PMID- 36189433
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231101
IS  - 2666-027X (Electronic)
IS  - 2666-027X (Linking)
VI  - 3
DP  - 2022
TI  - Interaction between mono-(2-ethylhexyl) phthalate and retinoic acid alters 
      Sertoli cell development during fetal mouse testis cord morphogenesis.
PG  - 100087
LID - 10.1016/j.crtox.2022.100087 [doi]
LID - 100087
AB  - 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.
CI  - (c) 2022 The Authors.
FAU - Alhasnani, Maha A
AU  - Alhasnani MA
AD  - Department of Pathology and Laboratory Medicine, Brown University, Box G-E5, 
      Providence, RI 02912, USA.
FAU - Loeb, Skylar
AU  - Loeb S
AD  - Department of Pathology and Laboratory Medicine, Brown University, Box G-E5, 
      Providence, RI 02912, USA.
FAU - Hall, Susan J
AU  - Hall SJ
AD  - Department of Pathology and Laboratory Medicine, Brown University, Box G-E5, 
      Providence, RI 02912, USA.
FAU - Caruolo, Zachary
AU  - Caruolo Z
AD  - Department of Pathology and Laboratory Medicine, Brown University, Box G-E5, 
      Providence, RI 02912, USA.
FAU - Simmonds, Faith
AU  - Simmonds F
AD  - Department of Pathology and Laboratory Medicine, Brown University, Box G-E5, 
      Providence, RI 02912, USA.
FAU - Solano, Amanda E
AU  - Solano AE
AD  - Department of Pathology and Laboratory Medicine, Brown University, Box G-E5, 
      Providence, RI 02912, USA.
FAU - Spade, Daniel J
AU  - Spade DJ
AD  - Department of Pathology and Laboratory Medicine, Brown University, Box G-E5, 
      Providence, RI 02912, USA.
LA  - eng
GR  - R00 ES025231/ES/NIEHS NIH HHS/United States
PT  - Journal Article
DEP - 20220921
PL  - Netherlands
TA  - Curr Res Toxicol
JT  - Current research in toxicology
JID - 101771915
PMC - PMC9520016
OTO - NOTNLM
OT  - ATRA, All-trans retinoic acid. CAS # 302-79-4
OT  - DMSO, dimethyl sulfoxide
OT  - Fetal testis development
OT  - GD, gestational day
OT  - GO, Gene Ontology
OT  - IPA, Ingenuity Pathway Analysis
OT  - ITCN, Image-based Tool for Counting Nuclei
OT  - MEHP, mono-(2-ethylheyxl) phthalate. CAS # 4376-20-9
OT  - MNGs, multinucleated germ cells
OT  - PVC, polyvinyl chloride
OT  - Phthalate toxicity
OT  - Retinoic acid
OT  - Sertoli cell
OT  - TDS, testicular dysgenesis syndrome
COIS- The authors declare the following financial interests/personal relationships 
      which may be considered as potential competing interests: Daniel Spade reports a 
      relationship with National Toxicology Program that includes: consulting or 
      advisory. Nothing else to disclose.
EDAT- 2022/10/04 06:00
MHDA- 2022/10/04 06:01
PMCR- 2022/09/21
CRDT- 2022/10/03 05:21
PHST- 2022/03/14 00:00 [received]
PHST- 2022/09/17 00:00 [revised]
PHST- 2022/09/17 00:00 [accepted]
PHST- 2022/10/03 05:21 [entrez]
PHST- 2022/10/04 06:00 [pubmed]
PHST- 2022/10/04 06:01 [medline]
PHST- 2022/09/21 00:00 [pmc-release]
AID - S2666-027X(22)00024-X [pii]
AID - 100087 [pii]
AID - 10.1016/j.crtox.2022.100087 [doi]
PST - epublish
SO  - Curr Res Toxicol. 2022 Sep 21;3:100087. doi: 10.1016/j.crtox.2022.100087. 
      eCollection 2022.