Archives of Sexual Behavior

, Volume 37, Issue 1, pp 9–18

Intrauterine Position Effects on Anogenital Distance and Digit Ratio in Male and Female Mice

  • Peter L. Hurd
  • Allison A. Bailey
  • Patricia A. Gongal
  • Reginia H. Yan
  • John J. Greer
  • Silvia Pagliardini
Original Paper: Minot Special Issue

Abstract

Anogenital distance (AGD) and the ratio of the second (index) to fourth (ring) digit lengths (2D:4D) are two widely used indicators of prenatal androgen exposure. The former is commonly used in rodent models, while the latter is principally used in human studies. We investigated variation in these two traits in C57BL/6J mice to test the hypothesis that variation in these two traits reflect a common underlying variable, presumably testosterone exposure. AGD is a sexually dimorphic trait used to sex young rodents. This distance typically increases and becomes more male-like in females pups when their uterine neighbors are male. 2D:4D is sexually dimorphic in a number of species, including humans and other great apes. Lower digit ratios may be associated with greater exposure to androgens during fetal development in humans. We found the expected sexual dimorphism in AGD, but no significant sex difference in 2D:4D, and no correlation between 2D:4D and AGD. Gestating next to males increased a pup’s 2D:4D ratio, but it had no effect on AGD. The lack of correlation between 2D:4D and AGDs in this mouse strain suggests that these two measures do not reflect a common influence of androgen exposure. The possible roles of temporal and localized effects of masculinization are discussed.

