Embryonic exposure to the flame retardant, 1,2,5,6-Tetrabromocyclooctane (TBCO) inhibits MIH-induced oocyte maturation and alters gene expression and DNA methylation in adult Japanese medaka (Oryzias latipes)

Abstract

Oocyte maturation, the final stage of oogenesis, occurs when maturation-inducing hormone (MIH) binds to its membrane progestin receptor (mPR). A previous study demonstrated that reduced fecundity of female Japanese medaka (Oryzias latipes) exposed as embryos to maternally transferred 1,2,5,6-Tetrabromocyclooctane (TBCO), an endocrine-disrupting chemical, was caused by impaired MIH-induced oocyte maturation. However, the molecular mechanism(s) of this effect are unknown. The objective of the present study was to investigate the molecular basis of decreased oocyte maturation leading to decreased fecundity in Japanese medaka exposed as embryos to maternally deposited TBCO. Sexually mature F0 females were fed 100 or 1000 µg TBCO/g diet for 21 days, and F1 embryos were reared to adulthood in clean water. F1 fecundity was decreased by 11.3% and 31.4% relative to the control. Using an ex vivo assay, MIH-stimulated maturation of fully grown stage IX oocytes to stage X matured oocytes was decreased by 16.1% and 22.3% relative to the control. To investigate the mechanistic underpinnings of this decreased oocyte maturation, mRNA sequencing and enzymatic methyl sequencing (EM-Seq) were used to compare the transcriptome and methylome of stage IX oocytes that matured to stage IX oocytes that failed to mature, from control and TBCO-exposed females. Pathway analysis revealed enrichment of the MAPK, insulin, GnRH, and oocyte-meiosis signalling pathways that are known to regulate oocyte maturation. Several genes that encode proteins in the AC/cAMP/PKA and PI3K/AKT signaling pathways had either gene body hypomethylation or altered transcript abundance. These changes likely explain the impaired MIH-induced oocyte maturation, leading to decreased fecundity, in medaka exposed to maternally transferred TBCO. This study provides novel insight into how early life exposure to endocrine-disrupting chemicals can lead to altered later life reproductive performance of fish.