Interaction between mono-(2-ethylhexyl) phthalate and retinoic acid alters Sertoli cell development during fetal mouse testis cord morphogenesis
Phthalic acid esters (phthalates) are a class of industrial chemicals that cause developmental and reproductive toxicity, but there are significant gaps in knowledge of phthalate toxicity mechanisms. There is evidence that phthalates disrupt retinoic acid signaling in the fetal testis, potentially d...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Current Research in Toxicology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666027X2200024X |
| _version_ | 1797978734258552832 |
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| author | Maha A. Alhasnani Skylar Loeb Susan J. Hall Zachary Caruolo Faith Simmonds Amanda E. Solano Daniel J. Spade |
| author_facet | Maha A. Alhasnani Skylar Loeb Susan J. Hall Zachary Caruolo Faith Simmonds Amanda E. Solano Daniel J. Spade |
| author_sort | Maha A. Alhasnani |
| collection | DOAJ |
| description | Phthalic acid esters (phthalates) are a class of industrial chemicals that cause developmental and reproductive toxicity, but there are significant gaps in knowledge of phthalate toxicity mechanisms. There is evidence that phthalates disrupt retinoic acid signaling in the fetal testis, potentially disrupting control of spatial and temporal patterns of testis development. Our goal was to determine how a phthalate would interact with retinoic acid signaling during fetal mouse testis development. We hypothesized that mono-(2-ethylhexyl) phthalate (MEHP) would exacerbate the adverse effect of all-trans retinoic acid (ATRA) on seminiferous cord development in the mouse fetal testis. To test this hypothesis, gestational day (GD) 14 C57BL/6 mouse testes were isolated and cultured on media containing MEHP, ATRA, or a combination of both compounds. Cultured testes were collected for global transcriptome analysis after one day in culture and for histology and immunofluorescent analysis of Sertoli cell differentiation after three days in culture. ATRA disrupted seminiferous cord morphogenesis and induced aberrant FOXL2 expression. MEHP alone had no significant effect on cord development, but combined exposure to MEHP and ATRA increased the number of FOXL2-positive cells, reduced seminiferous cord number, and increased testosterone levels, beyond the effect of ATRA alone. In RNA-seq analysis, ATRA treatment and MEHP treatment resulted in differential expression of genes 510 and 134 genes, respectively, including 70 common differentially expressed genes (DEGs) between the two treatments, including genes with known roles in fetal testis development. MEHP DEGs included RAR target genes, genes involved in angiogenesis, and developmental patterning genes, including members of the homeobox superfamily. These results support the hypothesis that MEHP modulates retinoic acid signaling in the mouse fetal testis and provide insight into potential mechanisms by which phthalates disrupt seminiferous cord morphogenesis. |
| first_indexed | 2024-04-11T05:28:49Z |
| format | Article |
| id | doaj.art-fc51fd5ec487471cba10cb8f94e91f54 |
| institution | Directory Open Access Journal |
| issn | 2666-027X |
| language | English |
| last_indexed | 2024-04-11T05:28:49Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Current Research in Toxicology |
| spelling | doaj.art-fc51fd5ec487471cba10cb8f94e91f542022-12-23T04:42:25ZengElsevierCurrent Research in Toxicology2666-027X2022-01-013100087Interaction between mono-(2-ethylhexyl) phthalate and retinoic acid alters Sertoli cell development during fetal mouse testis cord morphogenesisMaha A. Alhasnani0Skylar Loeb1Susan J. Hall2Zachary Caruolo3Faith Simmonds4Amanda E. Solano5Daniel J. Spade6Department of Pathology and Laboratory Medicine, Brown University, Box G-E5, Providence, RI 02912, USADepartment of Pathology and Laboratory Medicine, Brown University, Box G-E5, Providence, RI 02912, USADepartment of Pathology and Laboratory Medicine, Brown University, Box G-E5, Providence, RI 02912, USADepartment of Pathology and Laboratory Medicine, Brown University, Box G-E5, Providence, RI 