Keywords

Intrauterine position Digit ratio 2D:4D Anogenital distance Masculinization 

References

  1. Austin, E. J., Manning, J. T., McInroy, K., & Mathews, E. (2002). A preliminary investigation of the associations between personality, cognitive ability and digit ratio. Personality and Individual Differences, 33, 1115–1124.CrossRefGoogle Scholar
  2. Bailey, A. A., & Hurd, P. L. (2005). Finger length ratio (2D:4D) predicts physical aggression in men but not women. Biological Psychology, 68, 215–222.PubMedCrossRefGoogle Scholar
  3. Bailey, A. A., Wahlsten, D., & Hurd, P. L. (2005). Digit ratio (2D:4D) and behavioral differences between inbred mouse strains. Genes, Brain, and Behavior, 4, 318–323.PubMedCrossRefGoogle Scholar
  4. Benderlioglu, Z., & Nelson, R. J. (2004). Digit length ratios predict reactive aggression in women, but not in men. Hormones and Behavior, 46, 558–564.PubMedCrossRefGoogle Scholar
  5. Berenbaum, S. A., & Reinisch, J. M. (1997). Early androgen effects on aggression in children and adults with congenital adrenal hyperplasia. Psychoneuroendocrinology, 22, 505–515.PubMedCrossRefGoogle Scholar
  6. Brown, W. M., Finn, C. J., Bradley, M. C., & Breedlove, S. M. (2002). Differences in finger length ratios between self-identified “butch” and “femme” lesbians. Archives of Sexual Behavior, 31, 123–127.PubMedCrossRefGoogle Scholar
  7. Brown, W. M., Finn, C. J., & Breedlove, S. M. (2002). Sexual dimorphism in digit-length ratios of laboratory mice. Anatomical Record, 267, 231–234.PubMedCrossRefGoogle Scholar
  8. Burley, N. T., & Foster, V. S. (2004). Digit ratio varies with sex, egg order, and strength of mate preference in zebra finches. Proceedings of the Royal Society of London, 271, 239–244.CrossRefGoogle Scholar
  9. Clark, M. M., & Galef, B. G. J. (1995). Prenatal influences on reproductive life history strategies. Trends in Ecology and Evolution, 10, 151–153.CrossRefGoogle Scholar
  10. Clark, M. M., Robertson, R. K., & Galef, B. G. J. (1996). Effects of perinatal testosterone on handedness in gerbils: Support for part of the Geschwind-Galaburda hypothesis. Behavioral Neuroscience, 110, 1–5.Google Scholar
  11. Cohen-Bendahan, C. C. C., van de Beek, C., & Berenbaum, S. A. (2005). Prenatal sex hormone effects on child and adult sex-typed behavior: Methods and findings. Neuroscience and Biobehavioral Reviews, 29, 353–384.PubMedCrossRefGoogle Scholar
  12. Csathó, A., Osváth, A., Bicsák, E., Karádi, K., Manning, J., & Kállai, J. (2003). Sex role identity related to the ratio of second to fourth digit length in women. Biological Psychology, 62, 147–156.PubMedCrossRefGoogle Scholar
  13. Dohler, K. D., & Wuttke, W. (1975). Changes with age in levels of serum gonadotropins, prolactin, and gonadal steroids in prepubertal male and female rats. Endocrinology, 97, 898–907.PubMedGoogle Scholar
  14. Efron, B., & Tibshirani, R. J. (1994). Introduction to the bootstrap. New York: Chapman & Hall.Google Scholar
  15. Even, M. D., Dhar, M. G., & vom Saal, F. S. (1992). Transport of steroids between fetuses via amniotic fluid in relation to the uterine position in rats. Journal of Reproduction and Fertility, 96, 709–716.PubMedCrossRefGoogle Scholar
  16. Forstmeier, W. (2005). Quantitative genetics and behavioural correlates of digit ratio in the zebra finch. Proceedings: Biological Sciences/The Royal Society, 272, 2641–2649.CrossRefGoogle Scholar
  17. Gil, D., Graves, J., Hazon, N., & Wells, A. (1999). Male attractiveness and differential testosterone investment in zebra finch eggs. Science, 286, 126–128.PubMedCrossRefGoogle Scholar
  18. Goy, R. W., Bercovitch, F. B., & McBrair, M. C. (1988). Behavioral masculinization is independent of genital masculinization in prenatally androgenized female rhesus macaques. Hormones and Behavior, 22, 552–571.PubMedCrossRefGoogle Scholar
  19. Gupta, C. (2000). Reproductive malformation of the male offspring following maternal exposure to estrogenic chemicals. Proceedings of the Society for Experimental Biology and Medicine, 224, 61–68.PubMedCrossRefGoogle Scholar
  20. Hall, L. S., & Love, C. T. (2003). Finger-length ratios in female monozygotic twins discordant for sexual orientation. Archives of Sexual Behavior, 32, 23–28.PubMedCrossRefGoogle Scholar
