Teratogenic effects of in utero exposure to Di-(2-Ethylhexyl)-Phthalate (DEHP) in B6:129S4 Mice

Erica Ungewitter; Emmi Rotgers; Tanika Bantukul; Yasuhiko Kawakami; Grace E. Kissling; Humphrey Hung Chang Yao

doi:10.1093/toxsci/kfx019

Teratogenic effects of in utero exposure to Di-(2-Ethylhexyl)-Phthalate (DEHP) in B6:129S4 Mice

Erica Ungewitter, Emmi Rotgers, Tanika Bantukul, Yasuhiko Kawakami, Grace E. Kissling, Humphrey Hung Chang Yao

Genetics, Cell Biology and Development (TMED)

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Intrauterine exposure to phthalates is known to cause disorders ofmale reproductive function including androgen insufficiency, decreased fertility, and germ cell defects in rodents. In this study, we set out to investigate the effects of intrauterine exposure to di-(2-ethylhexyl)-phthalate (DEHP) on fetal development of the B6:129S4mouse strain. Time-mated pregnant C57BL/6 dams were exposed to 0, 5, 250, or 500mg/kg DEHP with corn oil as the vehicle via oral gavage fromembryonic days (E)7 to 16. Survival and grossmorphology of the pups were analyzed one day after the last treatment. Anogenital distance (AGD) and testicular cell functions were examined inmale embryos to confirm the known effects of phthalate exposure. DEHP exposure significantly reduced the survival rate of fetuses in the 250 and 500mg/kg dosage groups compared with the control and 5mg/kg groups. Exposure to 250 and 500mg/kg DEHP was teratogenic and induced exencephaly and limbmalformations such as polydactyly in the B6:126S4 embryos. No gross malformations were observed in control or 5mg/kg DEHP groups. Inmale embryos, exposure to both 5 and 250mg/kg DEHP in utero was sufficient to induce the formation ofmultinucleated germ cells in the testes and widespread changes in mRNA expression of germ cell, interstitiumand Sertoli cell-associated genes. These findings reveal that intrauterine DEHP exposure has a strong teratogenic, and lethal impact on the fetuses of B6:129S4mouse strain.

Original language	English (US)
Pages (from-to)	8-19
Number of pages	12
Journal	Toxicological Sciences
Volume	157
Issue number	1
DOIs	https://doi.org/10.1093/toxsci/kfx019
State	Published - May 1 2017

Bibliographical note

Funding Information:
We thank Louise Harris of the NIEHS Comparative Medicine Branch for assistance with dosing the animals and the NIEHS Cellular and Molecular Pathology Branch and Molecular Genomics Center for their services. We are very thankful toPaula Brown for her invaluable help with the collection of the fetuses. We are grateful for Dr Paul Foster for reading the manuscript and providing helpful suggestions. Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ES102965 to H.H.-C.Y.) and National Institute of Arthritis, Musculoskeletal and Skin Diseases (AR064195 to Y.K.). The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core is supported by the Eunice Kennedy Shriver NICHD/NIH (NCTRI) Grant P50-HD28934.

Publisher Copyright:
© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology.

Keywords

Endocrine disruptor
Germ cells
Phthalate
Polydactyly
Testis

Publisher link

10.1093/toxsci/kfx019

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6074946

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abstract = "Intrauterine exposure to phthalates is known to cause disorders ofmale reproductive function including androgen insufficiency, decreased fertility, and germ cell defects in rodents. In this study, we set out to investigate the effects of intrauterine exposure to di-(2-ethylhexyl)-phthalate (DEHP) on fetal development of the B6:129S4mouse strain. Time-mated pregnant C57BL/6 dams were exposed to 0, 5, 250, or 500mg/kg DEHP with corn oil as the vehicle via oral gavage fromembryonic days (E)7 to 16. Survival and grossmorphology of the pups were analyzed one day after the last treatment. Anogenital distance (AGD) and testicular cell functions were examined inmale embryos to confirm the known effects of phthalate exposure. DEHP exposure significantly reduced the survival rate of fetuses in the 250 and 500mg/kg dosage groups compared with the control and 5mg/kg groups. Exposure to 250 and 500mg/kg DEHP was teratogenic and induced exencephaly and limbmalformations such as polydactyly in the B6:126S4 embryos. No gross malformations were observed in control or 5mg/kg DEHP groups. Inmale embryos, exposure to both 5 and 250mg/kg DEHP in utero was sufficient to induce the formation ofmultinucleated germ cells in the testes and widespread changes in mRNA expression of germ cell, interstitiumand Sertoli cell-associated genes. These findings reveal that intrauterine DEHP exposure has a strong teratogenic, and lethal impact on the fetuses of B6:129S4mouse strain.",

