Fecal microbiota transplantation alleviates female offspring's ovarian inflammation in arsenic and fluoride co-exposed rats through the PI3K/ Akt /NF-?B pathway.

Abstract

Highlights

Arsenic and fluoride cause ovarian inflammation in offspring female rats.
PI3K/Akt /NF -?B pathway is involved in ovarian inflammation.
Fecal microbiota transplantation can alleviate the ovarian inflammation.

Numerous studies have shown that exposure to arsenic (As) or fluoride(F) can damage the reproductive system, but limited evidence exists regarding the combined toxicity and pathogenesis of As and F co-exposure in female reproduction. Moreover, the role of gut microbiota in mediating such toxicity remains unclear. This study investigated the effects of As and F co-exposure on ovarian development and the potential protective role of fecal microbiota transplantation (FMT). We established an animal model of ovarian injury induced via co-exposure to NaAsO₂ and NaF from birth to postnatal day 120(PND120) and introduced FMT from PND60. Co-exposure reduced serum levels of estradiol(E2) and luteinizing hormone (LH), along with morphological alterations in ovarian tissue. Meanwhile, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/nuclear transcription factor-?B (NF-?B) pathway, a known mediator of inflammation-related ovarian dysfunction, was significantly upregulated. Interestingly, with prolonged exposure, the inflammatory indicators (Akt, IL-1?, IL-6, TNF-a) on PND120 were significantly higher than those on PND60. Notably, FMT alleviated ovarian inflammation, potentially by improving colonic barrier function, thereby indirectly mitigating ovarian damage. Taken together, this study reveals that NaAsO₂ and NaF co-exposure induces progressive ovarian inflammation via the PI3K/Akt/NF-_kB pathway, and that FMT may offer protective effects. Our findings provide new insights into the environmental risks to female reproductive health.

Graphical Abstract

Diagram of the Mechanism by Which Co-Exposure to Arsenic and Fluoride Causes Ovarian Inflammation?By Figdraw?

EXCERPTS:

1. Introduction

Due to rapid changes in society and environment, infertility has emerged as a prevalent issue, affecting approximately 10–15?% of couples globally, with female factors accounting for over 50?% (Escada-Rebelo et al., 2022). A myriad of factors contribute to human infertility, and exposure to toxic heavy metals is considered one of the potential reasons (Canipari et al., 2020). Among these contaminants, fluoride (F) and arsenic (As) are particularly concerning, as they are among the most severe pollutants in drinking water, impacting the health of an estimated 300 million people worldwide are chronically exposed to high levels of these elements (Kumar et al., 2020, Mondal and Chattopadhyay, 2020). Ingestion of As and F through drinking water has been associated with toxic effects on various organs, including the heart (Li et al., 2022), liver (Guo et al., 2020), and the testicles (Liu et al., 2021), and increase the risk of female infertility. Epidemiological studies have shown that As and F, acting as endocrine disruptors, can affect steroid hormones and cause endocrine disruption (Tian et al., 2021, Bai et al., 2020, Zhang et al., 2023a). Animal studies have largely substantiated these adverse effects, with As exposure correlating to reduced ovarian weights and decreased estradiol levels in both adolescent and adult rats (Chen et al., 2022, Mondal et al., 2013). High levels of F can impair the structure and function of rat ovarian granulosa cells, inhibit the proliferation and development of oocytes, and ultimately result in ovarian dysfunction (Zhao et al., 2018). These detrimental factors may culminate in infertility. However, existing researches are mostly focused on the harmful effects of As or F individually at several stages of reproductive life in females, from fetal life to puberty and maturity. The impact of combined exposure to As and F on the comprehensive development of the female rat reproductive system, encompassing both puberty and maturity, remains insufficiently explored.

Notably, our recent studies have demonstrated that co-exposure to As and F can lead to more severe damage than either toxicant alone in organs such as the heart, kidney, and male reproductive system. For example, we have reported that co-exposure induced more pronounced oxidative stress, mitochondrial damage, and autophagy in cardiac and renal tissues (Yan et al., 2021, Tian et al., 2023). Similarly, in the male reproductive system, co-exposure significantly impaired sperm quality and hormone secretion compared to single exposures (Liu et al., 2021). These findings suggest potential synergistic toxicity that may also extend to female reproductive health.

