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Of mice and men (and rats): phthalate-induced fetal testis endocrine disruption is species-dependent
Kamin J Johnson1, Nicholas E Heger, Kim Boekelheide
1Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware 19803, USA. johnson@nemoursresearch.org
Abstract:
For over 15 years, reproductive toxicologists have explored the physiological outcomes and mechanism of fetal phthalate exposure to determine the risk posed to human male reproductive health. This review examines the fetal male reproductive system response to phthalate exposure across species including rat, mouse, and human, with emphasis on the testis. In the rat, in utero phthalate exposure causes male reproductive tract malformations, in large part, by targeting the testis and inhibiting fetal Leydig cell hormone production. Despite mouse phthalate pharmacokinetics being similar to the rat, inhibition of fetal Leydig cell hormone synthesis is not observed in the mouse. The species-specific differences in testicular response following in utero phthalate exposure and the discordant reaction of the rodent fetal testis when exposed to phthalates ex vivo versus in vivo have made determining risk to humans difficult, yet critically important. The recent use of fetal testis xenotransplants to study phthalate toxicity suggests that the human fetal testis responds like the mouse fetal testis; it appears refractory to phthalate-induced inhibition of testosterone production. Although this result is unfulfilling from the perspective of identifying environmental contributions to human reproductive maldevelopment, it has important implications for phthalate risk assessment.
Insights
Phthalate exposure during fetal development impacts male reproductive health. Human fetal testes appear resistant to phthalate-induced testosterone suppression, unlike rat models, complicating risk assessment.
Area of Science:
- Reproductive Toxicology
- Endocrinology
- Environmental Health
Background:
- Phthalate exposure is a concern for male reproductive health.
- Species-specific responses to fetal phthalate exposure complicate risk assessment.
- Understanding the mechanism of phthalate toxicity is crucial.
Purpose of the Study:
- To review the effects of fetal phthalate exposure on the male reproductive system across species.
- To investigate species-specific differences in testicular response to phthalates.
- To evaluate the implications for human health risk assessment.
Main Methods:
- Comparative analysis of rodent (rat, mouse) and human fetal testis responses to phthalates.
- Review of in vivo and ex vivo studies.
- Examination of fetal Leydig cell hormone production.
- Utilizing fetal testis xenotransplantation models.
Main Results:
- In utero phthalate exposure causes malformations in rat male reproductive tracts by inhibiting Leydig cell hormone production.
- Mice show similar phthalate pharmacokinetics but do not exhibit inhibited fetal Leydig cell hormone synthesis.
- Human fetal testes, studied via xenotransplantation, appear refractory to phthalate-induced testosterone production inhibition, similar to mice.
Conclusions:
- Species-specific differences in testicular response to phthalates exist, with rats being sensitive and mice/humans appearing refractory.
- The human fetal testis's apparent resistance to phthalate-induced testosterone suppression has significant implications for risk assessment.
- Further research is needed to fully understand environmental contributions to human reproductive maldevelopment.