  21. Hines, M., Brook, C., & Conway, G. S. (2004). Androgen and psychosexual development: Core gender identity, sexual orientation, and recalled childhood gender role behavior in women and men with congenital adrenal hyperplasia. Journal of Sex Research, 41, 75–81.PubMedCrossRefGoogle Scholar
  22. Hines, M., Fane, B. A., Pasterski, V. L., Mathews, G. A., Conway, G. S., & Brook, C. (2002). Spatial abilities following prenatal androgen abnormality: Targeting and mental rotations performance in individuals with congenital adrenal hyperplasia. Psychoenuroendocrinology, 28, 1010–1026.CrossRefGoogle Scholar
  23. Houtsmuller, E. J., Thornton, J., & Rowland, D. L. (1997). Using a regression approach to study the influence of male fetuses on the genital morphology of neonatal female rats. Multivariate Behavioral Research, 32, 77–94.CrossRefGoogle Scholar
  24. Husmann, D. A., & Cain, M. P. (1994). Microphallus: Eventual phallic size is dependent on the timing of androgen administration. Journal of Urology, 152, 734–739.PubMedGoogle Scholar
  25. Hutchison, J. B., Beyer, C., Green, S., & Wozniak, A. (1994). Brain formation of oestrogen in the mouse: Sex dimorphism in aromatase development. Journal of Steroid Biochemistry and Molecular Biology, 49, 407–415.PubMedCrossRefGoogle Scholar
  26. Hutchison, J. B., Wozniak, A., Beyer, C., Karolczak, M., & Hutchison, R. E. (1999). Steroid metabolising enzymes in the determination of brain gender. Journal of Steroid Biochemistry and Molecular Biology, 69, 85–96.PubMedCrossRefGoogle Scholar
  27. Kaufman, M. H. (1994). Atlas of mouse development. London: Academic Press.Google Scholar
  28. Leoni, B., Canova, L., & Saino, N. (2005). Sexual dimorphism in metapodial and phalanges length ratios in the wood mouse. Anatomical Record, 286A, 955–961.CrossRefGoogle Scholar
  29. Lephart, E. D., Lund, T. D., & Horvath, T. L. (2001). Brain androgen and progesterone metabolizing enzymes: Biosynthesis, distribution and function. Brain Research Reviews, 37, 25–37.PubMedCrossRefGoogle Scholar
  30. Levy, J. B., & Husmann, D. (1996). Congenital adrenal hyperplasia: Is there an effect on penile growth? Journal of Urology, 156, 780–782.PubMedCrossRefGoogle Scholar
  31. Lippa, R. A. (2003). Are 2D:4D finger-length ratios related to sexual orientation? Yes for men, no for women. Journal of Personality and Social Psychology, 85, 179–188.PubMedCrossRefGoogle Scholar
  32. Lutchmaya, S., Baron-Cohen, S., Raggatt, P., Knickmeyer, R., & Manning, J. T. (2004). 2nd to 4th digit ratios, fetal testosterone and estradiol. Early Human Development, 77, 23–28.PubMedCrossRefGoogle Scholar
  33. MacLusky, N. J., & Naftolin, F. (1981). Sexual differentiation of the central nervous system. Science, 211, 1294–1303.PubMedCrossRefGoogle Scholar
  34. MacLusky, N. J., Walters, M. J., Clark, A. S., & Toran-Allerand, C. D. (1994). Aromatase in the central cortex, hippocampus, and mid-brain: Ontogeny and developmental implications. Molecular and Cellular Neurosciences, 5, 691–698.PubMedCrossRefGoogle Scholar
  35. Manning, J. T. (2002). Digit ratio: A pointer to fertility, behavior, and health. New Brunswick, NJ: Rutgers University Press.Google Scholar
  36. Manning, J. T., Barley, L., Walton, J., Lewis-Jones, D., Trivers, R. L., Singh, D., et al. (2000). The 2nd:4th digit ratio, sexual dimorphism, population differences, and reproductive success: Evidence for sexually antagonistic genes. Evolution and Human Behavior, 21, 163–183.PubMedCrossRefGoogle Scholar
  37. Manning, J. T., Bundred, P. E., Newton, D. J., & Flanigan, B. F. (2003). The second to fourth digit ratio and variation in the androgen receptor gene. Evolution and Human Behavior, 24, 399–405.CrossRefGoogle Scholar
  38. Manning, J. T., Callow, M., & Bundred, P. E. (2003). Finger and toe ratios in humans and mice: Implications for the aetiology of diseases influenced by HOX genes. Medical Hypotheses, 60, 340–343.PubMedCrossRefGoogle Scholar
  39. Manning, J. T., Stewart, A., Bundred, P. E., & Trivers, R. L. (2004). Sex and ethnic differences in 2nd to 4th digit ratio of children. Early Human Development, 80, 161–168.PubMedCrossRefGoogle Scholar
  40. Manoli, I., Kanaka-Gantenbein, C., Voutetakis, A., Maniati-Christidi, M., & Dacou-Voutetakis, C. (2002). Early growth, pubertal development, body mass index and final height of patients with congenital adrenal hyperplasia: Factors influencing the outcome. Clinical Endocrinology, 57, 669–676.PubMedCrossRefGoogle Scholar
