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Updated: May 23, 2026
Germ Cell Transplantation and Testis Tissue Xenografting in Mice
Published on: February 6, 2012
Human fetal testis xenografts are resistant to phthalate-induced endocrine disruption
Nicholas E Heger1, Susan J Hall, Moses A Sandrof
1Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA.
Background:
In utero exposure to endocrine-disrupting chemicals may contribute to testicular dysgenesis syndrome (TDS), a proposed constellation of increasingly common male reproductive tract abnormalities (including hypospadias, cryptorchidism, hypospermatogenesis, and testicular cancer). Male rats exposed in utero to certain phthalate plasticizers exhibit multinucleated germ cell (MNG) induction and suppressed steroidogenic gene expression and testosterone production in the fetal testis, causing TDS-consistent effects of hypospadias and cryptorchidism. Mice exposed to phthalates in utero exhibit MNG induction only. This disparity in response demonstrates a species-specific sensitivity to phthalate-induced suppression of fetal Leydig cell steroidogenesis. Importantly, ex vivo phthalate exposure of the fetal testis does not recapitulate the species-specific endocrine disruption, demonstrating the need for a new bioassay to assess the human response to phthalates.
Objectives:
In this study, we aimed to develop and validate a rat and mouse testis xenograft bioassay of phthalate exposure and examine the human fetal testis response.
Methods:
Fetal rat, mouse, and human testes were xenografted into immunodeficient rodent hosts, and hosts were gavaged with a range of phthalate doses over multiple days. Xenografts were harvested and assessed for histopathology and steroidogenic end points.
Results:
Consistent with the in utero response, phthalate exposure induced MNG formation in rat and mouse xenografts, but only rats exhibited suppressed steroidogenesis. Across a range of doses, human fetal testis xenografts exhibited MNG induction but were resistant to suppression of steroidogenic gene expression.
Conclusions:
Phthalate exposure of grafted human fetal testis altered fetal germ cells but did not reduce expression of genes that regulate fetal testosterone biosynthesis.
Insights
Phthalate exposure alters fetal germ cells in human testes but does not suppress testosterone production. This study developed a new bioassay to assess human fetal testis response to endocrine disruptors.
Area of Science:
- Reproductive toxicology
- Endocrinology
- Developmental biology
Background:
- In utero exposure to endocrine-disrupting chemicals like phthalates may cause testicular dysgenesis syndrome (TDS) in males.
- Phthalates induce multinucleated germ cells (MNG) and suppress testosterone production in fetal rat testes, but only MNG in mice, indicating species-specific sensitivity.
- Existing methods like ex vivo exposure do not fully replicate in vivo endocrine disruption, necessitating a new bioassay for human fetal testis response.
Purpose of the Study:
- To develop and validate a rat and mouse testis xenograft bioassay for phthalate exposure.
- To assess the response of human fetal testes to phthalate exposure using this novel bioassay.
Main Methods:
- Fetal rat, mouse, and human testes were xenografted into immunodeficient rodents.
- Hosts received multiple daily doses of phthalates.
- Xenografts were analyzed for histopathology and steroidogenic gene expression.
Main Results:
- Phthalate exposure induced MNG formation in rat and mouse xenografts, mirroring in utero findings.
- Steroidogenesis was suppressed in rat xenografts but not in mouse xenografts.
- Human fetal testis xenografts showed MNG induction but were resistant to suppressed steroidogenic gene expression.
Conclusions:
- The xenograft model confirmed species-specific responses to phthalates.
- Human fetal testes xenografts demonstrated altered fetal germ cells but maintained testosterone biosynthesis gene expression.
- This bioassay provides a new tool to evaluate endocrine disruptor effects on the human fetal testis.
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