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Mouse leydig cells with different androgen production potential are resistant to estrogenic stimuli but responsive to
Iuliia Savchuk1, Olle Söder, Konstantin Svechnikov
1Pediatric Endocrinology Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
Abstract:
It is well known that estrogens and estrogen-like endocrine disruptors can suppress steroidogenic gene expression, attenuate androgen production and decrease differentiation of adult Leydig cell lineage. However, there is no information about the possible link between the potency of Leydig cells to produce androgens and their sensitivity to estrogenic stimuli. Thus, the present study explored the relationship between androgen production potential of Leydig cells and their responsiveness to estrogenic compounds. To investigate this relationship we selected mouse genotypes contrasting in sex hormone levels and differing in testosterone/estradiol (T/E2) ratio. We found that two mouse genotypes, CBA/Lac and C57BL/6j have the highest and the lowest serum T/E2 ratio associated with increased serum LH level in C57BL/6j compared to CBA/Lac. Analysis of steroidogenic gene expression demonstrated significant upregulation of Cyp19 gene expression but coordinated suppression of LHR, StAR, 3βHSDI and Cyp17a1 in Leydig cells from C57BL/6j that was associated with attenuated androgen production in basal and hCG-stimulated conditions compared to CBA/Lac mice. These genotype-dependent differences in steroidogenesis were not linked to changes in the expression of estrogen receptors ERα and Gpr30, while ERβ expression was attenuated in Leydig cells from C57BL/6j compared to CBA/Lac. No effects of estrogenic agonists on steroidogenesis in Leydig cells from both genotypes were found. In contrast, xenoestrogen bisphenol A significantly potentiated hCG-activated androgen production by Leydig cells from C57BL/6j and CBA/Lac mice by suppressing conversion of testosterone into corresponding metabolite 5α-androstane-3α,17β-diol. All together our data indicate that developing mouse Leydig cells with different androgen production potential are resistant to estrogenic stimuli, while xenoestrogen BPA facilitates hCG-induced steroidogenesis in mouse Leydig cells via attenuation of testosterone metabolism. This cellular event can cause premature maturation of Leydig cells that may create abnormal intratesticular paracrine milieu and disturb proper development of germ cells.
Insights
Leydig cells with varying androgen production potential show resistance to estrogenic compounds. However, the xenoestrogen bisphenol A enhances androgen production by suppressing testosterone metabolism, potentially disrupting germ cell development.
Area of Science:
- Endocrinology
- Reproductive Biology
- Toxicology
Background:
- Estrogens and endocrine disruptors are known to suppress steroidogenesis and Leydig cell differentiation.
- The relationship between Leydig cell androgen production capacity and estrogen sensitivity remains unexplored.
Purpose of the Study:
- To investigate the link between Leydig cell androgen production potential and their responsiveness to estrogenic stimuli.
- To analyze steroidogenic gene expression and androgen production in mouse genotypes with contrasting sex hormone profiles.
Main Methods:
- Selected mouse genotypes (CBA/Lac and C57BL/6j) with differing testosterone/estradiol (T/E2) ratios.
- Analyzed serum hormone levels, luteinizing hormone (LH) levels, and Leydig cell steroidogenic gene expression (Cyp19, LHR, StAR, 3βHSDI, Cyp17a1).
- Assessed estrogen receptor (ERα, ERβ, Gpr30) expression and Leydig cell responsiveness to estrogenic agonists and xenoestrogen bisphenol A (BPA).
Main Results:
- C57BL/6j mice exhibited a lower T/E2 ratio, higher LH, and suppressed steroidogenic gene expression (LHR, StAR, 3βHSDI, Cyp17a1) compared to CBA/Lac mice, resulting in lower androgen production.
- Genotype-dependent differences in steroidogenesis were not correlated with ERα or Gpr30 expression, but ERβ expression was lower in C57BL/6j Leydig cells.
- Estrogenic agonists had no effect, while BPA significantly potentiated hCG-induced androgen production by suppressing testosterone metabolism to 5α-androstane-3α,17β-diol.
Conclusions:
- Developing mouse Leydig cells with differing androgen production potentials are resistant to direct estrogenic stimuli.
- Xenoestrogen BPA enhances hCG-induced steroidogenesis in Leydig cells by altering testosterone metabolism, potentially leading to premature Leydig cell maturation and disturbed germ cell development.
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