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. 2025 Jul 31;26(15):7389.
doi: 10.3390/ijms26157389.

Reproductive Toxicity Effects of Phthalates Based on the Hypothalamic-Pituitary-Gonadal Axis: A Priority Control List Construction from Theoretical Methods

Botian Xiao  1   2 , Hao Yang  1   2 , Yunxiang Li  1   2 , Wenwen Wang  1   2 , Yu Li  1   2
Affiliations

Reproductive Toxicity Effects of Phthalates Based on the Hypothalamic-Pituitary-Gonadal Axis: A Priority Control List Construction from Theoretical Methods

Botian Xiao et al. Int J Mol Sci. .

Abstract

Phthalate esters (PAEs), frequently detected in various environmental media, are associated with multiple health issues, particularly reproductive toxicity. This study employed molecular docking and molecular dynamics simulations to investigate the reproductive toxicity risk of 22 PAEs on the regulation of the hypothalamic-pituitary-gonadal (HPG) axis. Analysis revealed that when the carbon number of PAEs was the same, those with branched side chains exhibited more pronounced reproductive toxicity risks. In PAE molecules with branched side chains, reproductive toxicity risk was inversely proportional to the number of carbon atoms. Furthermore, five PAE molecules with unacceptable risk (DIPRP, DMEP, DMP, DPP, and DUP) and four key indicators were proposed. Key descriptors influencing PAEs' reproductive toxicity risks were identified as Infrared and ATSC8e by machine learning analysis. Furthermore, carbonyl structure, substituent position, and electronegativity of PAE molecules are critical factors influencing PAE-induced reproductive toxicity risks via the HPG axis. This study provides a theoretical basis for further investigation of PAE-induced reproductive toxicity risk on the HPG axis, which facilitates the development of risk mitigation strategies for PAEs' reproductive toxicity and provides novel perspectives and approaches for exploring the molecular mechanisms underlying the endocrine effects of emerging contaminants such as PAEs.

Keywords: adverse outcome pathway; machine learning; molecular dynamics simulation; phthalate esters; priority control list; reproductive toxicity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Analysis of average values of reproductive toxic risk evaluation indicators at various levels of the HPG axis under PAE exposure.
Figure 2
Figure 2
Linear regression plot of FA comprehensive scores (a) and first-level evaluation index rankings (b) of reproductive toxic risks on the HPG axis under PAE molecules exposure.
Figure 3
Figure 3
Key PAE moleculars descriptors and SHAP value plot in the XGBoost model.
Figure 4
Figure 4
Receptor characterization of HPG axis reproductive toxicity risks under PAEs exposure (a): IGF-1R (ID: P08069); (b): GPR54 (ID: Q969F8); (c): PGE2R (ID: P34995); (d): G(q) (ID: P50148); (e): LHCGR (ID: P22888); (f): IRS-1(ID: P35568); (g): OxytocinR (ID: P30559); (h): GNRHR (ID: P30968); (i): G(s) (ID: O60726); (j): INSR (ID: P06213)). (Note: Red and blue represent alpha-helix and beta-sheet respectively).
Figure 5
Figure 5
Graded evaluation system of reproductive toxicity indicators based on the HPG axis under PAE exposure.
Figure 6
Figure 6
A flowchart illustrating the steps used for reproductive toxicity risks based on the HPG axis under PAE exposure constructed in this study.
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