Inflammation is a sophisticated biological response triggered when body tissues are subjected to a variety of external environmental toxins (Liu et al., 2021). Numerous studies have shown that inflammation is involved in the process of As and F induced damage (Ma et al., 2012, Ma et al., 2017, Tao et al., 2021, Khan et al., 2022). The nuclear factor-?B (NF-?B) pathway plays a central role in initiating and sustaining inflammatory responses by promoting the transcription of pro-inflammatory mediators such as tumor necrosis factor ? (TNF-?) and interleukin 1? (IL-1?) (Lawrence, 2009). Studies have indicated that arsenic can upregulate the expression of TNF-? and NF-?B within the ovaries (Dash et al., 2020). The phosphatidylinositol 3-kinase (PI3K) pathway is instrumental in regulating a spectrum of cellular processes, with Akt, a serine/threonine kinase, serving as a principal target within the PI3K signaling cascade. After Akt activation, NF-?B enters into the nucleus and acts as transcription factors, initiating downstream inflammatory responses (Molodecky et al., 2012, Qi et al., 2024). Evidence has confirmed that the PI3K/Akt signaling pathway is implicated in inflammatory responses through its interaction with NF-?B (Ma?yszko et al., 2005). Although these pathways have been studied individually in the context of As or F exposure, it remains unclear whether their co-activation under combined exposure leads to more potent or sustained ovarian inflammation. Co-exposure may induce a synergistic pro-inflammatory state by promoting excessive reactive oxygen species (ROS) production, disrupting hormonal signaling, and impairing mitochondrial function, all of which may amplify PI3K/Akt/NF-?B activation. These compounded effects could compromise ovarian integrity and follicular development more severely than single toxicant exposure. Therefore, elucidating whether the PI3K/Akt/NF-?B pathway mediates enhanced ovarian inflammation under As and F co-exposure is a key focus of this study.

A growing body of research indicates that heavy metals can disrupt the metabolic health of organisms by altering the composition and functionality of the gut microbiota (Bist and Choudhary, 2022, Liu et al., 2023a). Previous research has found that As and F can cause intestinal microbiota disorder (Lu et al., 2014, Lu et al., 2021). As an intricate ecosystem, the gut is intricately linked to other bodily systems. Our previous studies from our group have found that As and F exposure can cause intestinal flora disturbance and induce cardiovascular and male reproductive system damage (Liu et al., 2021, Yan et al., 2021). There is increasing evidence that the gut microbiota plays a critical role in regulating reproductive health. The gut microbiota affects reproduction through immune, hormonal and inflammatory mechanisms (Ashonibare et al., 2024)Imbalances in the gut microbiota are often accompanied by chronic inflammation (Rizzetto et al., 2018). An animal study has shown that arsenic exposure can compromise the intestinal barrier function, resulting in the translocation of lipopolysaccharide (LPS) from the gut into the bloodstream, and ultimately causing liver damage (Zhong et al., 2021). In addition, alterations in the gut microbiota are a significant contributor to ovarian inflammation in patients with Polycystic Ovary Syndrome (Liu et al., 2023b). Fecal microbiota transplantation (FMT), as an innovative therapeutic approach, has garnered increasing attention. In addition to being a proven effective treatment for Clostridium difficile infection, more extensive use of FMT has been seen in recent years. It can improve clinical symptoms by improving the dysbiosis of flora, restoring the intestinal barrier function, and regulating the metabolic process (Braniste et al., 2014, Antushevich, 2020). Recent studies have extended its application to reproductive health: Huang et al. demonstrated that FMT from patients with polycystic ovary syndrome (PCOS) into germ-free mice was shown to induce metabolic disturbances and ovarian dysfunction, emphasizing the critical role of gut dysbiosis in female reproductive (Huang et al., 2024). Similarly, fecal transfer from bisphenol S (BPS)-exposed mice impaired oocyte quality and mitochondrial function in recipient mice, suggesting that microbiota alterations mediated by environmental toxins may negatively influence female fertility (Zhang et al., 2025). However, according to the results of the current study, whether fecal microbiota transplantation can change the intestinal function induced by arsenic and fluorine and further reduce the occurrence of ovarian inflammation is worthy of further investigation.

Based on this, SD rats were selected as the research object in this experiment, and an animal model of As and F combined with drinking water poisoning and fecal bacteria transplantation intervention was established. To investigate the effects of combined exposure to As and F on the normal physiological function of ovaries in female mice during puberty and sexual maturity, and the role of PI3K/Akt/ NF-?B pathway-induced inflammation in them, and to further explore whether the intervention method of microbiota transplantation can alleviate the ovarian damage caused by arsenic fluoride exposure by changing the function of the intestinal barrier.

