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Monomethyl Phthalate Causes Early Embryo Development Delay, Apoptosis, and Energy Metabolism Disruptions Through Inducing Redox Imbalance

  • Reproductive Biology: Original Article
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Abstract  

Phthalates are a class of environmental endocrine disrupting chemicals which can cause reproductive system damages. However, data about reproductive toxicity spectrum of phthalate metabolites among Chinese women undergoing in vitro fertilization (IVF) treatments are scarce yet. Previous studies regarding underlying embryo toxicities focused on oxidative stress and apoptosis, while energy metabolism abnormality might be another key cause for embryo developmental disruptions. Here, we found that among the measured eight phthalate metabolites, monomethyl phthalate (MMP) had the second highest urinary concentration in women receiving IVF. Compare to the lowest exposure level group, MMP in tertile 3 was associated with fewer counts of oocyte retrieved and good-quality embryos, and MMP in tertile 2 was correlated with reduced good-quality embryo rate. The direct embryo toxicities of MMP were studied using mouse 2-cell embryos. Consistent to results found in human populations, exposure to MMP induced mouse early embryo developmental delay. Furthermore, MMP exposure led to excessive reactive oxygen species production in early embryos, and antioxidant can partially rescue the early embryo development slow down. Embryo apoptosis could also be caused by oxidative stress. To be noted, elevated apoptosis level was not found in live “slow” embryos but dead embryos, which suggested that apoptosis was not related to early embryo developmental delay. Additionally, MMP exposure depleted adenosine triphosphate (ATP) synthesis of early embryos, which could be reversed by antioxidant. In conclusion, MMP, as the newly found embryonic toxicant in Chinese women, resulted in early embryo development delay, apoptosis, and energy metabolism disruptions via inducing redox imbalance.

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Data Availability

All data generated or analyzed during this study are included in this article.

Code Availability

Not applicable.

Abbreviations

IVF:

In vitro fertilization

MMP:

Monomethyl phthalate

MBP:

Mono-n-butyl phthalate

MEP:

Monoethyl phthalate

MEHP:

Mono (2-ethylhexyl) phthalate

MEOHP:

Mono (2-ethyl-5-oxohexyl) phthalate

MEHHP:

Mono (2-ethyl-5-hydroxyhexyl) phthalate

MOP:

Mono-n-octyl phthalate

MBzP:

Monobenzyl phthalate

ROS:

Reactive oxygen species

ATP:

Adenosine triphosphate

NAC:

N-acetyl-L-cysteine

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Acknowledgements

The authors thank Dr. Deng and Dr. Li for their guidance on experiment design and paper writing; Dr. Yuan and Dr. Teng for clinical data collection; Dr. Du for valuable guidance throughout animal experiments; Ms. Liao and Mr. Li for suggestions on data statistical analysis; Ms. Yao and Ms. Li for suggestions on manuscript writing; Ms. Guo for helping establishing the IVF and in vitro culture systems of mouse embryos; all the doctors, embryologists, and nurses for following up the participants and collecting clinical data. This work was supported by the National Natural Science Foundation of China [No. 81571508; No. 81771654].

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Author notes

  1. Yufeng Li and Taoran Deng contributed equally to this work and should be considered co-corresponding authors.

Authors and Affiliations

  1. Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Wenqu Tian, Hongmei Liao, Nijie Li, Wen Yao, Yuying Li, Na Guo, Xiaoqiong Yuan, Yaoyao Du, Xuemei Teng, Yufeng Li & Taoran Deng

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  1. Wenqu Tian
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Correspondence to Yufeng Li or Taoran Deng.

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Ethics Approval

All included patients gave their oral and written informed consent. The study project was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (No. TJ-IRB20180607; [2019] S934).

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Tian, W., Liao, H., Li, N. et al. Monomethyl Phthalate Causes Early Embryo Development Delay, Apoptosis, and Energy Metabolism Disruptions Through Inducing Redox Imbalance. Reprod. Sci. 31, 139–149 (2024). https://doi.org/10.1007/s43032-023-01309-6

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