Developmental basis of sexually dimorphic digit ratios

Abstract

Males and females generally have different finger proportions. In males, digit 2 is shorter than digit 4, but in females digit 2 is the same length or longer than digit 4. The second-to fourth-digit (2D:4D) ratio correlates with numerous sexually dimorphic behavioral and physiological conditions. Although correlational studies suggest that digit ratios reflect prenatal exposure to androgen, the developmental mechanism underlying sexually dimorphic digit development remains unknown. Here we report that the 2D:4D ratio in mice is controlled by the balance of androgen to estrogen signaling during a narrow window of digit development. Androgen receptor (AR) and estrogen receptor α (ER-α) activity is higher in digit 4 than in digit 2. Inactivation of AR decreases growth of digit 4, which causes a higher 2D:4D ratio, whereas inactivation of ER-α increases growth of digit 4, which leads to a lower 2D:4D ratio. We also show that addition of androgen has the same effect as inactivation of ER and that addition of estrogen mimics the reduction of AR. Androgen and estrogen differentially regulate the network of genes that controls chondrocyte proliferation, leading to differential growth of digit 4 in males and females. These studies identify previously undescribed molecular dimorphisms between male and female limb buds and provide experimental evidence that the digit ratio is a lifelong signature of prenatal hormonal exposure. Our results also suggest that the 2D:4D ratio can serve as an indicator of disrupted endocrine signaling during early development, which may aid in the identification of fetal origins of adult diseases.limb development | sexual dimorphism | steroid hormones I n human hands, the relative lengths of the second and fourth fingers differ between males and females. In males, the second digit (2D, or index finger) is usually shorter than the fourth digit (4D, or ring finger), whereas in females the index finger is generally equal to or longer than the ring finger (Fig. 1A). The ratio of 2D length to 4D length, known as the 2D:4D ratio, is therefore 2D:4D < 1 for most men and 2D:4D $ 1 for most women. This sexually dimorphic character of the limb was described >120 y ago (1), but it was not until 1998 that the 2D:4D ratio was linked to sex steroids by the observation that men with lower 2D:4D ratios have higher serum testosterone and lower estrogen levels (2). The discovery that sexually dimorphic digit ratios exist in 2-y-old children raised the possibility that 2D:4D ratios are determined early in life (2). These studies led to the hypothesis that a low 2D:4D ratio reflects embryonic exposure to high levels of testosterone, whereas a high 2D:4D ratio reflects a prenatal environment low in testosterone (3). This hypothesis has not been tested experimentally.There has been increasing use of the 2D:4D ratio as an index of prenatal hormone exposure, and extensive studies in humans have found correlations between digit ratios and a variety of physiological and psychological conditions, including fertility (4),...

Digit ratio (2D:4D) in newborns: Influences of prenatal testosterone and maternal environment

“…The lack of correlation with the mother's 2D:4D could result from a high level of testosterone in the prenatal environment during digit-forming stages of embryonic development. Digit development is a complex process, involving the regulation of genes' expression by testosterone and estrogen [10] and high testosterone might induce a level of individual variability capable of breaking down correlation between males' 2D:4D and their mothers' 2D:4D. We also have not found correlation between males' 2D:4D and AF testosterone.…”

“…This has further been corroborated by work showing that variation in 2D:4D correlates with androgen receptor activity in men, as indicated by the number of CAG repeats in the androgen receptor allele [9]. More recently, an experimental study [10] with a mouse strain known to be sexually dimorphic, provided compelling evidence that prenatal testosterone and estrogen determine mouse 2D:4D during embryonic development, with sex steroids controlling digit development by regulating the skeletogenic expression of at least 19 genes. The 2D:4D ratio at birth should thus reflect a genetic background subjected to a given level of prenatal androgen and estrogen exposure.…”

Digit Ratio (2D:4D) and Attachment Styles in Middle Childhood: Indirect Evidence for an Organizational Effect of Sex Hormones

“…The fourth digit tends to be shorter in females; as a result, females have higher digit ratios than males. Digit ratios develop prenatally, and are partly determined by the balance of androgen and estrogen signaling during the time window for digit development in the fetus (see Berenbaum et al 2009;Manning et al 2014;Zheng and Cohn 2011). While the prenatal origin of digit ratios has been established conclusively, there is suggestive evidence that-at least in humans-sex hormones levels in early infancy may further contribute to individual and sex differences in relative finger length (Galis et al 2010;Knickmeyer et al 2011).…”

Females Have Larger Ratio of Second‐to‐Fourth Digits Than Males in Four Species of Salamandridae, Caudata

“…These changes occur through the ability of sex hormones to alter the expression of genes encoding the structural information of soft tissues and bone components in terminal limb buds and other sexually selected structures during sensitive phases coinciding with hormone production (Phoenix et al, 1959;Block et al, 2000;Daftary and Taylor, 2006;Zheng and Cohn, 2011). The overarching theory is that 2D:4D acts as a "readout" of the programming effects of sex hormones on the fetal brain and body, and that this period may impact adult sex-linked traits and behaviors.…”