Understanding the implications of microplastics on maternal health during pregnancy, gut dysbiosis, and gestational diabetes mellitus

INTRODUCTION

The plastic usage, particularly post-pandemic, has increased drastically and is now a part of our daily lives. Plastics are used in the manufacturing of a wide range of medical items, ranging from medical supplies to protective gear. Overproduction has resulted in extensive wastage, which in turn has resulted in elevated levels of microplastics (MPs) entering the environment.^[1] During the course of decomposition, plastics tend to accumulate in the environment. Large-sized plastics are degraded into smaller plastic particles around 5 mm or nano-sized plastics, <1 μm, which are the “microplastics.”^[2] The plastic waste may undergo degradation either by microbial degradation and hydrolysis or by photo and thermo-oxidative degradation. Irrespective of the method of degradation, the half-life period of MPs ranges from around 60 years to 450 years.

These micro and nanoplastics contaminate various environmental niches.^[3,4] By 2025, global plastic waste could reach around 11,000 Mtons. Regrettably, once plastics enter the environment, they tend to persist for a significant duration.^[5] The COVID-19 pandemic has significantly increased the use and disposal of single-use plastics by 40% in packaging and 17% in other applications, including medical uses.^[6,7] The pandemic resulted in a plastic waste of around 9 million tons across the globe between 2000 and 2021 alone.^[8]

ROUTE OF ENTRY

With the significant increment in the environmental concentrations of MP nanoparticles (MNPs), there have been increased levels detected in humans, animals, and plants.^[9,10] MNPs have been extensively identified on human skin, hair, saliva, sputum, and feces.^[11,12] Recent findings suggest that MPs are also present in human blood, urine, breast milk, and placenta, indicating their circulation within the body.^[13-15] The first report on the presence of MPs in human placenta and other compartments was provided by Ragusa et al.^[16] Moreover, a developing fetus exposed to MPs may have teratogenic changes in the reproductive as well as central nervous system as the primary target.^[17-19]

The absence of standardized techniques for assessing MNP levels across various matrices complicates the evaluation of exposure levels in both humans and animals, as well as the comparison of different research studies.^[20,21] Given that plastics have been identified in the meconium of newborns, it is evident that early life is indeed subject to exposure.^[22]

Primarily, the plastic particles enter the body through the oral route. Alternatively, they enter through inhalation and dermal contact.^[23] The presence of MNPs has been detected in a variety of products, ranging from seafood ^[24-26] to fresh fruits, to milk and milk products, and in packaged food items.^[27]

In recent years, the public as well as the scientific fraternity have become increasingly aware and concentrated on the health implications of MPs.^[28] The toxicological effects of micro and nanopolymers are due to their chemical composition and physicochemical characteristics, their concentration, rate of absorption, and interaction with the biological and physiological pathways.^[29]

MPs accumulate significantly in the aquatic and specifically marine animals, and consumption of seafood increases human exposure to MPs. MPs pose long-term health implications. The gastrointestinal (GI) tract and the resident gut microbiome are majorly affected, leading to their possible association with chronic diseases. In addition, inhaling urban air contributes to human exposure to MPs [Figure 1].^[30]

Close

Figure 1:

General overview of the impact of microplactics on gut dysbiosis, pregnancy and its complications. The arrow indicates the primacy targets which are emphasized in the manuscript. ROS: Reactive oxygen species, GDM: Gestational diabetes mellitus.

Export to PPT

MPs CELLULAR UPTAKE

MPs, which are either ingested or inhaled, enter into circulation, are endocytosed depending on their size.^[31] Small-sized MPs enter through passive diffusion while larger particles are taken in through active transport mechanisms. MPs, subsequently, get accumulated in the cytoplasm, and while phagocytosed MPs fuse with endosomes are accumulated within the lysosomes.^[32] The study provided an alarming insight into the presence of MPs in several tissues other than the peripheral tissues, such as the brain and uterus.^[31]

MPs AND GUT DYSBIOSIS

MPs can build up in the GI tract following ingestion and remain there for extended periods due to their resilience against digestion. Numerous studies conducted on animal models have indicated that MPs physically interact with the intestinal lining, resulting in mechanical damage and possibly triggering inflammatory reactions. MPs and MNPs enter the lymph and circulation by adhering to the intestinal epithelium and crossing the barrier.^[32,33] Furthermore, MPs may increase intestinal permeability, leading to a leaky gut syndrome, resulting in metabolites from the GI tract entering the circulation.^[34]

