Skip to main content

Advertisement

SpringerLink
Log in

Identifying craniofacial features associated with prenatal exposure to androgens and testing their relationship with brain development

  • Original Article
  • Published:
Brain Structure and Function Aims and scope Submit manuscript

Abstract

We used magnetic resonance (MR) images obtained in same-sex and opposite-sex dizygotic twins (n = 119, 8 years of age) to study possible effects of prenatal androgens on craniofacial features. Using a principal component analysis of 19 craniofacial landmarks placed on the MR images, we identified a principal component capturing craniofacial features that distinguished females with a presumed differential exposure to prenatal androgens by virtue of having a male (vs. a female) co-twin (Cohen’s d = 0.76). Subsequently, we tested the possibility that this craniofacial “signature” of prenatal exposure to androgens predicts brain size, a known sexually dimorphic trait. In an independent sample of female adolescents (singletons; n = 462), we found that the facial signature predicts up to 8 % of variance in brain size. These findings are consistent with the organizational effects of androgens on brain development and suggest that the facial signature derived in this study could complement other indirect measures of prenatal exposure to androgens.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Anblagan D, Jones NW, Costigan C, Parker AJJ, Allcock K, Aleong R, Coyne LH, Deshpande R, Fenning NR, Bugg G, Roberts N, Pausova Z, Paus T, Gowland PA (2013) Maternal smoking during pregnancy and fetal organ growth: a magnetic resonance imaging study. PLoS One 8(6):e67223. doi:10.1371/journal.pone.0067223

  • Anders Van, Verhon PA (2006) Finger-length ratios show evidence of prenatal hormone transfer between opposite-sex twins. Horm Behav 49:315–319

    Article  PubMed  Google Scholar 

  • Avants BB, Epstein CL, Grossman M, Gee JC (2008) Symmetric diffeomorphic image registration with cross-correlation: evaluating automated labeling of elderly and neurodegenerative brain. Med Image Anal 12(1):26–41

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Baker JH, Lichtenstein P, Kendler KS (2009) Intrauterine testosterone exposure and risk for disordered eating. Br J Psychiatry 194:375–376

    Article  PubMed Central  PubMed  Google Scholar 

  • Bartley AJ, Jones DW, Weinberger DR (1997) Genetic variability of human brain size and cortical gyral patterns. Brain 120(2):257–269

    Article  PubMed  Google Scholar 

  • Borghammer P, Ostergaard K, Cumming P, Gjedde A, Rodell A, Hall N, Chakravarty MM (2010) A deformation-based morphometry study of patients with early-stage Parkinson’s disease. Eur J Neurol 17(2):314–320

    Article  CAS  PubMed  Google Scholar 

  • Bulygina E, Mitteroecker P, Aiello L (2006) Ontogeny of facial dimorphism and patterns of individual development within one human population. Am J Phys Anthropol 131:432–443

    Article  CAS  PubMed  Google Scholar 

  • Chakravarty M, Aleong R, Leonard G, Perron M, Pike B, Richer L, Veillette S, Pausova Z, Paus T (2011) Automated analysis of craniofacial morphology using magnetic resonance images. PLoS One 6(5):e20241. doi:10.1371/journal.pone.0020241

  • Chen WJ, Maier SE, Parnell SE, West JR (2003) Alcohol and the developing brain: neuroanatomical studies. Alcohol Res Health 27(2):174–180

    PubMed  Google Scholar 

  • Chura LR, Lombardo MV, Ashwin E, Auyenung B, Chakrabarti B, Bullmore ET, Cohen SB (2010) Organizational effects of fetal testosterone on human corpus callosum size and asymmetry. Psychoneuroendocrinology 35(1):122–132

  • Clemens LG, Gladue BA, Coniglio LP (1978) Prenatal endogenous androgenic influences on masculine sexual behavior and genital morphology in male and female rats. Horm Behav 10:40–53

    Article  CAS  PubMed  Google Scholar 

  • Cohen-Bendahan CCC, Buitelaar JK, van Goozen SMH, Cohen-Kettenis PT (2004) Prenatal exposure to testosterone and functional cerebral lateralization: a study in same-sex and opposite-sex twin girls. Psychoneuroendocrinology 29:911–916

