综述：基于动物研究的微塑料对下丘脑-垂体-卵巢轴影响的系统评价

《Toxicology Letters》：A systematic review on the effect of microplastics on the hypothalamus-pituitary-ovary axis based on animal studies

本综述系统评价了微塑料（MPs）通过干扰下丘脑-垂体-卵巢轴（HPO轴）对雌性生殖系统的毒性效应。文章指出，聚苯乙烯（PS）是研究最广泛的微塑料，暴露后可导致17β-雌二醇（E2）水平降低，引发卵巢氧化应激与细胞凋亡，并影响促卵泡激素（FSH）、促黄体生成素（LH）等关键激素及相关基因表达，最终损害生殖功能。该研究为评估微塑料的生殖健康风险提供了重要依据。

　　

Abstract

Humans are exposed to microplastics through three routes: oral, dermal, and respiratory. These tiny polymer particles enter the body and accumulate in various organs. One of the most sensitive organs to microplastics is the female reproductive system. In this review, manuscripts that investigated the effects of various microplastics on the hypothalamic-pituitary-ovarian axis in laboratory animals were collected with relevant keywords. This axis plays an important role in the function of the female reproductive system. Effects on endpoints of this axis, including hormonal changes, gene expression, and histopathological changes, were assessed. The most studied microplastic was polystyrene. Hormone levels were measured in all studies. In almost all studies, 17β-estradiol was decreased. Apoptosis and oxidative stress-induced damage in the ovaries were also observed in some studies. The results summarized from the manuscript emphasize the adverse effects of microplastics, especially polystyrene microplastics, on the female reproductive system following exposure.

Introduction

Plastics are made of synthetic polymers and have been in human life for more than 50 years. Their global production, consumption, and waste are growing. Most of the time, plastics are not recycled and a significant amount of plastic is released and accumulated in the environment. On average, it takes 100 years for plastics to completely decompose in the environment. As a result of natural processes such as solar radiation and hydrolysis, or due to physical impact, they are converted into smaller particles called microplastics. Microplastic particles are considered to be less than 5 mm in size.

Various plastics, including polyethylene (PE), polystyrene (PS), polypropylene (PP), polyamide (PA), polyvinyl chloride (PVC), and polyethylene terephthalate (PET), are being used. The production of polypropylene, polystyrene, and polyethylene is higher than that of others.

Oceans and waters contain significant amounts of microplastics. Due to the entry of plastics into the seas and waters, the level of pollution in the areas is significant. Consequently, food products of marine origin are a major source of exposure. Several studies have identified these particles in bivalve molluscs from different bays. Also, in table salt, which is usually prepared from seawater, microplastics have been isolated. Therefore, marine food and sea salt can be a significant source of microplastics for humans. Another important source is airborne microplastics. The source of airborne microplastics is urban and household dust and particles from worn tires and torn and old textiles that are released into the air. The risks from airborne exposures are greater than those from water and food. The amount of microplastics in soils is also significant, and it has even been reported to be 4–23 times higher than in water. Microplastics have the ability to enter vegetables from agricultural fields. Therefore, people are exposed through various foods, especially seafood products, plant food, cosmetics, and airborne fibers.

It is estimated that people are exposed to 74,000–121,000 microplastic particles per day. The Tolerable Daily Intake for these particles is considered to be 5 mg/kg bw/day. Exposure to microplastics is also through ingestion, inhalation, and dermal routes. Microplastics accumulate in various tissues and cause negative effects on organs. They are present in various areas of the body, including the skin of the hands, face, hair, saliva, breast milk, and organs. They have the property of accumulating in the liver and lead to lipid oxidation in the liver. The cumulative properties of polyethylene microplastics have been observed in Physalaemus cuvieri tadpoles.

