A study of possible substitutes for the endocrine disruptor DEHP in two hormone receptors

Abstract

Bis(2-ethylhexyl) phthalate (DEHP) has been widely used for the production of plastics, and the compound has also been found to act as endocrine disruptor. Exposure to DEHP has been found to cause several hormonal problems, including decreased fertility. Due to the environmental and health risks posed by the use of DEHP, the present study employed molecular docking, molecular dynamics, and free energy analyses (MM-GBSA, MM-PBSA, and SIE) aiming at evaluating the action of DEHP and that of two other compounds (ATEC and DL9TH), tested as potential DEHP substitutes, on two hormone receptors (sex hormone-binding globulin – SHBG – and progesterone receptor – PR). The results obtained showed that ATEC may be a good substitute for DEHP in the production of plastics, such as PVC, considering that the compound recorded the greatest free energy values with respect to binding with SHBG (−31.36 kcal/mol obtained from MM-GBSA; −20.28 kcal/mol for MM-PBSA, and −7.40 for SIE) and PR (−36.40 kcal/mol for MM-GBSA; −27.00 kcal/mol for MM-PBSA, and −8.51 kcal/mol for SIE) – this shows that ATEC presented the least activity in the two hormone receptors. The findings of this study provide relevant insights on potential substitutes for DEHP and help shed light on the action of these new efficient substances, which have similar properties to DEHP (ATEC and DL9TH) yet do not act as endocrine disruptors.

Communicated by Ramaswamy H. Sarma

Keywords:

• Endocrine disruptor
• DEHP
• docking
• molecular dynamics
• binding free energy

Acknowledgements

The authors acknowledge the financial support provided by the following Brazilian funding agencies: Brazilian National Council for Scientific and Technological Development – CNPq (grant #465571/2014-0, #302874/2017-8 and #427452/2018-0), São Paulo Research Foundation – FAPESP (grants #2014/50945-4, #2017/10118-0 and #2018/19103-8) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES – Finance Code 001 and Grant 88.887.126/2017/00).

Disclosure statement

There are no conflicts of interest to declare.

Data availability statement

All data obtained in this study are deposited at Mendeley Data and can be found from the following DOI: dx.doi.org/10.17632/yyhpgyyfs3.1.

Additional information

Funding

The authors acknowledge the financial support provided by the following Brazilian funding agencies: Brazilian National Council for Scientific and Technological Development – CNPq (grant #465571/2014-0, #302874/2017-8 and #427452/2018-0), São Paulo Research Foundation – FAPESP (grants #2014/50945-4, #2017/10118-0 and #2018/19103-8) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES – Finance Code 001 and Grant 88.887.126/2017/00).