Impact of Fetal Exposure to Endocrine Disrupting Chemical Mixtures on FOXA3 Gene and Protein Expression in Adult Rat Testes
Perinatal exposure to endocrine disrupting chemicals (EDCs) has been shown to affect male reproductive functions. However, the effects on male reproduction of exposure to EDC mixtures at doses relevant to humans have not been fully characterized. In previous studies, we found that in utero exposure...
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/2/1211 |
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| author | Casandra Walker Annie Boisvert Priyanka Malusare Martine Culty |
| author_facet | Casandra Walker Annie Boisvert Priyanka Malusare Martine Culty |
| author_sort | Casandra Walker |
| collection | DOAJ |
| description | Perinatal exposure to endocrine disrupting chemicals (EDCs) has been shown to affect male reproductive functions. However, the effects on male reproduction of exposure to EDC mixtures at doses relevant to humans have not been fully characterized. In previous studies, we found that in utero exposure to mixtures of the plasticizer di(2-ethylhexyl) phthalate (DEHP) and the soy-based phytoestrogen genistein (Gen) induced abnormal testis development in rats. In the present study, we investigated the molecular basis of these effects in adult testes from the offspring of pregnant SD rats gavaged with corn oil or Gen + DEHP mixtures at 0.1 or 10 mg/kg/day. Testicular transcriptomes were determined by microarray and RNA-seq analyses. A protein analysis was performed on paraffin and frozen testis sections, mainly by immunofluorescence. The transcription factor forkhead box protein 3 (FOXA3), a key regulator of Leydig cell function, was identified as the most significantly downregulated gene in testes from rats exposed in utero to Gen + DEHP mixtures. FOXA3 protein levels were decreased in testicular interstitium at a dose previously found to reduce testosterone levels, suggesting a primary effect of fetal exposure to Gen + DEHP on adult Leydig cells, rather than on spermatids and Sertoli cells, also expressing FOXA3. Thus, FOXA3 downregulation in adult testes following fetal exposure to Gen + DEHP may contribute to adverse male reproductive outcomes. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T12:24:09Z |
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| spelling | doaj.art-cf1f3bf28d9d45ea85a913243cfeb6ad2023-11-30T22:37:01ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01242121110.3390/ijms24021211Impact of Fetal Exposure to Endocrine Disrupting Chemical Mixtures on FOXA3 Gene and Protein Expression in Adult Rat TestesCasandra Walker0Annie Boisvert1Priyanka Malusare2Martine Culty3Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089-9121, USAThe Research Institute of the McGill University Health Centre, McGill University, Montreal, QC H4A 3J1, CanadaDepartment of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089-9121, USADepartment of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089-9121, USAPerinatal exposure to endocrine disrupting chemicals (EDCs) has been shown to affect male reproductive functions. However, the effects on male reproduction of exposure to EDC mixtures at doses relevant to humans have not been fully characterized. In previous studies, we found that in utero exposure to mixtures of the plasticizer di(2-ethylhexyl) phthalate (DEHP) and the soy-based phytoestrogen genistein (Gen) induced abnormal testis development in rats. In the present study, we investigated the molecular basis of these effects in adult testes from the offspring of pregnant SD rats gavaged with corn oil or Gen + DEHP mixtures at 0.1 or 10 mg/kg/day. Testicular transcriptomes were determined by microarray and RNA-seq analyses. A protein analysis was performed on paraffin and frozen testis sections, mainly by immunofluorescence. The transcription factor forkhead box protein 3 (FOXA3), a key regulator of Leydig cell function, was identified as the most significantly downregulated gene in testes from rats exposed in utero to Gen + DEHP mixtures. FOXA3 protein levels were decreased in testicular interstitium at a dose previously found to reduce testosterone levels, suggesting a primary effect of fetal exposure to Gen + DEHP on adult Leydig cells, rather than on spermatids and Sertoli cells, also expressing FOXA3. Thus, FOXA3 downregulation in adult testes following fetal exposure to Gen + DEHP may contribute to adverse male reproductive outcomes.https://www.mdpi.com/1422-0067/24/2/1211endocrine disruptorsEDC mixturesin utero exposurestranscriptome analysistesticular functionLeydig cells |
| spellingShingle | Casandra Walker Annie Boisvert Priyanka Malusare Martine Culty Impact of Fetal Exposure to Endocrine Disrupting Chemical Mixtures on FOXA3 Gene and Protein Expression in Adult Rat Testes International Journal of Molecular Sciences endocrine disruptors EDC mixtures in utero exposures transcriptome analysis testicular function Leydig cells |
| title | Impact of Fetal Exposure to Endocrine Disrupting Chemical Mixtures on FOXA3 Gene and Protein Expression in Adult Rat Testes |
| title_full | Impact of Fetal Exposure to Endocrine Disrupting Chemical Mixtures on FOXA3 Gene and Protein Expression in Adult Rat Testes |
| title_fullStr | Impact of Fetal Exposure to Endocrine Disrupting Chemical Mixtures on FOXA3 Gene and Protein Expression in Adult Rat Testes |
| title_full_unstemmed | Impact of Fetal Exposure to Endocrine Disrupting Chemical Mixtures on FOXA3 Gene and Protein Expression in Adult Rat Testes |
| title_short | Impact of Fetal Exposure to Endocrine Disrupting Chemical Mixtures on FOXA3 Gene and Protein Expression in Adult Rat Testes |
| title_sort | impact of fetal exposure to endocrine disrupting chemical mixtures on foxa3 gene and protein expression in adult rat testes |
| topic | endocrine disruptors EDC mixtures in utero exposures transcriptome analysis testicular function Leydig cells |
| url | https://www.mdpi.com/1422-0067/24/2/1211 |
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