 Jul;33(3):365–8.
www.ncbi.nlm.nih.gov/pubmed/6499938

High incidence of distal vaginal atresia in mice lacking Tyro3 RTK subfamily by Wu H, Tang H, Chen Y, Wang H, Han D. Molecular Reproduction and Development. 2008 Dec;75(12):1775–82.www.ncbi.nlm.nih.gov/pubmed/%2018393392

This article from PNAS (Proceedings of the National Academy of Sciences) has photos that match our mice: Common and specific roles of the related CDK inhibitors p27 and p57 revealed by a knock-in mouse model by Etsuo Susakia, Keiko Nakayamab, Lili Yamasaki, and Keiichi I. Nakayama. PNAS, March 31, 2009, vol. 106 no. 13, 5192–5197. www.pnas.org/content/106/13/5192.full.pdf; and Fig. 2 (E) from the full article where you can see the photo in a larger size of one with vaginal atresia atresiawww.pnas.org/content/106/13/5192/F2.large.jpg

Fancy Mice Breeders forum
www.fancymicebreeders.com/phpBB3/viewtopic.php?f=21&t=4085&sid=deca09d3d2da893261decf3976a92b37&a,p;start=0

Vaginal Imperforation

Gene detail for vaginal imperforation (vgim) mutation - Lhfpl2: describes them with closed vagina, soft swelling of the perineum, and buildup of viscous fluid in the uteri, Lhfpl2: lipoma HMGIC fusion partner-like 2
www.informatics.jax.org/marker/MGI:2145236

(2011) Jackson Laboratory web site article tells about complete closure of the vagina, soft, reducible swelling of the perineum, and seen in mice at 4–5 weeks: Vaginal imperforation; a new mutation on Chromosome 13 causing a reproductive phenotype by Son Yong Karst, Patricia F. Ward-Bailey, Linda L.Washburn, David E. Bergstrom, Leah Rae Donahue, and Muriel T. Davisson-Fahey. Site: Research and resources, Genetic resource science, Mouse Mutant Resource https://web.archive.org/web/20150510181131/http://mousemutant.jax.org/articles/mmrmutantvgim.html

(2008) NCBI web site tells about and shows a 10-week-old mouse with perineal swelling, occluded vaginal opening so fluid produced during the estrous cycles is retained, resulting in uterine and vaginal distension: Perineal swelling in a mouse by Irene Ginty, BS, LATG and Shelley Hoogstraten-Miller, DVM, MS, DACLAM. Lab Anim (NY). 2008 May; 37(5): 196–199. www.ncbi.nlm.nih.gov/pmc/articles/PMC2597298/

(1990) Jackson Laboratory web site article describing distention and atony (slackness, debility) of the vagina, cervix, and uterus, and being a recessive trait: Imperforate Vagina and Mucometra in Mice by John P. Sundberg, DVM, PhD. JAX® NOTES Issue 441, Spring 1990. https://www.jax.org/news-and-insights/1990/april/imperforate-vagina-and-mucometra-in-mice

(1989) PubMed for imperforate vagina (ipv) describes a marked swelling of the perineum, complete closure of the vagina, is a recessive trait, and the uterus and vagina were greatly distended by fluid: A recessive mutation causing imperforate vagina in mice by Eisen EJ, Hauser ME, Pomp D, Anderson SG, Newbold RR, McCormick GY. Journal of Heredity. 1989 Nov–Dec; 80(6):478–82. www.ncbi.nlm.nih.gov/pubmed/2614062

Vaginal Occlusion

(1936) This article describes a perineal hernia seen at puberty and later an expanded belly; vagina ends blindly. The Anatomical Record Volume 66, Issue 4, pages 449–454, November 1936: Vaginal occlusion, an abnormality in mice by Lore Marx. http://onlinelibrary.wiley.com/doi/10.1002/ar.1090660408/abstract

*Perineal Bulge/Pelvic Organ Prolapse

Mice with a perineal bulge that usually happens after they give birth; they are capable of reproducing

(2009) This article describes pelvic organ prolapse as not developing until later in life. Biology of Reproduction March 1, 2009, vol. 80 no. 3, 407–414: Quantification of Pelvic Organ Prolapse in Mice: Vaginal Protease Activity Precedes Increased MOPQ Scores in Fibulin 5 Knockout Mice by Cecilia K. Wieslander, David D. Rahn, Donald D. McIntire, Jesús F. Acevedo, Peter G. Drewes, Hiromi Yanagisawa, and R. Ann Word. www.biolreprod.org/content/80/3/407.full

(2008) American Journal of Physiology (AJP) - Renal Physiology August 2008 vol. 295 no. 2, F545–F555: Lower urogenital tract anatomical and functional phenotype in lysyl oxidase like-1 knockout mice resembles female pelvic floor dysfunction in humans by Una J. Lee, A. Marcus Gustilo-Ashby, Firouz Daneshgari, Mei Kuang, Drina Vurbic, Dan Li Lin, Chris A. Flask, Tiansen Li, and Margot S. Damaser. https://journals.physiology.org/doi/full/10.1152/ajprenal.00063.2008

Regarding males, this article describes and shows drawings that look like some male mice I have gotten that have a big testicle area (big rears) but never keep: Sexual Development and Fertility of Loxl1-/- Male Mice by Hadley M. Wood, Una J. Lee, Drina Vurbic, Edmund Sabanegh, Jonathan H. Ross, Tiansen Li, and Margot S. Damaser. Journal of Andrology, Vol. 30, No. 4, July/August 2009, pages 452–459. http://onlinelibrary.wiley.com/doi/10.2164/jandrol.108.006122/pdf

Hermaphrodite

Propagation of an infertile hermaphrodite mouse lacking germ cells by using nuclear transfer and embryonic stem cell technology by Sayaka Wakayama, Satoshi Kishigami, Nguyen Van Thuan, Hiroshi Ohta, Takafusa Hikichi, Eiji Mizutani, Ryuzo Yanagimachi, and Teruhiko Wakayama. Proceedings of the National Academy of Sciences USA (PNAS), January 4, 2005, vol. 102 no. 1, 29–33. www.pnas.org/content/102/1/29.full.pdf

An article on pseudohermaphroditism: Testicular Feminization of the Mouse by Janardan K. Reddy, MD, and Susumu Ohno, DVM, PhD. American Journal of Pathology. 1981 April; 103(1): 96–104. www.ncbi.nlm.nih.gov/pmc/articles/PMC1903810/pdf/amjpathol00217-0100.pdf

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