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Sexual Development and Fertility of Loxl1^–/– Male Mice

DRINA VURBIC

TIANSEN LI

MARGOT S. DAMASER^*,,

From the ^* Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio; the Research Service, Wade Park Cleveland Veterans Affairs Medical Center, Cleveland, Ohio; The Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; and the Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.

Correspondence to: Dr Margot Damaser, Department of Biomedical Engineering, The Cleveland Clinic, 9500 Carnegie Ave ND20, Cleveland, OH 44195 (e-mail: damasem{at}ccf.org).

Abstract

Our objective was to investigate the genitourinary defects and fertility of the male lysyl oxidase-like 1 gene (Loxl1) knockout (Loxl1^–/–) mouse, with particular attention to fecundity and testicular, epididymal, gubernacular, and penile histopathology, which may lead us to a better understanding of the role of the elastin-homeostasis gene, LOXL1, in male sexual development. Genital morphometric evaluation of 6- to 9-month-old male Loxl1^–/– mice (n = 26) was compared with C57Bl/6 controls (n = 24). Measurements included: body weight, scrotal development, evidence of feminization (nipples or vaginal pouch), penile malformations, anogenital distance, and absence/presence and size of perineal bulge. Sperm production was estimated using a standardized technique. A breeding program was conducted to determine how much of the infertility observed in Loxl1^–/– pairs was due to the male factor. Finally, we performed histopathologic comparison of the genitourinary organs of Loxl1^–/– and control mice. Loxl1^–/– mice weighed less than their age-matched C57Bl/6 counterparts (P < .001). Size-adjusted perineal bulge was larger (P < .001), and resting location of the gonads was higher intra-abdominally (P = .048) in the Loxl1^–/– mice. Estimates of daily sperm counts revealed that the Loxl1^–/– mice had lower sperm production (P = .048). Loxl1^–/– males bred with control females demonstrated relative fecundity values intermediate between Loxl1^–/– pairs (lowest fecundity) and control pairs (highest fecundity), suggesting a component of male-factor infertility. No histologic differences were noted using hematoxylin-eosin or specialized elastin staining of the gonads, gubernaculum, and penis. Although further studies are warranted, these findings suggest a subtle and likely multifactorial role of the LOXL1 protein in male sexual development and fertility.

     Key words: Mouse, elastin, penis, reproductive tract, semen analysis, testis, mouse model