4. Discussion

There is mounting evidence that long-term exposure to NaAsO₂ and NaF may affect ovarian and estrogen function, which may lead to female infertility (Jhala et al., 2008, Eslami et al., 2024, Zhou et al., 2013). Due to the susceptibility of adolescent reproduction to heavy metals and the long-term process of ovarian damage, As exposure during juvenile and puberty is well-documented (Chen et al., 2022). However, the effects of co-exposure to arsenic and fluorine on the female reproductive system from fetal life through adolescence and maturity remain largely unknown. At critical windows across the lifespan-PND60, FMT, an effective approach to reshape microbial homeostasis, affects on the disturbance in the feces-brain axis following chronic arsenic exposure (Luo et al., 2023). Thus, in order to investigate the possible mechanisms of NaAsO₂ and NaF -induced damage to the female reproductive system, we established an animal model of NaAsO₂ and NaF co-exposure from gestation to adolescence or adulthood. In addition, an FMT animal model at PND60 was established, hoping to comprehensively explore the effects of FMT on rats with arsenic and fluorine combined poisoning. Here, our results showed that exposure to As and F caused ovary injury in rats by activation of PI3K/Akt/ NF-?B pathways with the prolongation of exposure time, particularly at PND120. FMT aggravated or alleviated the ovarian inflammation by regulating inflammatory factors in serum through colon barrier injury or recovery.In this study, we found that serum hormones levels(E₂ ?LH) were significantly reduced following NaAsO₂ and NaF co-exposure, supporting their detrimental effects on ovarian development in offspring. This aligns with epidemiological evidence showing that individual exposure to either NaAsO₂ or NaF is associated with decreased E2 and LH levels in adolescent females (Zhang et al., 2023a, Wang et al., 2020, Zhao et al., 2015). For instance, a case-control study involving 609 participants at Anhui Medical University Hospital revealed a negative correlation between NaAsO₂ exposure and female reproductive development. Our animal study confirmed that prenatal NaAsO₂ and NaF exposure resulted in impairments in the female reproductive system of offspring rats, which were consistent with the aforementioned epidemiological studies and showed up as decreased serum hormone levels and impaired ovary structure (Georges et al., 2014, Ommati et al., 2020). Interestingly, while serum E2 and LH levels remained relatively unchanged at PND60, they significantly declined at PND120, suggesting that the toxic effects of NaAsO₂ and NaF may be both developmental stage-specific and cumulative. This difference may be attributed to the physiological characteristics of the two developmental stages. At PND60, rats are in the peripubertal stage, during which the ovary undergoes rapid folliculogenesis, and the hypothalamic–pituitary–gonadal (HPG) axis is still maturing. The detoxification and antioxidant defense systems may not yet be fully developed, rendering the ovary sensitive but still capable of partial compensation. In contrast, by PND120, rats have reached full sexual maturity, with more stable endocrine regulation. However, prolonged exposure during early life may lead to cumulative toxic damage that surpasses the ovary’s repair capacity, resulting in more pronounced structural and hormonal impairments. Morphological analysis further supported this conclusion: at PND120, follicular damage was more severe, with granulosa cell disorganization, zona pellucida degeneration, and ultrastructural mitochondrial disruption (Zhao et al., 2018; Ommati et al., 2020). These findings suggest that NaAsO₂ and NaF exert developmental stage-dependent effects on the ovary, with greater vulnerability and damage manifesting in adulthood. Although the gut microbiota plays a crucial role in NaAsO₂ and NaF -induced infertility (Liu et al., 2021), its exact function has not been thoroughly investigated. In this study, FMT significantly reduced the reproduction damage caused by exposure to As and F in offspring rats. As far as we are aware, this is the first study to concentrate on employing FMT as a protective strategy to alter the gut microbiota in order to combat reproductive impairment induced by As and F. Our findings align with an experimental study demonstrating enhanced ovarian function following the FMT from high-laying rate breeders (Cao et al., 2023). After FMT treatment, the AsF+FMT(C) group exhibited increased LH levels and improved ovarian coefficients. Histological and ultrastructural analyses of the ovary also demonstrated corresponding damage. Moreover, FMT alleviated the hormone reduction and ovarian structural damage caused by NaAsO₂ and NaF in AsF+FMT(C) group.