The dynamically and complexly interacting microorganisms within the gut microbiome influence digestion, metabolism, and immune response, and thereby the overall health of the individual. This microbiome is particularly susceptible to exposure to MPs. Researchers have established a link between the MPs exposure and gut dysbiosis. Microbial dysbiosis results in altered digestive physiology and altered immune response and the probability of multiple disorders.^[35] In addition, exposure to MPs alters the gut microbiome, triggering systemic inflammation, a recognized contributor to various chronic diseases. However, the disease condition of the GI physiology due to the exposure to MPs is not confined to the GI tract. However, this systemic inflammation may aggravate into other chronic health issues, including metabolic disorders, cardiovascular diseases, and autoimmune disorders.^[36-38] Furthermore, as MPs are also reportedly detected in the brain tissues, there is an increasing association between MPs and neuroinflammation, which emphasizes their role in psychological and neurological disorders by modulating the gut-brain axis.^[39,40]

The major constituents of the MPs, such as copper ions, polymeric materials, and other additives, have been reported to be potent endocrine disruptors.^[41] Researchers have revealed elevated levels of inflammatory markers such as interleukin (IL)-1β, IL-6, and IL-8 in rodent models administered with polyethylene MPs. The exposure to MPs upregulates reactive oxygen species (ROS) and inflammatory mediators, resulting in oxidative stress (OS), leading to DNA damage, immune response, and chronic inflammation. In vitro studies suggest an altered liver metabolism leading the hepatotoxicity and diminished lipid and carbohydrate metabolism.^[42] In addition, there was a marked reduction in the colonic expression of mucin, significant downregulation in lipopolysaccharide (LPS) metabolism. The study also emphasizes altered intestinal microflora which contributed in an enhanced the amino acid metabolic pathway.^[43] MPs’ exposure significantly altered the biosynthesis and metabolism of key amino acids and nucleotide bases following alteration in the gut microbiota.^[44] Qiao et al.^[45] showed that early exposure to MPs resulted in their accumulation in the vital organs, leading to disrupted energy as well as lipid metabolism and increased OS.

The gut microbiome prevents the colonization of non-resident bacterial strains, and any dysbiosis in this condition or equilibrium may trigger the onset of diseases. MPs trigger gut dysbiosis, leading to intestinal inflammation. The dysbiosis is primality due to an increase in the Proteobacteria, which are the major contributors of LPS.^[46] Furthermore, alteration of the gut microbiota through altered levels of Proteobacteria, Bacteroidetes, Fusobacteria, and Firmicutes by MPs led to elevated levels of ROS.^[47] MPs drastically affect the proliferation and renewal of the epithelial cells.^[48]

The gut microbiome, in the last few decades, has been identified as a potent and crucial modulator of the host immune response, as well as involved in the metabolic degradation of carbohydrates and proteins.^[49] Experiments on the mucosal artificial colon model suggested that prolonged exposure to polyethylene MPs altered both intestinal epithelial and mucus-producing cells and gut microbiota and significantly altered the intestinal barrier permeability. There were increased levels of Desulfovibrionaceae and Enterobacteriaceae, while the numbers of mucin-producing bacteria such as Christensenellaceae and Akkermansia decreased.^[50]

A study undertaken by Zha et al.^[51] suggested that an alteration in the infant’s gut microbiota was observed irrespective of entry of these MPs into the infant system through breastfeeding, environmental exposure, or bottle feeding.^[51] There is an alteration in the microflora reported upon consumption of food from disposable plastic containers, suggesting plastic containers as a potent mediator for gut dysbiosis as well as for GI dysfunction.^[52] The intestinal barrier functions are compromised on prolonged exposure to pristine polystyrene micro-nanoplastics.^[53]

MPs AND MATERNAL HEALTH

A study demonstrated the existence of MPs within human placental tissues. The study identified polypropylene, polyethylene terephthalate, and polyvinyl chloride within the human placental tissue. These constituents of MPs have been reported as potential mutagenic or carcinogenic agents. The presence of these potentially mutagenic and carcinogenic MPs in the placental tissue evokes a greater concern pertaining to their role in fetal growth and development.^[16]

