TCP structure intensified the chlorpyrifos-induced decrease in testosterone synthesis via LH-LHR-PKA-CREB-Star pathway

Abstract

Similar to diethylphosphate (DEP), 3,5,6-trichloro-2-pyridinol (TCP) is also a characteristic chemical substance and ultimate transformation product of chlorpyrifos (CPF) because the structure of TCP is equivalent to the trichloro pyridine structure of CPF. TCP is often used as a biomarker of CPF exposure. TCP and DEP are often detected in human blood and urine due to the widespread use of CPF. No studies have sufficiently clarified which structure contributes to the negative effect of CPF on testosterone synthesis. This study aims to explain which structure promotes the inhibitory effect of CPF on testosterone synthesis and the related influence mechanisms. After 20 weeks of exposure, the testosterone level in testes was significantly reduced by different doses of CPF (0.3 mg/kg body weight CPF and 3.0 mg/kg body weight CPF). Meanwhile, the level of testosterone synthesized by isolated primary Leydig cells was also reduced by CPF. In addition, TCP but not DEP aggravated the decrease in testosterone synthesis in isolated primary Leydig cells. On the other hand, CPF and TCP significantly decreased the levels of the Star protein, CREB phosphorylation and PKA phosphorylation, which are important in regulating testosterone synthesis. Based on these results, TCP is a key structure that mediates the CPF-induced decrease in testosterone synthesis by terminating the signal transmission of the LH-LHR-PKA-CREB-Star pathway. Thus, chemicals with the TCP structure may be potential endocrine disruptors that decrease fertility. Chemicals that can be converted to TCP or achieve a trichloro pyridine structure must be considered during reproductive toxicity risk assessment.