MON-142 - Sex-Specific Disruption of Placental Endocrine Gene Networks Following Maternal Ingestion of the Cyanotoxin Microcystin

High concentrations of microcystin-leucine-arginine (MC-LR) have been detected in freshwater systems, such as in the Great Lakes of Northern America, due to increased presence of cyanobacterial harmful algae blooms (cHABs). The reproductive effects of this hepatotoxin during pregnancy and fetal development remain poorly understood. Nutrient delivery, hormone production, immune protection, and regulation of growth signals are crucial parts of placental function, including modulation of fetal exposure to maternal glucocorticoids through the hypothalamic pituitary adrenal (HPA) axis. Here, we investigated the hypothesis that MC-LR may disrupt placental regulation of the developmental programming of the fetus. For this purpose, pregnant mice were gavaged with either a low but ecologically relevant MC-LR dose (10 µg/kg) or vehicle (sterile water). Male and female placentas were collected at embryonic day 18. To analyze the transcriptome, total RNA was extracted and processed for RNA-seq. Genetic clustering and network enrichment analyses showed that sex was a principal contributor of the transcriptional differences observed, with treatment effects developing within sex-specific differentially expressed genes (DEG) profiles. Of these differentially expressed genes, many were associated with stress response, immune protection, and hormonally regulated signaling pathways directly linked to HPA-axis functions and sex-dependent regulation. Additionally, qPCR analysis of 11 β -hydroxysteroid dehydrogenase (11β-HSD), aromatase, and modulators of macronutrient uptake (CD36 and GLUT1) revealed that MC-LR exposure can significantly reduce 11β-HSD in MC-LR treated mice, with expression of CD36 significantly elevated in MC-LR treated male mice. These findings suggest that non-lethal MC-LR dosing disrupt sex-specific transcriptional responses associated with the modulation of stress-related pathways in females and disruption of cell cycle, immune gene networks, and steroidogenesis in males, possibly resulting in abnormal fetal development and HPA-axis programming.

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