The endocrine-disrupting chemicals (EDCs) have the potential to cross the placenta and induce detrimental effects on the fetus. EDCs have been reported in cosmetic items which have a potential teratogenic effect on fetal growth and development, at the same time impairing the placenta.^[54] Evidence suggests that MPs disrupt various placental cellular pathways, leading to pregnancy-related complications such as pre-eclampsia and circumscribed fetal growth. As the placenta is extremely crucial for a healthy pregnancy, it is imperative to focus more on the environmental factors that influence its functionality.^[55]

Furthermore, Luo et al.^[56] revealed a reduction in the percentage of Th17 cells, alongside the induction of intestinal dysbiosis and inflammation, particularly affecting the duodenum and colon. Pre-primary children and toddlers are particularly susceptible to MPs exposure and other pollutants associated with plastic items, such as toys, fabrics, and feeding bottles, due to their tendency to chew and lick these objects. The majority of toys are made primarily of plastic and include a number of hazardous additives, such as Bisphenol A (BPA), plasticizers, and cadmium, which are used primarily to improve and maintain the physicochemical characteristics of the products.^[57]

One of the key characteristic features of pregnancy is an elevated ROS, mediated by the placenta. An abnormal increase in the OS during pregnancy results in tissue damage. The elevated OS is countered by the antioxidant produced by the placenta.^[57,58] The consumed MPs in various in vivo animal studies showed a significant accumulation in the gut, disrupting its physiological functions. Large-sized MPs (more than 150 μm) adhere to the mucosal layer of the intestine, thereby directly affecting the intestinal epithelial cells, while small-sized MPs penetrate the mucosal layer, resulting in intestinal inflammation and various immunological effects.^[59]

One of the probable pathways of polystyrene MPs-induced ovarian fibrosis is through activation of the toll like receptor 4 (TLR4)/nicotinamide adenine dinucleaotide phosphate (NADPH) oxidase 2 signaling pathway. This may result in an increased oxidative stress and activating the neurogenic locus notch homolog protein (NOTCH) signaling pathway, resulting in elevated transforming growth factor beta (TGF-β) in the endometrium and the uterus.^[60]

Pregnancy is marked by a harmonious balance maintained between the maternal and the fetal immune systems. Environmental pollutants, such as carbon monoxide, kitchen smoke, and particulate matter, can disrupt this balance, potentially increasing the risk of spontaneous abortion.^[57] Research indicates that early exposure to MPs significantly impacts immune homeostasis, particularly affecting reproductive health at the maternal-fetal interface. Studies have demonstrated that a 5-week exposure to polyethylene MPs leads to notable changes in serum IL-1 and granulocyte colony-stimulating factor, while also reducing T-reg and increasing Th17 cell populations in splenocytes.^[57] In addition, MPs and di(2-ethylhexyl) phthalate potentially modify gut microflora, resulting in substantial alterations in the bacteria.^[43,58-62]

INTERPLAY BETWEEN GUT MICROBIOME AND GESTATIONAL DIABETES MELLITUS (GDM)

The gut microbial dysbiotic condition in the human GI system may represent a considerable risk factor for the disruption of host metabolism.^[63] Liu et al.^[64] reported that a reduction in Bifidobacteria resulted in an increased production of endogenous LPS, which is linked to insulin resistance and obesity. Furthermore, exposure to environmental chemicals can modify gut microflora, correlating with various diseases.^[65] Exposure to MPs during pregnancy alters maternal gut microbial composition and increases the risk of GDM.^[66] The regulation of gut microbiota presents newer avenues for the management of GDM that arises from environmental exposures. Metabolic disorders such as GDM, independently, trigger alterations in maternal gut microbiota.^[67,68]

There is sufficient literature available elaborating a strong link between gut microbiota dysbiosis and GDM. Studies have revealed that patients with GDM have low gut microbiota diversity compared to healthy individuals. The GDM patients characterized an increased presence of Prevotella, Ruminococcaceae, Parabacteroides distasonis, and Desulfovibrionaceae, to name a few. These individuals showed decreased levels of Bifidobacterium spp., Akkermansia, Bacteroides, and Faecalibacterium.^[69,70]

