312. 5-hydroxytryptophan Alleviates Toxic Fescue-induced Disruption of Fetal Muscle Development and Associated Gene Expression Pathways During Late Gestation.

Abstract

Fescue toxicosis is a condition in livestock caused by the ingestion of ergot alkaloids in toxic endophyte-infected tall fescue. Ergot alkaloids induce vasoconstriction through smooth muscle contraction, reducing blood flow and resulting in uteroplacental vasoconstriction that can impair fetal growth, skeletal muscle development, and overall animal performance. We hypothesized that 5-hydroxytryptophan (5-HTP) would counteract the negative effects of toxic fescue. The objectives of this study were to: 1) evaluate the effect of 5-HTP on fetal muscle weight; 2) determine changes in transcriptional gene expression in fetal semitendinosus (ST) muscle. Ewes (n = 30) pregnant with twins were randomly assigned to one of the three treatments: 1) negative control, (CON, n = 10), 2) 5-HTP (2.5 mg/kg BW), and toxic tall fescue seed containing 1.77 mg ewe-1 d-1 ergovaline/ergovalinine (E+/5-HTP, n = 10), or 3) positive control, fed toxic tall fescue seed containing 1.77 mg ewe-1 d-1 ergovaline/ergovalinine (E+, n = 10). Before treatment administration, ewes were individually fed total mixed ration (TMR) at 2.5% of body weight on a dry matter basis for seven days to adjust to individual feeding, followed by TMR and treatment (CON, E+/5-HTP, or E+) at 2.5% of body weight on a dry matter basis from d 86 to d 111. A terminal necropsy was performed on the ewes on d 111, and individual muscles were dissected from each fetus, and weights were obtained. The fetal ST muscle was immediately frozen in liquid nitrogen for subsequent RNA extraction. RNA was obtained from the extracted ST muscle sample and subjected to RNA sequencing. Fetal ST and longissimus muscle (LM) weight did not differ (P > 0.05) between E+/5-HTP and CON groups. However, both ST and LM muscle weights were reduced (P < 0.05) in E+ compared to E+/5-HTP and CON. For ST RNA sequencing analysis, no genes were differentially expressed (Padj > 0.05) between E+/5-HTP and CON. We observed 163 differentially upregulated genes and 107 differentially downregulated genes (Padj < 0.05) for E+/5-HTP vs E+ and 40 differentially downregulated genes and 27 differentially upregulated genes (Padj < 0.05) for E+ vs CON. The enrichment pathway of downregulated genes for E+ vs CON showed that muscle-related gene programs and signaling pathways required for contraction were suppressed; however, the E+/5-HTP vs E+ upregulated genes appear to counter this by reactivating metabolic pathways and restoring muscle-associated signaling and structural pathways. These results suggest that 5-HTP mitigated the negative effects of fescue toxicosis on fetal muscle development in ewes fed toxic tall fescue during late gestation. Specifically, 5-HTP prevented reductions in fetal muscle weight and helped restore transcriptional pathways associated with muscle growth and function.