02912, USADepartment of Pathology and Laboratory Medicine, Brown University, Box G-E5, Providence, RI 02912, USADepartment of Pathology and Laboratory Medicine, Brown University, Box G-E5, Providence, RI 02912, USADepartment of Pathology and Laboratory Medicine, Brown University, Box G-E5, Providence, RI 02912, USA; Corresponding author at: Department of Pathology and Laboratory Medicine, Brown University, Providence, RI 02912, USA.Phthalic acid esters (phthalates) are a class of industrial chemicals that cause developmental and reproductive toxicity, but there are significant gaps in knowledge of phthalate toxicity mechanisms. There is evidence that phthalates disrupt retinoic acid signaling in the fetal testis, potentially disrupting control of spatial and temporal patterns of testis development. Our goal was to determine how a phthalate would interact with retinoic acid signaling during fetal mouse testis development. We hypothesized that mono-(2-ethylhexyl) phthalate (MEHP) would exacerbate the adverse effect of all-trans retinoic acid (ATRA) on seminiferous cord development in the mouse fetal testis. To test this hypothesis, gestational day (GD) 14 C57BL/6 mouse testes were isolated and cultured on media containing MEHP, ATRA, or a combination of both compounds. Cultured testes were collected for global transcriptome analysis after one day in culture and for histology and immunofluorescent analysis of Sertoli cell differentiation after three days in culture. ATRA disrupted seminiferous cord morphogenesis and induced aberrant FOXL2 expression. MEHP alone had no significant effect on cord development, but combined exposure to MEHP and ATRA increased the number of FOXL2-positive cells, reduced seminiferous cord number, and increased testosterone levels, beyond the effect of ATRA alone. In RNA-seq analysis, ATRA treatment and MEHP treatment resulted in differential expression of genes 510 and 134 genes, respectively, including 70 common differentially expressed genes (DEGs) between the two treatments, including genes with known roles in fetal testis development. MEHP DEGs included RAR target genes, genes involved in angiogenesis, and developmental patterning genes, including members of the homeobox superfamily. These results support the hypothesis that MEHP modulates retinoic acid signaling in the mouse fetal testis and provide insight into potential mechanisms by which phthalates disrupt seminiferous cord morphogenesis.http://www.sciencedirect.com/science/article/pii/S2666027X2200024XRetinoic acidSertoli cellFetal testis developmentPhthalate toxicity |
| spellingShingle | Maha A. Alhasnani Skylar Loeb Susan J. Hall Zachary Caruolo Faith Simmonds Amanda E. Solano Daniel J. Spade Interaction between mono-(2-ethylhexyl) phthalate and retinoic acid alters Sertoli cell development during fetal mouse testis cord morphogenesis Current Research in Toxicology Retinoic acid Sertoli cell Fetal testis development Phthalate toxicity |
| title | Interaction between mono-(2-ethylhexyl) phthalate and retinoic acid alters Sertoli cell development during fetal mouse testis cord morphogenesis |
| title_full | Interaction between mono-(2-ethylhexyl) phthalate and retinoic acid alters Sertoli cell development during fetal mouse testis cord morphogenesis |
| title_fullStr | Interaction between mono-(2-ethylhexyl) phthalate and retinoic acid alters Sertoli cell development during fetal mouse testis cord morphogenesis |
| title_full_unstemmed | Interaction between mono-(2-ethylhexyl) phthalate and retinoic acid alters Sertoli cell development during fetal mouse testis cord morphogenesis |
| title_short | Interaction between mono-(2-ethylhexyl) phthalate and retinoic acid alters Sertoli cell development during fetal mouse testis cord morphogenesis |
| title_sort | interaction between mono 2 ethylhexyl phthalate and retinoic acid alters sertoli cell development during fetal mouse testis cord morphogenesis |
| topic | Retinoic acid Sertoli cell Fetal testis development Phthalate toxicity |
| url | http://www.sciencedirect.com/science/article/pii/S2666027X2200024X |
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