    Article  CAS  PubMed  Google Scholar 

  • Cohen-Bendahan CCC, van de Beek C, Berenbaum SA (2005) Prenatal sex hormone effects on child and adult sex-typed behavior: methods and findings. Neurosci Biobehav Rev 29:353–384

    Article  CAS  PubMed  Google Scholar 

  • Collins DL, Holmes CJ, Peters TM, Evans AC (1994) Automatic 3-D model-based neuroanatomical segmentation. Hum Brain Mapp 3(3):190–208

    Article  Google Scholar 

  • Cootes TF, Taylor CJ (1992) Active shape models – ‘smart snakes’. In: Hogg D, Boyle R (eds) BMVC92. Springer-Verlag, London, pp 266–275

  • Couly GF, Coltey PM, Le Douarin NM (1993) The triple origin of skull in higher vertebrates: a study in quail-chick chimeras. Development 117:409–429

    CAS  PubMed  Google Scholar 

  • Dempsey PJ, Townsend GC, Richards LC (1999) Increased crown size in females with twin brothers: evidence for hormonal diffusion between human twins in utero. Am J Hum Biol 11:577–586

    Article  PubMed  Google Scholar 

  • Diewert VM, Lozanoff S (1993) A morphometric analysis of human embryonic craniofacial growth in the median plane during primary palate formation. J Craniofac Genet Dev Biol 13:184–192

    Google Scholar 

  • Diewert VM, Lozanoff S, Choy V (1993) Computer reconstructions of human embryonic craniofacial morphology showing changes in relations between the face and brain during primary palate formation. J Craniofac Genet Dev Biol 13(3):193–201

    CAS  PubMed  Google Scholar 

  • Even MD, Dhar MG, vom Saal FS (1992) Transport of steroids between fetuses via amniotic fluid in relation to the intrauterin position phenomenon in rats. J Reprod Fertility 96:709–716

    Article  CAS  Google Scholar 

  • Fink B, Grammer K, Mitteroecker P, Gunz P, Schaefer K, Bookstein FL, Manning IT (2005) Second to fourth digit ratio and face shape. Proc R Soc Lond B Biol Sci 272:1995–2000

    Article  Google Scholar 

  • Frey S, Pandya DN, Chakravarty MM, Bailey L, Petrides M, Cllins L (2011) An MRI based average macaque monkey stereotaxic atlas and space (MNI monkey space). Neuroimage 55(4):1435–1442

    Article  PubMed  Google Scholar 

  • Galsworthy MJ, Dionne G, Dale PS, Plomin R (2000) Sex differences in early verbal and non-verbal cognitive development. Dev Sci 3:206–215

    Article  Google Scholar 

  • Grabner G, Janke AL, Budge MM, Smith D, Pruessner J, Collins DL (2006) Symmetric atlasing and model based segmentation: an application to the hippocampus in older adults. Med Image Comput Comput Assist Interv 9(Pt 2):58–66

    PubMed  Google Scholar 

  • Guihard-Costa AM, Khung S, Delbecque K, Menez F, Delezoide AL (2006) Biometry of face and brain in fetuses with trisomy 21. Pediatr Res 59:33–38

    Article  PubMed  Google Scholar 

  • Henderson BA, Berenbaum SA (1997) Sex-typed play in opposite-sex twins. Dev Psychobiol 31:115–123

    Article  CAS  PubMed  Google Scholar 

  • Hönekopp J, Bartholdt L, Beier L, Liebert A (2007) Second to fourth digit length ratio (2D:4D) and adult sex hormone levels: new data and a meta-analytic review. Psychoneuroendocrinology 32(4):313–321

    Article  PubMed  Google Scholar 

  • Isaacs EB, Fischl BR, Quinn BT, Chong WK, Gadian DG, Lucas A (2010) Impact of breast milk on IQ, brain size and white matter development. Pediatr Res 67(4):357–362

    Article  PubMed Central  PubMed  Google Scholar 

  • Kinsley C, Miele J, Konen C, Ghiraldi L, Svare B (1986) Intrauterine contiguity influences regulatory activity in adult female and adultmale-mice. Horm Behav 20:7–12

    Article  CAS  PubMed  Google Scholar 

  • Knickmeyer RC, Wheelwright S, Taylor K, Raggatt P, Hackett G, Baron-Cohen S (2005) Gender-typed play and amniotic testosterone. Dev Psychol 41:517–528

