Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse

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Maxwell C K Leung1, Jimmy Phuong, Nancy C Baker

  • 1Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee.

Environmental Health Perspectives
|December 15, 2015
PubMed
Abstract

Insights

Environmental chemicals are linked to male reproductive health issues. This study identified 774 chemicals and their molecular targets, revealing a hierarchy of adverse outcomes consistent with the testicular dysgenesis syndrome (TDS) hypothesis.

Area of Science:

  • Environmental toxicology
  • Reproductive toxicology
  • Computational toxicology

Background:

  • Male reproductive health issues like testicular cancer and low semen quality are rising.
  • Prenatal exposure to environmental chemicals is a suspected cause, supported by human and animal studies.

Purpose of the Study:

  • To identify correlations between environmental chemicals, molecular targets, and adverse male reproductive outcomes.
  • To investigate the developmental toxicity of the male reproductive system across a wide range of chemicals.

Main Methods:

  • Utilized the U.S. EPA's ToxRefDB animal study database and literature analysis to select 774 chemicals.
  • Employed U.S. EPA's ToxCastDB high-throughput screening database to profile chemical bioactivity against ~800 molecular and cellular features.

Main Results:

  • Observed a phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations in 281 chemicals, aligning with the testicular dysgenesis syndrome (TDS) hypothesis.
  • Identified 54 chemicals with male developmental effects, linking them to 156 gene annotations in a network.

Conclusions:

  • Computational modeling confirmed a phenotypic hierarchy consistent with the TDS hypothesis.
  • Confirmed roles of estrogen and androgen pathways, and identified new targets including retinoic acid signaling, vascular remodeling proteins, GPCRs, and cytochrome P450s.

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