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Chlorocholine chloride delays progenitor Leydig cell differentiation via PI3K/AKT pathway activation in rats
Haoran Zhang1, Yijia Li1, Xiaoxia Wang1
1Department of Toxicology, School of Public Health, Peking University, Beijing 100191, China.
Abstract:
Chlorocholine chloride (CCC) is a commonly used plant growth regulator. It was shown that CCC exposure could lead to decreased testosterone biosynthesis, delayed puberty onset, and damaged spermatogenesis in pubertal rodents, but the underlying mechanism is still not well understood. The testosterone level is determined not only by the functional activity of Leydig cell but also by its number and maturational status. To identify the critical developmental stage at which CCC impairs Leydig cell maturation and elucidate its underlying mechanisms, pubertal rats were exposed to 0, 75, 137.5, and 200 mg/kg bw/day CCC from PND14 (progenitor Leydig cells, PLCs) to PND28 (immature Leydig cells, ILCs) and from PND28 to PND56 (adult Leydig cells, ALCs) respectively. The results showed that, for exposure from PLCs stage, CCC exposure at 137.5 and 200 mg/kg bw/day led to histopathological changes of rat testes and impaired Leydig cell lineage specification in rats. CCC exposure at 200 mg/kg bw/day significantly decreased the mRNA expression of Star, Lhcgr, Cyp17a1, and Hsd17b3. Hormonal measurement and proteomic analysis revealed that both the disruption of the hypothalamic-pituitary-testis axis and the aberrant activation of the PI3K/AKT signaling pathway contribute to the impairment of Leydig cell lineage specification. For exposure from ILCs stage, Leydig cell development was not affected, but serum and testicular testosterone levels decreased resulting from the down-regulation of StAR, CYP11A1, and HSD3B1. In conclusion, our study found that CCC exposure could delay the development process of rat Leydig cells by disruption of Leydig cell differentiation during early developmental stage, which might lead to decreased testosterone level.
Insights
Chlorocholine chloride (CCC) exposure during early development impairs rat Leydig cell differentiation, leading to reduced testosterone levels. This plant growth regulator disrupts testicular development and hormonal balance.
Area of Science:
- Endocrinology
- Reproductive Toxicology
- Developmental Biology
Background:
- Plant growth regulators like chlorocholine chloride (CCC) can impact reproductive health.
- Previous studies indicate CCC exposure affects testosterone biosynthesis and spermatogenesis, but mechanisms remain unclear.
- Leydig cell number, maturation, and function are critical for testosterone production.
Purpose of the Study:
- To identify the critical developmental stage where CCC impairs Leydig cell maturation.
- To elucidate the underlying mechanisms of CCC-induced reproductive toxicity.
- To investigate the effects of CCC on Leydig cell lineage specification and differentiation.
Main Methods:
- Pubertal rats were exposed to varying doses of CCC from postnatal day 14 (PND14) to PND28 (progenitor Leydig cells stage) and PND28 to PND56 (immature Leydig cells stage).
- Histopathological examination, gene expression analysis (mRNA of key steroidogenic enzymes), hormonal assays, and proteomic analysis were performed.
- Specific focus on Leydig cell lineage specification and differentiation markers.
Main Results:
- CCC exposure from PND14-PND28 impaired Leydig cell lineage specification and caused testicular histopathology at higher doses (137.5 and 200 mg/kg bw/day).
- CCC significantly decreased mRNA expression of steroidogenic genes (Star, Lhcgr, Cyp17a1, Hsd17b3) and disrupted the hypothalamic-pituitary-testis axis.
- PI3K/AKT pathway activation was implicated in Leydig cell impairment; however, exposure from PND28-PND56 did not affect Leydig cell development but reduced testosterone levels due to down-regulation of StAR, CYP11A1, and HSD3B1.
Conclusions:
- CCC exposure during the progenitor Leydig cell stage disrupts differentiation and delays Leydig cell development.
- This early-stage disruption can lead to reduced testosterone levels and potential long-term reproductive health issues.
- CCC's impact on Leydig cell development highlights the sensitivity of early testicular development to environmental factors.
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