    Article  PubMed  Google Scholar 

  • Kontges G, Lumsden A (1996) Rhombencephalic neural crest segmentation is preserved throughout craniofacial ontogeny. Development 122:3229–3242

    CAS  PubMed  Google Scholar 

  • Larkby C, Day N (1997) The effects of prenatal alcohol exposure. Alcohol Health Res World 21(3):192–198

    CAS  PubMed  Google Scholar 

  • Liu F, van der Lijn F, Schurmann C, Zhu G, Chakravarty MM et al (2012) A genome-wide association study identifies five loci influencing facial morphology in europeans. PLoS Genet 8(9):1–13

    Article  CAS  Google Scholar 

  • Lombardo MV, Ashwin E, Auyeung B, Chakrabarti B, Taylor K, Hackett G, Bullmore ET, Baron-Cohen S (2012) Fetal testosterone influences sexually dimorphic gray matter in the human brain. J Neurosci 32(2):674–680

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Manning JT, Stewart A, Bundred PE, Trivers RL (2004) Sex and ethnic differences in 2nd to 4th digit ratio of children. Early Hum Dev 80(2):161–168

    Article  CAS  PubMed  Google Scholar 

  • Manning JT, Churchill JGA, Peters M (2007) The effects of sex, ethnicity, and sexual orientation of sef-measured digit ratio (2D:4D). Arch Sex Behav 36(2):223–233

    Article  PubMed  Google Scholar 

  • Marečková K, Weinbrand Z, Chakravarty MM, Lawrence C, Aleong R, Leonard G et al (2011) Testosterone-mediated sex differences in the face shape during adolescence: subjective impressions and objective features. Horm Behav 60(5):681–690

    Article  PubMed  Google Scholar 

  • Marečková K, Chakravarty MM, Huang M, Lawrence C, Leonard G, Perron M (2013) Does skull shape mediate the relationship between objective features and subjective impressions about the face? Neuroimage 79:234–240

    Article  PubMed  Google Scholar 

  • McIntyre MH (2006) The use of digit ratios as markers for perinatal androgen action. Reprod Biol Endocrinol 4(10). doi:10.1186/1477-7827-4-10

  • Medland SE, Loehlin JC, Willemsen G, Hatemi PK, Keller MC, Boomsma DI, Eaves LJ, Martin NG (2008) Males do not reduce the fitness of their female cotwins in contemporary samples, Twin Res. Hum Genet 11:481–487

    Google Scholar 

  • Meindl K, Windhager S, Wallener B, Schaefer K (2012) Second-to-fourth digit ratio and facial shape in boys: the lower the digit ratio, the more robust the face. Proc R Soc B 279(1737):2457–2463

    Article  PubMed Central  PubMed  Google Scholar 

  • Miller EM (1994) Prenatal sex hormone transfer: a reason to study opposite-sex twins. Personal Individ Differ 17:511–529

    Article  Google Scholar 

  • Muenke M, Beachy PA (2000) Genetics of ventral forebrain development and holoprosencephaly. Curr Opin Genet Dev 10:262–269

    Article  CAS  PubMed  Google Scholar 

  • Neave N, Laing S, Fink B, Manning JT (2003) Second to fourth digit ratio, testosterone and perceived male dominance. Proc R Soc Lond B 270:2167–2172

    Article  Google Scholar 

  • Noden DM (1978) The control of Avian cephalic neural crest cytodifferentiation: skeletal and connective tissues. Dev Bio 96:144–165

    Article  Google Scholar 

  • Paus T (2010) Sex differences in the human brain: a developmental perspective. Prog Brain Res 186:13–28

    Article  PubMed  Google Scholar 

  • Paus T (2013) Population neuroscience. Springer-Verlag, Berlin, Heidelberg, ISBN-10: 3642364497

  • Paus T, Bernard M, Chakravarty MM, Smith GD, Gillis J, Lourdusamy A, Leonard G, Melka MG, Pavlidis P, Perron M, Pike GB, Richer L, Schumann G, Timpson N, Toro R, Veillette S, Pausova Z (2012) KCTD8 gene and brain growth in adverse intrauterine environment: a genome-wide association study. Cereb Cortex 22:2634–2642