Our team has previously shown that maternal NaAsO₂ and NaF exposure alters the gut microbiota composition in offspring rats (Liu et al., 2021, Yan et al., 2021, Qiu et al., 2020). Dysbiotic microbiota can impact other organs and cause disruption of the intestinal barrier (Qi et al., 2021). Recent studies have recognized that altering the gut microbiota can mitigate hepatic inflammation triggered by microplastic particles, attributed to improved colonic inflammation and intestinal barrier function (Zhang et al., 2023b). So we focused on intestinal barrier to explore how altered microbiota community affected NaAsO₂ and NaF -intoxicated ovary dysfunction in offspring. Consistent with our findings, injured colonic barriers were observed in NaAsO₂ and NaF exposed rats, as evidenced by HE and PAS staining. The expression of tight junction Occludin, Claudin-4 and ZO-1 showed significant reduction in colonic tissues of offspring rats in the AsF group. Additionally, the number of goblet cells, essential for maintaining the intestinal mucus barrier, was decreased (Zhang et al., 2022). Previous research has found that maternal FMT treatment can improve mRNA expression of tight junction-related molecules in intestinal barrier induced by As (Zhao et al., 2023). Here, the AsF+FMT(C) group exhibited increased goblet cell numbers and mRNA expression of tight junction-related molecules, indicating the positive effects of FMT. So all these results confirmed that As and F exposure changed the composition of gut microbiota, and FMT had a certain intervention effect on barrier damage.

FMT can reduce the level of inflammatory damage by remodeling microbial homeostasis (Liu et al., 2024, Ooijevaar et al., 2019). Most recently, there is growing recognition that altering the gut microbiota mitigated MPs-induced hepatic inflammation, which may be attributed to the colonic inflammation and improved intestinal barrier function (Zhang et al., 2023b). Previous research has also found that maternal FMT treatment can suppress mRNA expression of tight junction-related molecules in intestinal barrier induced by As (Zhao et al., 2023). Furthermore, FMT has been shown to restore the abundance of beneficial bacteria such as Lactobacillus and Bifidobacterium, which are known to enhance gut barrier integrity and modulate systemic immune responses. Therefore, we focused on gut barrier to explore how altered microbiota community affected NaAsO₂ and NaF -intoxicated ovary dysfunction in offspring. The mRNA expression of key tight junction-related molecules further supported our findings, showing that the injured colonic barrier s in NaAsO₂ and NaF exposure rats improved after FMT administration, suggesting the protective effect of FMT treatment against inflammation-related intestinal barrier damage. Further research into the potential underlying mechanisms of FMT’s therapeutic effects on female reproductive dysfunction caused by NaAsO₂ and NaF revealed elevated serum LPS levels and enrichment of the inflammation-related NF-?B pathway in As and F-induced ovarian injuries. Correspondingly, LPS-induced signaling pathways promote the release of pro-inflammatory mediators and activate the NF-?B pathway (Zeng et al., 2024). The decreased protein expression of PI3K, NF-?Bp65, and IL-6 suggested that FMT reduced serum LPS levels and mitigated NaAsO₂ and NaF related systemic and ovary inflammation. In addition, FMT regulates estrogen levels and improves ovarian pathological changes. All of these results suggest that FMT can recover female reproductive function by improving the barrier function of the intestinal tract and reducing inflammatory damage to the ovaries induced by NaAsO₂ and NaF.However, several limitations should be acknowledged. Notably, we did not quantify As and F levels in biological samples, limiting our ability to correlate exposure levels with observed reproductive effects. Furthermore, the long-term efficacy and safety of FMT remain uncertain, as its durability and potential adverse effects over extended periods are not well understood. Additionally, potential confounding factors, such as genetic variability and environmental influences, were not controlled in this study, which may affect the generalizability of our findings. Future research should focus on quantifying As and F levels in biological samples, conducting long-term studies to assess the sustainability and safety of FMT interventions, and exploring the effects of FMT in diverse populations to enhance generalizability. By addressing these areas, future studies can better elucidate the potential of FMT as a sustainable and safe therapeutic approach for mitigating reproductive toxicity caused by environmental contaminants.

5. Conclusion

The combined exposure of As and F can induce damage to rats, disrupt hormone levels, and alter the morphology and ultrastructure in ovarian tissue. At the same time, the PI3K/Akt/NF-?B pathway is involved in ovarian injury induced by As and F, particularly on PND 120. FMT can recover female reproductive function by improving the barrier function of the intestinal tract and reducing inflammatory damage to the ovaries induced by As and F.

Appendix A. Supplementary material
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Fecal microbiota transplantation alleviates female offspring’s ovarian inflammation in arsenic and fluoride co-exposed rats through the PI3K/ Akt /NF-?B pathway.

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