  41. Martin, J. T., & Nguyen, D. H. (2004). Anthropometric analysis of homosexuals and heterosexuals: Implications for early hormone exposure. Hormones and Behavior, 45, 31–39.PubMedCrossRefGoogle Scholar
  42. McFadden, D. (2002). Masculinization effects in the auditory system. Archives of Sexual Behavior, 31, 99–111.PubMedCrossRefGoogle Scholar
  43. McFadden, D., & Bracht, M. S. (2005). Sex differences in the relative lengths of metacarpals and metatarsals in gorillas and chimpanzees. Hormones and Behavior, 47, 99–111.PubMedCrossRefGoogle Scholar
  44. McFadden, D., Loehlin, J. C., Breedlove, S. M., Lippa, R. A., Manning, J. T., & Rahman, Q. (2005). A reanalysis of five studies on sexual orientation and the relative length of the 2nd and 4th fingers (the 2D:4D ratio). Archives of Sexual Behavior, 34, 341–356.PubMedCrossRefGoogle Scholar
  45. McFadden, D., & Shubel, E. (2002). Relative lengths of fingers and toes in human males and females. Hormones and Behavior, 42, 492–500.PubMedCrossRefGoogle Scholar
  46. McMahon, D. R., Kramer, S. A., & Husmann, D. A. (1995). Micropenis: Does early treatment with testosterone do more harm than good? Journal of Urology, 154, 825–829.PubMedCrossRefGoogle Scholar
  47. McMechan, A. P., O’Leary-Moore, S. K., Morrison, S. D., & Hannigan, J. H. (2004). Effects of prenatal alcohol exposure on forepaw digit length and digit ratios in rats. Developmental Psychobiology, 45, 251–258.PubMedCrossRefGoogle Scholar
  48. Morishima, A., Grumbach, M., Simpson, E., Fisher, C., & Qin, K. (1995). Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. Journal of Clinical Endocrinology and Metabolism, 80, 3689–3698.PubMedCrossRefGoogle Scholar
  49. Naftolin, F., & MacLusky, N. (1984). Aromatization hypothesis revisited. In M. Serio, M. Motta, M. Zanisi, & L. Marini (Eds.), Sexual differentiation: Basic and clinical aspects (Vol. 11, pp. 79–91). New York: Raven Press.Google Scholar
  50. Nagao, T., Wada, K., Kuwagata, M., Nakagomi, M., Watanabe, C., Yoshimura, S., et al. (2004). Intrauterine position and postnatal growth in Sprague Dawley rats and ICR mice. Reproductive Toxicology, 18, 109–120.PubMedCrossRefGoogle Scholar
  51. New, M. I. (2004). An update of congenital adrenal hyperplasia. Annals of the New York Academy of Sciences, 1038, 14–43.PubMedCrossRefGoogle Scholar
  52. Öz, O. K., Millsaps, R., Welch, R., Birch, J., & Zerwekh, J. E. (2001). Expression of aromatase in the human growth plate. Journal of Molecular Endocrinology, 27, 249–253.PubMedCrossRefGoogle Scholar
  53. Peters, M., Tan, U., Kang, Y., Teixeira, L., & Mandal, M. (2002). Sex-specific finger-length patterns linked to behavioral variables: Consistency across various human populations. Perceptual and Motor Skills, 94, 171–181.PubMedCrossRefGoogle Scholar
  54. Premawardhana, L. D. K. E., Hughes, I. A., Read, G. F., & Scanlon, M. F. (1997). Longer term outcome in females with congenital adrenal hyperplasia (CAH): The Cardiff experience. Clinical Endocrinology, 46, 327–332.PubMedCrossRefGoogle Scholar
  55. R Development Core Team. (2004). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.Google Scholar
  56. Rahman, Q., & Wilson, G. D. (2003). Sexual orientation and the 2nd to 4th finger length ratio: Evidence for organizing effects of sex hormones or developmental instability? Psychoneuroendocrinology, 28, 288–303.PubMedCrossRefGoogle Scholar
  57. Reinisch, J. M. (1981). Prenatal exposure to synthetic progestins increases potential for aggression in humans. Science, 211, 1171–1173.PubMedCrossRefGoogle Scholar
  58. Resko, J. A., Feder, H. H., & Goy, R. W. (1968). Androgen concentrations in plasma and testis of developing rats. Journal of Endocrinology, 40, 485–491.PubMedCrossRefGoogle Scholar
  59. Romano, M., Rubolini, D., Martinelli, R., Alquati, A. B., & Saino, N. (2005). Experimental manipulation of yolk testosterone affects digit length ratios in the ring-necked pheasant (Phasianus colchicus). Hormones and Behavior, 48, 342–346.PubMedCrossRefGoogle Scholar
  60. Rubolini, D., Pupin, F., Sacci, R., Gentilli, A., Zuffi, M. A. L., Galeotti, P., et al. (2006). Sexual dimorphism in digit length ratios in two lizard species. Anatomical Record, 288A, 491–497.CrossRefGoogle Scholar