    Article  PubMed Central  PubMed  Google Scholar 

  • Pausova Z, Paus T, Abrahamowicz M, Almerigi J, Arbour N, Bernard M et al (2007) Genes, maternal smoking, and the offspring brain and body during adolescence: design of the Saguenay Youth Study. Hum Brain Mapp 28:502–518

    Article  PubMed  Google Scholar 

  • Peper JS, Brouwer RM, van Baal G, Schnack H, leeuwen M, Boomsma D, Kahn R, Pol H (2009) Does having a twin brother make for a bigger brain? Eur J Endocrinol 160:739–746

    Article  CAS  PubMed  Google Scholar 

  • Phoenix CH, Goy RW, Gerall AA, Young WC (1959) Organizing action of prenatally administered testosterone propionáte on the tissue mediating mating behavior in the female guinea pig. Endocrinology 65:369–382

    Article  CAS  PubMed  Google Scholar 

  • Pujol J, Soriano-Mas C, Gispert JD, Bossa M, Reig S, Ortiz H et al (2011) Variation in the shape of the frontobasal brain region in obsessive–compulsive disorder. Hum Brain Mapp 32:1100–1108

    Article  PubMed  Google Scholar 

  • Quadagno DM, McQuitty C, McKee J, Koelliker L, Wolfe G, Johnson DC (1987) The effects of intrauterine position on competition and behavior in the mouse. Physiol Behav 41:639–642

    Article  CAS  PubMed  Google Scholar 

  • Rainey WE, Rehman KS, Carr BR (2004) The human fetal adrenal: making adrenal androgens for placental estrogens. Semin Reprod Med 22:327–336

    Article  CAS  PubMed  Google Scholar 

  • Ryan BC, Vandenberg JG (2002) Intrauterine position effects. Neurosci Biobehav Rev 26:665–678

    Article  PubMed  Google Scholar 

  • Sarkar P, Bergman K, Fisk NM, O’Connor TG, Glover V (2007) Amniotic fluid testosterone: relationship with cortisol and gestational age. Clin Endocrinol (Oxf) 67:743–747

    Article  CAS  Google Scholar 

  • Sibson R (1978) Studies in the robustness of multidimensional scaling: procrustes statistics. J Roy Stat Soc 40:234–238

    Google Scholar 

  • Sled JG, Zijdenbos AP, Evans AC (1998) A nonparametric method for automatic correction of intensity nonuniformity in MRI data. IEEE Trans Med Imaging 17:87–97

    Article  CAS  PubMed  Google Scholar 

  • Smith SM (2002) Fast robust automated brain extraction. Hum Brain Mapp 17(3):143–155

    Article  PubMed  Google Scholar 

  • Smith SM, De Stefano N, Jenkinson M, Matthews PM (2001) Normalised accurate measurement of longitudinal brain change. J Comput Assist Tomogr 25(3):466–475

    Article  CAS  PubMed  Google Scholar 

  • Smith SM, Zhang Y, Jenkinson M, Chen J, Matthews PM, Federico A, De Stefano N (2002) Accurate, robust and automated longitudinal and cross-sectional brain change analysis. Neuroimage 17(1):479–489

    Article  PubMed  Google Scholar 

  • Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TEJ, Johansen-Berg H et al (2004) Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23(S1):208–2019

    Article  Google Scholar 

  • Sperber GH, Sperber SM, Guttmann GD (2000) Craniofacial embryogenetics and development, Shelton, CT: People’s Medical Pub. House, USA

    Google Scholar 

  • Tapp AL, Maybery MT, Whitehouse AJO (2011) Evaluating the twin testosterone transfer hypothesis: a review of the empirical evidence. Horm Behav 60:713–722

    Article  CAS  PubMed  Google Scholar 

  • Valla K, Halazonetis DJ (2014) Correlation of 2D:4D digit ratio and craniofacial shape in prepubertal children. Am J Hum Biol 26(3):337–346

  • Van de Beek C, Thijssen JHH, Cohen-Kettenis PT, van Goozen SHM, Buitelaar JK (2004) Relationships between sex hormones assessed in amniotic fluid, and maternal and umbilical cord serum: what is the best source of information to investigate the effects of fetal hormonal exposure? Horm Behav 46:663–669

