Developmental Exposures to Three Mammalian Teratogens Produce Dysmorphic Phenotypes in Adult <i>Caenorhabditis elegans</i>
Efficient new methods are needed to support initiatives to reduce, refine, and/or replace toxicity testing in vertebrates. 5-fluorouracil (5FU), hydroxyurea (HU), and ribavirin (RV) are mammalian teratogens. Skeletal, endocrine organ, and cardiac effects are often associated with teratogenesis, and...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-07-01
|
| Series: | Toxics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2305-6304/13/7/589 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1839615105290993664 |
|---|---|
| author | Piper Reid Hunt Martine Ferguson Nicholas Olejnik Jeffrey Yourick Robert L. Sprando |
| author_facet | Piper Reid Hunt Martine Ferguson Nicholas Olejnik Jeffrey Yourick Robert L. Sprando |
| author_sort | Piper Reid Hunt |
| collection | DOAJ |
| description | Efficient new methods are needed to support initiatives to reduce, refine, and/or replace toxicity testing in vertebrates. 5-fluorouracil (5FU), hydroxyurea (HU), and ribavirin (RV) are mammalian teratogens. Skeletal, endocrine organ, and cardiac effects are often associated with teratogenesis, and a simple nematode like <i>C. elegans</i> lacks these systems. However, many genetic pathways required for mammalian morphogenesis have at least some conserved elements in this small, invertebrate model. The <i>C. elegans</i> lifecycle is 3 days. The effects of 5FU, HU, and RV on the <i>C. elegans</i> morphology were evaluated on day 4 post-initiation of the feeding after hatching for continuous and 24 h (early-only) developmental exposures. Continuous exposures to 5FU and HU induced increases in the incidences of abnormal gonadal structures that were significantly reduced in early-only exposure groups. The incidence of prolapse increased with continuous 5FU and HU exposures and was further increased in early-only exposure groups. Intestinal prolapse through the vulval muscle in <i>C. elegans</i> may be related to reported 5FU and HU effects on skeletal muscle and the gastrointestinal tract in mammals. Continuous RV exposures induced a phenotype lacking a uterus and gonad arms, as well as vulval anomalies that were largely, but not completely, reversed with early-only exposures, which is consistent with reported reversible reproductive tract anomalies after an RV exposure in mammals. These findings suggest that <i>C. elegans</i> can be used to detect the hazard risk from chemicals that adversely affect conserved pathways involved in organismal morphogenesis, but to determine the fit-for-purpose use of this model in chemical safety evaluations, further studies using larger and more diverse chemical test panels are needed. |
| format | Article |
| id | doaj-art-9cd67113bd04422a8fc21f0ee1ff8ab5 |
| institution | Matheson Library |
| issn | 2305-6304 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxics |
| spelling | doaj-art-9cd67113bd04422a8fc21f0ee1ff8ab52025-07-25T13:37:38ZengMDPI AGToxics2305-63042025-07-0113758910.3390/toxics13070589Developmental Exposures to Three Mammalian Teratogens Produce Dysmorphic Phenotypes in Adult <i>Caenorhabditis elegans</i>Piper Reid Hunt0Martine Ferguson1Nicholas Olejnik2Jeffrey Yourick3Robert L. Sprando4U.S. Food and Drug Administration, Human Foods Program, Office of Chemistry and Toxicology, Laurel, MD 20708, USAU.S. Food and Drug Administration, Human Foods Program, Office of Surveillance Strategy & Risk Prioritization, Division of Surveillance & Data Integration, College Park, MD 20740, USAU.S. Food and Drug Administration, Human Foods Program, Office of Chemistry and Toxicology, Laurel, MD 20708, USAU.S. Food and Drug Administration, Human Foods Program, Office of Chemistry and Toxicology, Laurel, MD 20708, USAU.S. Food and Drug Administration, Human Foods Program, Office of Chemistry and Toxicology, Laurel, MD 20708, USAEfficient new methods are needed to support initiatives to reduce, refine, and/or replace toxicity testing in vertebrates. 