  61. Ryan, B. C., & Vandenbergh, J. G. (2002). Intrauterine position effects. Neuroscience and Biobehavioral Reviews, 26, 665–678.PubMedCrossRefGoogle Scholar
  62. Saino, N., Rubolini, D., Romano, M., & Boncoraglio, G. (2007). Increased egg estradiol concentration feminizes digit ratios of male pheasants (Phasianus colchicus). Naturwissenschaften, doi: 10.1007/s00114-006-0188-9.
  63. Sasano, H., Uzuki, M., Sawai, T., Nagura, H., Matsunaga, G., Kashimoto, O., et al. (1997). Aromatase in human bone tissue. Journal of Bone and Mineral Research, 12, 1416–1423.PubMedCrossRefGoogle Scholar
  64. Simon, N. G., & Cologer-Clifford, A. (1991). In utero contiguity to males does not influence morphology, behavioral sensitivity to testosterone, or hypothalamic androgen binding in CF-1 female mice. Hormones and Behavior, 25, 518–530.PubMedCrossRefGoogle Scholar
  65. Sutherland, R. S., Kogan, B. A., Baskin, L. S., Mevorach, R. A., Conte, F., Kaplan, S., et al. (1996). The effect of prepubertal androgen exposure on adult penile length. Journal of Urology, 156, 783–787.PubMedCrossRefGoogle Scholar
  66. Svare, B., Kinsley, C. H., Mann, M. A., & Broida, J. (1984). Infanticide: Accounting for genetic variation in mice. Physiology and Behavior, 33, 137–152.PubMedCrossRefGoogle Scholar
  67. Timms, B. G., Petersen, S. L., & vom Saal, F. S. (1999). Prostate gland growth during development is stimulated in both male and female rat fetuses by intrauterine proximity to female fetuses. Journal of Urology, 161, 1694–1701.PubMedCrossRefGoogle Scholar
  68. Tobet, S. A., Baum, M. J., Tang, H. B., Shim, J. H., & Canick, J. A. (1985). Aromatase activity in the perinatal rat forebrain: Effects of age, sex and intrauterine position. Developmental Brain Research, 25, 171–178.CrossRefGoogle Scholar
  69. Turkelson, C. M., Dunlap, J. L., MacPhee, A. A., & Gerall, A. A. (1977). Assay of perinatal testosterone and influence of anti-progesterone and theophylline on induction of sterility. Life Sciences, 21, 1149–1157.PubMedCrossRefGoogle Scholar
  70. van Anders, S. M., Vernon, P. A., & Wilbur, C. J. (2006). Finger-length ratios show evidence of prenatal hormone-transfer between opposite-sex twins. Hormones and Behavior, 49, 315–319.PubMedCrossRefGoogle Scholar
  71. vom Saal, F. (1984). The intrauterine position phenomenon: Effects on physiology, aggressive behavior and population dynamics in house mice. In K. Flannelly, R. Blanchard, & D. Blanchard (Eds.), Biological perspectives on aggression (pp. 135–179). New York: Alan R. Liss.Google Scholar
  72. vom Saal, F. S. (1989). Sexual differentiation in litter bearing animals: Influence of sex of adjacent fetuses in utero. Journal of Animal Sciences, 67, 1824–840.Google Scholar
  73. vom Saal, F. S., Grant, W. M., McMullen, C. W., & Laves, K. S. (1983). High fetal estrogen concentrations: Correlations with increased sexual activity and decreased aggression in male mice. Science, 220, 1306–1309.PubMedCrossRefGoogle Scholar
  74. vom Saal, F. S., Timms, B. G., Montano, M. M., Planza, P., Thayer, K. A., & Thayer, K. A. (1997). Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite at high doses. Proceedings of the National Academy of Sciences of the United States of America, 94, 2056–2061.PubMedCrossRefGoogle Scholar
  75. Weisz, J., & Ward, I. I. (1980). Plasma testosterone and progesterone titers of pregnant rats, their male and female fetuses, and neonatal offspring. Endocrinology, 106, 306–316.PubMedCrossRefGoogle Scholar
  76. Williams, T. J., Pepitone, M. E., Christensen, S. E., Cooke, B. M., Huberman, A. D., Breedlove, N. J., et al. (2000). Finger-length ratios and sexual orientation. Nature, 404, 455–456.Google Scholar
  77. Woodson, J. C., & Gorski, R. A. (1999). Structural sex differences in the mammalian brain: Reconsidering the male/female dichotomy. In A. Matsumoto (Ed.), Sexual differentiation of the brain (pp. 229–255). Boca Raton, FL: CRC Press.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Peter L. Hurd
    • 1
  • Allison A. Bailey
    • 1
  • Patricia A. Gongal
    • 1
  • Reginia H. Yan
    • 1
  • John J. Greer
    • 1
  • Silvia Pagliardini
    • 1
  1. 1.Department of PsychologyUniversity of AlbertaEdmontonCanada

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