*6.3. Metabolic Homeostasis*

In addition to the induction of inflammation and apoptosis, recent studies have revealed that microplastics and nanoplastics can impair cellular metabolism in both in vitro and in vivo models. Polystyrene-based nanoparticles influence signaling systems in airway epithelial cells due to nanoparticle-cytoplasmic membrane interactions. After exposure to negatively charged carboxylated polystyrene nanoparticles measuring 20 nm, basolateral K+ ion channels were found to be activated in human lung cells [136]. The nanoplastic particles caused persistent and concentration-dependent increases in short-circuit currents by the activation of the ion channels and the stimulation of Cl− and HCO3 − ion efflux [136].

Furthermore, 30 nm polystyrene nanoparticles induced large vesicle-like structures in the endocytic route in macrophages and human cancer cell lines A549, HepG-2, and HCT116. As a result, vesicle transport and the distribution of proteins involved in cytokinesis are blocked, thus stimulating the formation of binucleated cells [137]. In addition, acute oral exposure to positively charged polystyrene nanoparticles has the potential to disrupt intestinal iron transport and cellular uptake [138].

When mice were fed with pristine polystyrene microparticles (5 μm and 20 μm) for 28 days, the microplastics were found to be distributed in the liver, kidneys and gut, with larger particles dispersed regularly across all tissues, while the smaller particles found at higher concentration in the gu<sup>t</sup> [125]. Inflammation and lipid droplets were also evident in the histopathological analysis. There was evidence that showed microplastic accumulation in murine tissue caused impairment of energy metabolism, lipid metabolism, oxidative stress and neurotoxic responses. There were decreases noted in hepatic levels of ATP, total cholesterol and triglycerides, as well as reduction in catalase activity, whereas increases were observed in the activity of several biomarkers (LDH, SOD, GSH-Px and AchE) [125,139,140].

Furthermore, pregnan<sup>t</sup> mice exposed to microplastics via ingestion developed gu<sup>t</sup> microbiota dysbiosis, intestinal barrier dysfunction and metabolic disorders. The effects of microplastics exposure at the maternal level also conferred permanent altered metabolism in

the F1 and F2 generations [135,141]. The key results from these studies showed: (1) Change in the gu<sup>t</sup> microbiota; (2) change in the intestinal barrier where less mucus was secreted and lower levels of ion transporter gene expression; and (3) alterations to lipid/fatty acid metabolism, as demonstrated by the differences in serum and liver triglyceride and total cholesterol levels [134,135,140,141].

### **7. Leaching of Toxic Chemicals from Plastics**

As discussed above, plastics usually contain chemicals from the raw monomers and various types of additives to improve their properties. In addition, plastics also absorb chemicals from their surroundings [144,145]. As a result, these chemicals have the potential to leach from the polymer and into the environment around them. For example, polycyclic aromatic hydrocarbons (PAHs) have been shown to be adsorbed by microplastics and causing various toxic effects when ingested by various organisms [145]. Chemical species diffuses from the interior of a particle to its surface, leaching into the surrounding environment, and is possibly driven by a gradient function. Although these chemical species are transient and degrade rapidly in the human body, these plastic particles provide a durable 'reservoir' for chemical leaching into tissues and body fluid [146].

To date, toxic chemical additives in plastic that are known to affect human health include bisphenol A (BPA), phthalates, triclosan, bisphenone, organotins and brominated flame retardants (BFR) (Figure 4) [147]. Although limited information is available whether these additives leach into the biological tissues directly, certain additives, such as nonylphenol and BPA, are found to be ingested by marine biota [148]. In particular, exposure to leached BPA, an additive that is commonly used to make polycarbonate (PC) plastics and epoxy resin as lining layer of food and beverage cans, has been shown to cause endocrine disorders and impact human health [147,149,150].

**Figure 4.** Overview of the toxic effects of chemicals leaching from plastics. Plastics are made up of different chemical compositions, in which some are hazardous that can leach to the surroundings upon degradation. Plastics typically contain additives that can improve their properties, such as durability and elasticity. The leaching of these additives from plastics to the surrounding environment, not only causing harmful impacts to the aquatic environment, but also human health. For instance, bisphenol A (BPA), an industrial chemical that is widely used to make polycarbonate (PC) plastics and epoxy resin

as lining layer of food and beverage containers. Studies reported that the leaching of BPA from food containers into the food and drinks can cause a series of diseases, including obesity and cardiovascular diseases. BPA also acts as a hormonal disruptor, imitating or blocking the production, action, and function of hormones in the human body. BPA also known to affect brain development in the womb, causing damage to the developing fetus. Polyvinyl chloride (PVC) polymers and plastisol generally contain phthalate esters as plasticizers, in order to increase their durability and flexibility. Human exposure to phthalate esters has been shown to associate with abnormal sexual development and changes in the levels of sex hormones. Additionally, studies have demonstrated that some phthalate esters such as butyl benzyl phthalate (BBP) and di-2-ethylhexyl phthalate (DEHP) can increase tumor incidence in human, representing potential carcinogens.

> Importantly, studies have found that BPA will leach from PC into food and drinks [147,151,152], and that the toxicity of BPA causes changes in liver function and insulin resistance, damage of a developing fetus and modification of the reproductive system and neurological functions [153]. BPA acts as an agonist for estrogen receptors and inhibits thyroid hormone-mediated transcription by acting as an antagonist [154], and alters pancreatic beta cell function [155]. Increased likelihood of developing obesity and cardiovascular diseases [156–158], and several other reproductive and developmental issues have been noted when humans are exposed to BPA at concentrations of 0.2–20 ng/mL [147].

> Phthalate esters are used as plasticizers in the manufacturing of PVC polymers and plastisol to achieve enhanced flexibility and durability [159]. Human exposure to phthalate esters are potentially harmful and may cause abnormal sexual development and birth defects [160]. Additionally, butyl benzyl phthalate (BBP) has been named as a probable carcinogen, and di-2-ethylhexyl phthalate (DEHP) has been cited as a possible carcinogen by U.S. EPA [15].