keywords = "Endocrine disruptor, Germ cells, Phthalate, Polydactyly, Testis",

author = "Erica Ungewitter and Emmi Rotgers and Tanika Bantukul and Yasuhiko Kawakami and Kissling, {Grace E.} and Yao, {Humphrey Hung Chang}",

note = "Funding Information: We thank Louise Harris of the NIEHS Comparative Medicine Branch for assistance with dosing the animals and the NIEHS Cellular and Molecular Pathology Branch and Molecular Genomics Center for their services. We are very thankful toPaula Brown for her invaluable help with the collection of the fetuses. We are grateful for Dr Paul Foster for reading the manuscript and providing helpful suggestions. Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ES102965 to H.H.-C.Y.) and National Institute of Arthritis, Musculoskeletal and Skin Diseases (AR064195 to Y.K.). The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core is supported by the Eunice Kennedy Shriver NICHD/NIH (NCTRI) Grant P50-HD28934. Publisher Copyright: {\textcopyright} The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology.",

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AU - Bantukul, Tanika

AU - Kawakami, Yasuhiko

AU - Kissling, Grace E.

AU - Yao, Humphrey Hung Chang

N1 - Funding Information: We thank Louise Harris of the NIEHS Comparative Medicine Branch for assistance with dosing the animals and the NIEHS Cellular and Molecular Pathology Branch and Molecular Genomics Center for their services. We are very thankful toPaula Brown for her invaluable help with the collection of the fetuses. We are grateful for Dr Paul Foster for reading the manuscript and providing helpful suggestions. Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ES102965 to H.H.-C.Y.) and National Institute of Arthritis, Musculoskeletal and Skin Diseases (AR064195 to Y.K.). The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core is supported by the Eunice Kennedy Shriver NICHD/NIH (NCTRI) Grant P50-HD28934. Publisher Copyright: © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology.

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N2 - Intrauterine exposure to phthalates is known to cause disorders ofmale reproductive function including androgen insufficiency, decreased fertility, and germ cell defects in rodents. In this study, we set out to investigate the effects of intrauterine exposure to di-(2-ethylhexyl)-phthalate (DEHP) on fetal development of the B6:129S4mouse strain. Time-mated pregnant C57BL/6 dams were exposed to 0, 5, 250, or 500mg/kg DEHP with corn oil as the vehicle via oral gavage fromembryonic days (E)7 to 16. Survival and grossmorphology of the pups were analyzed one day after the last treatment. Anogenital distance (AGD) and testicular cell functions were examined inmale embryos to confirm the known effects of phthalate exposure. DEHP exposure significantly reduced the survival rate of fetuses in the 250 and 500mg/kg dosage groups compared with the control and 5mg/kg groups. Exposure to 250 and 500mg/kg DEHP was teratogenic and induced exencephaly and limbmalformations such as polydactyly in the B6:126S4 embryos. No gross malformations were observed in control or 5mg/kg DEHP groups. Inmale embryos, exposure to both 5 and 250mg/kg DEHP in utero was sufficient to induce the formation ofmultinucleated germ cells in the testes and widespread changes in mRNA expression of germ cell, interstitiumand Sertoli cell-associated genes. These findings reveal that intrauterine DEHP exposure has a strong teratogenic, and lethal impact on the fetuses of B6:129S4mouse strain.

AB - Intrauterine exposure to phthalates is known to cause disorders ofmale reproductive function including androgen insufficiency, decreased fertility, and germ cell defects in rodents. In this study, we set out to investigate the effects of intrauterine exposure to di-(2-ethylhexyl)-phthalate (DEHP) on fetal development of the B6:129S4mouse strain. Time-mated pregnant C57BL/6 dams were exposed to 0, 5, 250, or 500mg/kg DEHP with corn oil as the vehicle via oral gavage fromembryonic days (E)7 to 16. Survival and grossmorphology of the pups were analyzed one day after the last treatment. Anogenital distance (AGD) and testicular cell functions were examined inmale embryos to confirm the known effects of phthalate exposure. DEHP exposure significantly reduced the survival rate of fetuses in the 250 and 500mg/kg dosage groups compared with the control and 5mg/kg groups. Exposure to 250 and 500mg/kg DEHP was teratogenic and induced exencephaly and limbmalformations such as polydactyly in the B6:126S4 embryos. No gross malformations were observed in control or 5mg/kg DEHP groups. Inmale embryos, exposure to both 5 and 250mg/kg DEHP in utero was sufficient to induce the formation ofmultinucleated germ cells in the testes and widespread changes in mRNA expression of germ cell, interstitiumand Sertoli cell-associated genes. These findings reveal that intrauterine DEHP exposure has a strong teratogenic, and lethal impact on the fetuses of B6:129S4mouse strain.

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Teratogenic effects of in utero exposure to Di-(2-Ethylhexyl)-Phthalate (DEHP) in B6:129S4 Mice

Abstract

Bibliographical note

Keywords

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