Impaired primordial follicle assembly in offspring ovaries from zearalenone-exposed mothers involves reduced mitochondrial activity and altered epigenetics in oocytes

Abstract

Previous works have shown that zearalenone (ZEA), as an estrogenic pollutant, has adverse effects on mammalian folliculogenesis. In the present study, we found that prolonged exposure of female mice to ZEA around the end of pregnancy, caused severe impairment of primordial follicle formation in the ovaries of newborn mice and altered the expression of many genes in oocytes as revealed by scRNA-seq.These changes were associated with morphological and molecular alterations of mitochondria, increased autophagic markers in oocytes, and epigenetic changes in the ovaries of newborn mice from ZEA exposed mothers. The latter increased expression of HDAC2 deacetylases was leading to decreased levels of H3K9ac and H4K12ac. Most of these modi cations were relieved when the expression of HDAC2 in newborn ovaries was reduced by RNA interference during in vitro culture in the presence of ZEA. Such changes were also alleviated in offspring ovaries from mothers treated with both ZEA and the ubiquinone coenzyme Q10 (CoQ10), which is known to be able to restore mitochondrial activities. We concluded that impaired mitochondrial activities in oocytes caused by ZEA are at the origin of metabolic alterations that modify the expression of genes controlling autophagy and primordial follicle assembly through changes in epigenetic histones.

Maternal Zearalenone Exposure Affects Gut Microbiota and Follicular Development in Suckled Offspring

“…Zearalenone is one of the most prevalent mycotoxins globally; the Food and Agriculture Organization (FAO) estimated that 25% of crop production worldwide per year is contaminated with mycotoxins, and ZEN was detected in more than 62% of corn samples in the Asia-Pacific region in 2020. , Recent studies have shown that ZEN can be rapidly absorbed and metabolized by the gastrointestinal tract and distributed to different organs after ZEN ingestion by animals, and can even be transferred from the maternal body to breast milk. − Numerous studies have shown that ZEN and its metabolites can cause toxic poisoning in animals, resulting in, for example, severe hepatotoxicity and reproductive toxicity. Previously, our studies have shown that maternal exposure to ZEN increased DNA damage, apoptosis, and impacted on mitochondrial activity, which is associated with the impaired primordial follicle assembly in ovaries of newborn pups. ,, However, very few studies have examined the effect of ZEN transmitted through maternal breast milk on follicular development in offspring.…”

“…Previously, our studies have shown that maternal exposure to ZEN increased DNA damage, apoptosis, and impacted on mitochondrial activity, which is associated with the impaired primordial follicle assembly in ovaries of newborn pups. 17,19,33 However, very few studies have examined the effect of ZEN transmitted through maternal breast milk on follicular development in offspring.…”

“…Recent studies have shown that the RIG-I-like receptor (RLRs) signaling pathway is activated upon exposure to ZEN, thereby increasing the expression levels of DNA damage and apoptosis-related proteins that interfere with follicle development . During the process of primordial follicle assembly, single-cell transcriptomics revealed that maternal ZEN exposure affects the developmental trajectory of germ cells and GCs, triggers DNA damage and cell apoptosis via the Hippo pathway, and leads to oocyte autophagy, which is involved in the mitochondrial activity and the modification of histone deacetylases. , However, whether ZEN can be transmitted to offspring through breast milk or produce toxic effects on follicular development in offspring is still unclear.…”

Cyanidin-3-O-glucoside Mitigates the Ovarian Defect Induced by Zearalenone via p53-GADD45a Signaling during Primordial Follicle Assembly

“…In this regard, it was exemplified that ZEN decreased the expression of oocyte-specific genes in germ cells, such as Lhx8 , Nobox , Sohlh2 , and Figla , increased the number of TUNEL positive cells, and reduced the number of germ cells in the ovaries of neonatal mice in vitro. ZEN also decreased mitochondrial activity, elevated autophagy levels, and altered the histone acetylation level of oocytes during primordial follicle formation . The previous study showed that ZEN exposure affected germ cell and granulosa cell development and impacted the ovarian reserve through Hippo and RIG-I receptor signaling pathways. , On the other hand, ZEN exposure would seriously reduce the expression of meiosis-related genes and result in a significant increase of DNA double-strand breaks (DSBs) in germ cells; at the same time, the aberrant morphologic features and cell cycle arrest were discovered. , Therefore, ZEN exposure has brought about severe ovarian toxicity, and the search for effective rescue agents is urgent.…”

“…19 ZEN also decreased mitochondrial activity, elevated autophagy levels, and altered the histone acetylation level of oocytes during primordial follicle formation. 20 The previous study showed that ZEN exposure affected germ cell and granulosa cell development and impacted the ovarian reserve through Hippo and RIG-I receptor signaling pathways. 21,22 On the other hand, ZEN exposure would seriously reduce the expression of meiosisrelated genes and result in a significant increase of DNA double-strand breaks (DSBs) in germ cells; 23 at the same time, the aberrant morphologic features and cell cycle arrest were discovered.…”