Developmental vitamin D deficiency increases foetal exposure to testosterone

Area of Science:

• Neurodevelopmental disorders
• Endocrinology
• Environmental health

Background:

• Autism spectrum disorder (ASD) is more prevalent in males, and the prenatal sex steroid hypothesis suggests excessive fetal sex steroid exposure contributes to ASD.
• Environmental factors like developmental vitamin D (DVD) deficiency are linked to ASD, but the mechanism remains unclear.
• DVD deficiency in an animal model showed placental inflammation in male fetuses and Vitamin D's role in regulating steroidogenic enzymes.

Purpose of the Study:

• To investigate if DVD deficiency leads to increased sex-steroid levels in maternal and fetal compartments using an animal model.
• To explore potential molecular mechanisms, including gene expression and DNA methylation, underlying altered sex steroid levels.

Main Methods:

• Female rats were fed a vitamin D deficient diet before mating and throughout gestation.
• Levels of testosterone, androstenedione, and corticosterone were measured in maternal plasma, fetal brains, and amniotic fluid.
• Gene expression of steroidogenic enzymes and DNA methylation of aromatase promoters in fetal brains were analyzed.

Main Results:

• DVD deficiency increased maternal blood testosterone levels.
• Elevated testosterone and androstenedione were found in the amniotic fluid of female, but not male, DVD-deficient fetuses.
• Testosterone levels were higher in male fetal brains, associated with hyper-methylation of the aromatase promoter.

Conclusions:

• This study demonstrates how an environmental risk factor (DVD deficiency) can selectively increase testosterone in male embryonic brains.
• Findings provide mechanistic support for the prenatal sex steroid theory of ASD.
• Reduced aromatase due to hyper-methylation may contribute to excessive testosterone and potentially impact estradiol levels.