    Article  PubMed  Google Scholar 

  • vom Saal FS, Bronson FH (1980) Sexual characteristics of adult female mice are correlated with their blood testosterone levels during prenatal development. Science 208:597–599

    Article  Google Scholar 

  • Voracek M, Dressler SG (2007) Digit ratio (2D:4D) in twins: heritability estimates and evidence for a masculinized trait expression in women from opposite-sexpairs. Psychol Rep 100:115–126

    Article  PubMed  Google Scholar 

  • Zhang Y, Brady M, Smith S (2001) Segmentation of brain MR images through a hidden Markov random field model and the expectation maximization algorithm. IEEE Trans Med Imaging 20(1):45–57

    Article  CAS  PubMed  Google Scholar 

  • Zheng Z, Cohn MJ (2011) Developmental basis of sexually dimorphic digit ratios. Proc Nat Acad Sci 108:16289–16294

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zingeser MR, Phoenix CH (1978) Metric characteristics of the canine dental complex in prenatally androgenized female rhesus monkeys (Macaca mulatta). Am J Phys Anthrop 49:187–192

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The Saguenay Youth Study was funded by the Canadian Institute of Health Research, Heart and Stroke Foundation of Quebec, and the Canadian Foundation of Innovation. The Quebec Newborn Twin Study was funded by Canadian Institute of Health Research and Fonds de la recherche en santé du Quebec. We would like to thank SciNet for access to its supercomputer platform, which is funded by the Canada Foundation for Innovation, NSERC, the Government of Ontario, FedDev Ontario, and the University of Toronto. Finally, we would also like to thank the European Social Fund and the government of Czech Republic who co-financed the project „Employment of Newly Graduated Doctors of Science for Scientific Excellence (grant number CZ.1.07/2.3.00/30.0009).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Rotman Research Institute, University of Toronto, 3560 Bathurst Street, Toronto, ON, M6A 2E1, Canada

    Klára Marečková, Mallar M. Chakravarty & Tomáš Paus

  2. School of Psychology, University of Nottingham, Nottingham, NG72RD, UK

    Klára Marečková, Claire Lawrence, Zdenka Pausova & Tomáš Paus

  3. Behavioral and Social Neuroscience Research Group, CEITEC-Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic

    Klára Marečková

  4. Centre for Addiction and Mental Health, 250 College St., Toronto, ON, M5T1R8, Canada

    Mallar M. Chakravarty

  5. Department of Psychiatry, University of Toronto, 250 College Street, Toronto, ON, M5T 1R8, Canada

    Mallar M. Chakravarty

  6. Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, M5S 3G9, Canada

    Mallar M. Chakravarty

  7. Montréal Neurological Institute, McGill University, Montréal, QC, H3A 2B4, Canada

    Gabriel Leonard

  8. CHU Sainte-Justine, 3175 Chemin de la Cote, Sainte-Catherine, Montreal, QC, H3T 1C5, Canada

    Daniel Perusse

  9. ECOBES, Recherche et transfert, Cegep de Jonquière, Jonquière, QC, G7X 3W1, Canada

    Michel Perron & Suzanne Veillette

  10. Université du Québec a Chicoutimi, Saguenay, QC, G7H 2B1, Canada

    Michel Perron & Suzanne Veillette

  11. Département des sciences de la santé, Université du Québec à Chicoutimi, Chicoutimi, QC, G7H 2B1, Canada

    Bruce G. Pike & Louis Richer

  12. The Hospital of Sick Children, Toronto, ON, M5G 1X8, Canada

    Zdenka Pausova

  13. Centre de recherche, Centre hospitalier de l’Université de Montréal, Montreal, QC, H2L 4M1, Canada

    Zdenka Pausova

Authors
  1. Klára Marečková
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mallar M. Chakravarty
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claire Lawrence
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gabriel Leonard
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel Perusse
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michel Perron
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bruce G. Pike
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Louis Richer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Suzanne Veillette
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zdenka Pausova
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tomáš Paus
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tomáš Paus.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 31 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Marečková, K., Chakravarty, M.M., Lawrence, C. et al. Identifying craniofacial features associated with prenatal exposure to androgens and testing their relationship with brain development. Brain Struct Funct 220, 3233–3244 (2015). https://doi.org/10.1007/s00429-014-0852-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00429-014-0852-3

Keywords

Search

Navigation