The gut microbiota showed a distinct variation in their composition in normal pregnant, diabetic pregnant, and GDM pregnant women. This indicated that a clear and significant variation has been reported even among diabetic pregnant and GDM pregnant women. The study highlighted Bacteroides dorei, a key member of the gut microbiome community, which plays an important role in carbohydrate metabolism and immune regulation. B. dorei may serve as a promising diagnostic and therapeutic indicator for GDM.^[71]

CONNECTING MPS, GUT MICROBIOTA, AND GDM

The exact mechanism that may connect MPs, gut microbiota, and GDM is still under investigation.^[72] MPs can physically interact with gut bacteria, leading to alterations in their growth and functionality. Furthermore, MPs might serve as vectors for other detrimental chemicals, including endocrine disruptors, affecting the gut microbiota composition.^[73] In addition, there is an alteration in the gut microbiota due to the adverse immune response triggered by MPs in the GI tract.^[58] The onset of chronic inflammation before GDM is characterized by impaired gut permeability, resulting in leaky gut syndrome, leading to bacterial metabolites such as LPS and metabolic end products infiltrating the circulation. In addition, MPs may disrupt hormonal signaling, thereby aggravating the metabolic imbalances linked to GDM.^[74] Experiments in the rodent models demonstrated that exposure to MPs induced systemic inflammation, leads to insulin resistance and hyperglycemia.^[75] These pathophysiological changes mimic the effects observed in GDM. Docking studies suggested modulation of signal transducer and activator of transcription 1 (STAT1) and Phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) signaling following exposure to MPs.^[76] STAT1 and PIK3R1 functioning are critical in understanding the actual mechanism of GDM induction and pathogenesis in MPs individuals exposed.

WAY FORWARD

With the enhanced understanding of the connection between the three, i.e., gut microbiota, GDM, and MPs, this would open potential preventive as well as therapeutic strategies for the future to be explored. It is crucial to undertake extensive epidemiological research to decipher the mechanistic pathway involved in associating MPs and GDM and other host co-morbidities. Furthermore, the possible consequences for public health are substantial. Should a definitive connection between MPs, gut microbiota, and GDM be established, it would prompt the need for public health initiatives aimed at minimizing MPs’ exposure, especially among pregnant women. This could lead to necessary policy reforms, including the regulation of MPs’ levels in consumer goods, alongside educational efforts to inform the public about the potential dangers associated with MPs’ exposure. As our understanding of the adverse effects of MPs has increased, the detrimental effects on maternal and fetal health have become of primary focus. The future study should focus on determination of the molecular mechanisms, ways to prevent its intake, identification and investigation of therapies and equally essential is to have an early and non-invasive detection techniques from biological and non-biological samples. Second, theranostic biological markers need to be identified for early detection as a probable treatment for the health complications [Figure 2 and Table 1].

Close

Figure 2:

Mechanistic view of microplastics entry, its effect on the host as well as maternal health. GI: Gastrointestinal

Export to PPT

CONCLUSION

MPs pose a serious danger to the stability of our ecosystems because of their harmful impacts on microbiota, living creatures, and nutrient dynamics. The key characteristics of MPs, including their composition, shape, and concentration, play a crucial role in their adverse influence on the surrounding environments. The studies revealed potential effects of MPs on gut microflora, leading to gut dysbiosis and GDM individually. However, the exact mechanisms and interaction between exposure to MPs leading to gut dysbiosis and potential induction of GDM and other co-morbidities still need to the ascertained. During pregnancy, biological systems undergo various changes and adaptations, which may naturally alter the gut microbiome. This alteration can directly or indirectly contribute to metabolic changes associated with GDM. Consequently, a multitude of shifts and changes occur throughout the gestational period. The precise role and effect of the exposure to MPs on the host as well as the maternal gut microbiome still need to be identified. There is a need to understand the potential effects of MPs’ exposure on the gut microbiome, specifically the maternal gut microbiome, as well as to identify the microbiome’s role in the degradation of MPs. In addition, the onset and prevalence of GDM among MP-exposed groups must be examined. There needs to be an increased awareness of the implications of MPs of the health of individuals regardless of their sex, age, and reproductive status of the individual. Lacunae that need immediate attention are pertaining to the duration of exposure to the chronic health complications as well as the health implications through different phases of pregnancy and post-partum duration.