Testosterone enhancement during pregnancy influences the 2D:4D ratio and open field motor activity of rat siblings in adulthood

Talarovičová, Alžbeta; Kršková, Lucia; Blažeková, Jana

doi:10.1016/j.yhbeh.2008.10.010

Cited by 129 publications

(108 citation statements)

References 31 publications

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“…The difference in scale between mouse and human digit ratios, along with differences among mouse strains, might explain the variable results of previous studies of rodent digit ratios (12,14,24,25). The dimorphism of 2D:4D ratios between male and female mice examined by us (this study) and by others (12) is considerably less pronounced than that reported for humans.…”

Section: Discussioncontrasting

confidence: 61%

Developmental basis of sexually dimorphic digit ratios

Zheng

Cohn

2011

Proc. Natl. Acad. Sci. U.S.A.

576

568

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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),...

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Section: Discussioncontrasting

confidence: 61%

Developmental basis of sexually dimorphic digit ratios

Zheng

Cohn

2011

Proc. Natl. Acad. Sci. U.S.A.

576

568

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“…Nevertheless, our results suggest indirectly that the developmental basis of 2D : 4D should be similar in mice, rats and humans [11,28]. Only two studies on digit length ratios in rats have been published, both indicating that testosterone supply or prenatal exposures modifying testosterone levels modulate forepaw digit length and digit ratios in prepubertal rats [26,27]. In humans and mice, various conditions are more frequently associated with right rather than left 2D : 4D [29,30].…”

Section: Discussionmentioning

confidence: 59%

Environmental levels of oestrogenic and antiandrogenic compounds feminize digit ratios in male rats and their unexposed male progeny

Auger¹,

Denmat

Berges

et al. 2013

Proc. R. Soc. B.

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Digit length ratios, especially the second-to-fourth digit ratio (2D : 4D), are associated with various pathological and behavioural conditions in many species including humans and are dependent upon prenatal androgen to oestrogen balance. It is unknown whether digit ratios are modified by environmental exposure to ubiquitous endocrine disruptors. We studied the effect on adult male Wistar rat digit ratios of a gestational exposure to the oestrogenic and antiandrogenic compounds bisphenol A (BPA), genistein and vinclozolin, in low doses, and in combination with investigating in parallel a possible sexual dimorphism of this trait. We also investigated the effects on the male progeny not exposed during gestation. X-rays were taken of the left and right forepaws, and 2D-5D proximal to distal phalanx distances were measured by a standardized procedure based on semi-automatic image analysis. We provide evidence that there is a sexual dimorphism of digit ratios in the Wistar rat, and we found that BPA alone or in combination with genistein and vinclozolin significantly feminized digit ratios in male rats. Intriguingly, significant feminization of digit ratios was also found in the unexposed male progeny of males that had been exposed to compound mixtures. In conclusion, prenatal environmental levels of endocrine-active substances permanently disrupt digit ratios. Digit ratio measurement in adults is thus a promising biomarker of prenatal exposure to low-dose endocrine disruptors in rodents, with potential implications for future studies in humans.

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“…For instance in the human endometrium, HOXA10 mRNA levels are enhanced by oestradiol acting through the ERs (Taylor et al 1998;Akbas et al 2004) but repressed by testosterone acting through the AR (Cermik et al 2003). In line with this, it has been found that digit ratio correlates with perinatal sex hormone levels in humans (Lutchmaya et al 2004; but see also Medland et al 2008) and, in birds and rats, is affected by experimental sex hormone treatment (Saino et al 2007;Talarovičová et al 2009; but see Romano et al 2005). Also, men with complete androgen insensitivity owing to non-functional ARs show digit ratios typical of women (Berenbaum et al 2009).…”

Section: Introductionmentioning

confidence: 76%

“…Future studies could help to clarify whether this is related to the observation that in mammals, as a rule, males have lower digit ratios than females, while reversed sexual dimorphism seems to prevail among amphibians, reptiles and birds (Chang 2008). More data on mammals is clearly needed, given that the association with the AR genotype is based on only 50 individuals (Manning et al 2003) plus 16 individuals with non-functional ARs (Berenbaum et al 2009), and that the experimental treatment with testosterone has only been applied to three pregnant female rats (Talarovičová et al 2009). These sample sizes are too small to reliably estimate effect sizes (see above).…”

Section: Discussionmentioning

confidence: 99%

“…More experimental studies will be needed to pinpoint the developmental time window during which digit ratio is affected by (and hence will be an indicator of) sex hormones. Positive evidence for sex hormone effects on digit ratio points to early (Saino et al 2007) or late (Talarovičová et al 2009) embryo development, while juvenile digit growth seems to be unaffected by oestrogen treatment (Forstmeier et al 2008). One possibility is that the sex hormones affect HOX gene expression in the developing limb bud and thereby shift the anterior -posterior axis, such that the entire morphology of the second digit (or the fourth digit, respectively) would become more 'third-digit like'.…”

Section: Discussionmentioning

confidence: 99%

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A polymorphism in the oestrogen receptor gene explains covariance between digit ratio and mating behaviour

2010

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In vertebrates, including humans, the relative length of the second to the fourth digit correlates with sex hormone-dependent behavioural, psychological and physiological traits. However, despite a decade of research, the underlying mechanism linking digit ratio to these sex hormone-dependent traits remains unclear. Previous work suggests that during embryo development, circulating levels of plasma androgens or oestrogens may act through their receptors to affect transcription levels of posterior HOX genes in the developing digits, thereby possibly influencing their relative length. The correlation between digit ratio and sex hormone-dependent traits might thus stem from variation in expression or sensitivity of the sex hormone receptors, or from variation in sex hormone levels in the embryo. Here, we show that in a population of 1156 zebra finches Taeniopygia guttata, a polymorphism in the oestrogen receptor a gene (ESR1) explains 11.3 per cent of the variation in digit ratio, and is also associated with male and female-mating behaviour. By contrast, we found no associations between digit ratio or mating behaviours and polymorphisms in the androgen receptor gene. Thus, our results (i) provide an explanation for the observed significant genetic covariance between digit ratio and male and female mating behaviour and (ii) strongly confirm the indicator function of digit ratio through the oestrogen pathway. Finally, we note that the commonly invoked effect of foetal testosterone on human digit ratio seems to be substantially weaker than the effect described here.

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Testosterone enhancement during pregnancy influences the 2D:4D ratio and open field motor activity of rat siblings in adulthood

Cited by 129 publications

References 31 publications

Developmental basis of sexually dimorphic digit ratios

Developmental basis of sexually dimorphic digit ratios

Environmental levels of oestrogenic and antiandrogenic compounds feminize digit ratios in male rats and their unexposed male progeny

A polymorphism in the oestrogen receptor gene explains covariance between digit ratio and mating behaviour

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