Separate Critical Periods Exist for Testosterone-Induced Differentiation of the Brain and Genitals in Sheep

Abstract

Sheep exposed to testosterone during a critical period from gestational day (GD) 30 to GD 90 develop masculine genitals and an enlarged male-typical ovine sexually dimorphic nucleus of the preoptic area (oSDN). The present study tested the hypothesis that separate critical periods exist for masculinization of these two anatomical end points. Pregnant ewes were treated with testosterone propionate (TP) either from GD 30 to GD 60 (early TP) or GD 60 to GD 90 (late TP). Control (C) pregnant ewes were treated with corn oil. Fetuses were delivered at GD 135 and the volume of the oSDN was measured. Early TP females possessed a penis and a scrotum devoid of testes, whereas late TP and C females had normal female genitals. Neither period of TP exposure grossly affected the genitals of male fetuses. Despite masculinized genitals, the mean volume of the oSDN in early TP females (0.32 ± 0.06 mm³) was not different from C females (0.24 ± 0.02 mm³) but was significantly enlarged in late TP females (0.49 ± 0.04 mm³; P < 0.05 vs. C) when the genitals appeared normal. In contrast, the volume of the oSDN in late TP males (0.51 ± 0.02 mm³) was not different from C males (0.51 ± 0.04 mm³) but was significantly smaller in the early TP males (0.35 ± 0.04 mm³; P < 0.05 vs. C). These results demonstrate that the prenatal critical period for androgen-dependent differentiation of the oSDN occurs later than, and can be separated temporally from, the period for development of masculine genitals.

Adult digit ratio (2D:4D) is not related to umbilical cord androgen or estrogen concentrations, their ratios or net bioactivity

“…The current evidence shows a more marked sex difference in fetal testosterone concentrations in mid-gestation compared to levels measured at birth [43]. However, there is increasing recognition from experimental studies that the effect of prenatal sex steroid exposure on postnatal development is not restricted to early fetal development and that sex steroid levels in the final trimester also contribute to fetal development [41,56]. Furthermore, evidence from studies examining relationships between umbilical cord sex steroids and subsequent development [10,19,22,23,39,55], indicate that these sex steroid concentrations are informative markers for childhood development.…”

Ontogeny of Cytochrome P450 Aromatase mRNA Expression in the Developing Sheep Brain

“…The gestational stage of pregnancy was defined as the time after mating (gestational day 1 (GD 1) = 24 h after mating). Lamb fetuses of various gestational ages ± 2 days (i.e., GD 53, 65, 85, 100, 120, and 135) were delivered surgically as described previously (32). Three to six fetuses of each sex were studied at each age.…”

Prenatal testosterone exposure is related to sexually dimorphic facial morphology in adulthood

“…A limitation of this approach is that testosterone levels in cord blood may not reflect concentrations during the first and second trimester, in particular gestational weeks 8-24, which has traditionally been regarded as a 'sensitive period' for the maximal effects of sex steroids on human development [24]. However, there is increasing recognition that there may be multiple sensitive periods, and animal studies have found that postnatal development may be affected by hormones at different times throughout prenatal development [25]. Human studies have also started to link sex steroids from umbilical cord blood to a range of childhood behaviours, including language development [26,27], internalizing and externalizing behaviours [28], and spatial abilities [29].…”