The reproductive system is one of the most sensitive systems in the body. In recent years, there has been a growing trend in infertility and interference with the reproductive system. According to reports from the World Health Organization, one in every six adults in the world experiences infertility. Infertility has negative effects on individuals' psychological and social functioning. According to recent reports from the World Health Organization, one in six adults experience infertility. Infertility is the fifth most serious disability worldwide. Unfortunately, in many societies, the blame for infertility and childlessness falls on women.

Fish can ingest and accumulate microplastics. In studies on fish exposed to microplastics, it has been observed that the ovaries, after the intestines and gills, will contain significant amounts of microplastics. Furthermore, polystyrene microplastics accumulated in the uterus and ovaries of exposed female mice for 35 days. One organ where microplastics specifically accumulate is the placenta. In a study conducted on 17 human placenta samples, microplastics, including polypropylene and polyvinyl chloride, were identified. Microplastics are able to interfere with the hypothalamus-pituitary-gonad axis (HPG). In a study, it was observed that the expression of genes related to this axis was altered in carp exposed to polyvinyl chloride microplastics. One of the new models for examining the effects of pollutants on endocrine glands and steroid hormone synthesis is to examine their effects on this axis. Any damage to this axis by the pollutant leads to a reduction in reproductive capacity. This axis is responsible for regulating hormones. The hypothalamus secretes gonadotropin-releasing hormone (GnRH). Gonadotrophins lead to gametogenesis and steroidogenesis. GnRH also causes the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland. FSH and LH cause the maturation of ovarian follicles and ovulation. If the follicles are damaged, it leads to abnormalities in sex hormones, including estradiol. Estradiol plays an important role in gonad development. Estradiol under the control of FSH leads to the development of oocytes. The reduction in gonadotropins subsequently causes LH and FSH deficiency. This reduces gametogenesis and the production of steroid hormones, thereby reducing fertility.

Studies have shown that polystyrene microplastics disrupt the hypothalamic-pituitary-gonadal axis. Furthermore, microplastics interfere with ovary development by interfering with the HPG axis. They have been observed to reduce the transcription of GnRH. The aim of this study is to systematically investigate the effects of these compounds on the hypothalamus-pituitary-ovary axis.

Method

This systematic review was written based on the 27-item PRISMA checklist. To avoid bias, all steps of this research (database search, manuscript screening, and data extraction) were performed independently by two of the authors. Disagreements between two authors were resolved and reviewed by the corresponding author.

Results

The research path involved selecting keywords and conducting a search in databases. 312 manuscripts from the databases were entered into the EndNote software. Duplicate articles were removed. An initial evaluation was conducted based on the inclusion and exclusion criteria by studying the title and abstract of each manuscript. Manuscripts that met the inclusion criteria were stored. In the next step, full texts were reviewed for eligibility.

Discussion

One of the current world's concerns regarding human health and the environment is microplastics. Currently, these particles have been reported in a range of foods such as seafood, table salt, tea bags, and various beverages. Therefore, exposure to these particles is inevitable.

The concentration of microplastic and its type and size play a role in its toxicity. Polystyrene is the most commonly identified microplastic in studies focusing on the female reproductive system. The reviewed studies consistently demonstrated that exposure to microplastics, particularly polystyrene, leads to a decrease in 17β-estradiol levels. This hormonal disruption is a key indicator of impaired HPO axis function. Additionally, apoptosis and oxidative stress-induced damage in the ovaries were observed, further compromising reproductive health. The accumulation of microplastics in reproductive tissues, such as the ovaries and placenta, underscores their potential to directly interfere with reproductive processes.

Conclusion and recommendations

By extracting and reviewing data from the selected manuscripts, it was observed that the presence of microplastics in the ovaries after exposure is debatable, but they have the potential to damage the female reproductive system. Three types of microplastics, polystyrene, polyvinyl chloride, and polyethylene, have been studied in this regard. In most studies, 17β-estradiol and progesterone decreased. Subsequently, estrogen and progesterone gene expression also decreased. The findings highlight the adverse effects of microplastics on the HPO axis and female reproductive health, calling for further research and regulatory attention.