Mapping Steroidogenic Perturbations Under Endocrine Disruptor Mixtures Across Demographic Subgroups: Structural and...

Area of Science:

• Environmental Health
• Endocrinology
• Toxicology

Background:

• Endocrine-disrupting chemicals (EDCs) are widespread environmental contaminants that interfere with hormonal systems.
• Assessing the population-level impact of EDC mixtures on hormone homeostasis is complex.
• Understanding the molecular mechanisms underlying EDC effects is crucial for risk assessment.

Purpose of the Study:

• To investigate associations between exposure to 37 EDCs and hormone levels in a large U.S. population.
• To identify specific EDCs and their molecular targets responsible for observed hormonal disruptions.
• To validate findings through computational and experimental approaches and provide an accessible resource.

Main Methods:

• Analysis of data from 4255 U.S. participants.
• Profiling of 37 environmental chemicals and their metabolites.
• Computational modeling (docking/molecular dynamics) and experimental validation (SPR, metabolomics, cell assays).

Main Results:

• Consistent associations found between phthalate metabolites and reduced testosterone levels, particularly in adult males.
• Mono-(3-carboxypropyl) phthalate (MCPP) identified as a significant disruptor.
• MCPP was shown to inhibit the CYP17A1 enzyme by interacting with its heme center, confirmed by multiple validation methods.

Conclusions:

• Phthalate metabolites, especially MCPP, are linked to testosterone disruption in the human population.
• The inhibition of CYP17A1 by MCPP represents a key molecular mechanism for EDC-induced hormonal imbalance.
• An interactive web resource is available for exploring EDC-hormone associations and aiding risk prioritization.