5-fluorouracil (5FU), hydroxyurea (HU), and ribavirin (RV) are mammalian teratogens. Skeletal, endocrine organ, and cardiac effects are often associated with teratogenesis, and a simple nematode like <i>C. elegans</i> lacks these systems. However, many genetic pathways required for mammalian morphogenesis have at least some conserved elements in this small, invertebrate model. The <i>C. elegans</i> lifecycle is 3 days. The effects of 5FU, HU, and RV on the <i>C. elegans</i> morphology were evaluated on day 4 post-initiation of the feeding after hatching for continuous and 24 h (early-only) developmental exposures. Continuous exposures to 5FU and HU induced increases in the incidences of abnormal gonadal structures that were significantly reduced in early-only exposure groups. The incidence of prolapse increased with continuous 5FU and HU exposures and was further increased in early-only exposure groups. Intestinal prolapse through the vulval muscle in <i>C. elegans</i> may be related to reported 5FU and HU effects on skeletal muscle and the gastrointestinal tract in mammals. Continuous RV exposures induced a phenotype lacking a uterus and gonad arms, as well as vulval anomalies that were largely, but not completely, reversed with early-only exposures, which is consistent with reported reversible reproductive tract anomalies after an RV exposure in mammals. These findings suggest that <i>C. elegans</i> can be used to detect the hazard risk from chemicals that adversely affect conserved pathways involved in organismal morphogenesis, but to determine the fit-for-purpose use of this model in chemical safety evaluations, further studies using larger and more diverse chemical test panels are needed.https://www.mdpi.com/2305-6304/13/7/589teratogenmorphometrydevelopmental toxicitychemical screeningalternative toxicity test methodsmall model organism |
| spellingShingle | Piper Reid Hunt Martine Ferguson Nicholas Olejnik Jeffrey Yourick Robert L. Sprando Developmental Exposures to Three Mammalian Teratogens Produce Dysmorphic Phenotypes in Adult <i>Caenorhabditis elegans</i> Toxics teratogen morphometry developmental toxicity chemical screening alternative toxicity test method small model organism |
| title | Developmental Exposures to Three Mammalian Teratogens Produce Dysmorphic Phenotypes in Adult <i>Caenorhabditis elegans</i> |
| title_full | Developmental Exposures to Three Mammalian Teratogens Produce Dysmorphic Phenotypes in Adult <i>Caenorhabditis elegans</i> |
| title_fullStr | Developmental Exposures to Three Mammalian Teratogens Produce Dysmorphic Phenotypes in Adult <i>Caenorhabditis elegans</i> |
| title_full_unstemmed | Developmental Exposures to Three Mammalian Teratogens Produce Dysmorphic Phenotypes in Adult <i>Caenorhabditis elegans</i> |
| title_short | Developmental Exposures to Three Mammalian Teratogens Produce Dysmorphic Phenotypes in Adult <i>Caenorhabditis elegans</i> |
| title_sort | developmental exposures to three mammalian teratogens produce dysmorphic phenotypes in adult i caenorhabditis elegans i |
| topic | teratogen morphometry developmental toxicity chemical screening alternative toxicity test method small model organism |
| url | https://www.mdpi.com/2305-6304/13/7/589 |
| work_keys_str_mv | AT piperreidhunt developmentalexposurestothreemammalianteratogensproducedysmorphicphenotypesinadulticaenorhabditiselegansi AT martineferguson developmentalexposurestothreemammalianteratogensproducedysmorphicphenotypesinadulticaenorhabditiselegansi AT nicholasolejnik developmentalexposurestothreemammalianteratogensproducedysmorphicphenotypesinadulticaenorhabditiselegansi AT jeffreyyourick developmentalexposurestothreemammalianteratogensproducedysmorphicphenotypesinadulticaenorhabditiselegansi AT robertlsprando developmentalexposurestothreemammalianteratogensproducedysmorphicphenotypesinadulticaenorhabditiselegansi |