INTRODUCTION

Toothpaste is the most widely used cosmetic product for teeth protection in modern societies. There are many chemicals and natural products that act as an antibacterial, antifungal, and protectant for teeth. However, its constituents include Triclosan (TCS), an antibacterial and antifungal agent to protect teeth from deleterious effects. TCS is also used in other cosmetic products such as soaps, detergents, toys, and surgical cleaning treatments1, 2. TCS is widely regarded as a broad-spectrum biocide that targets bacterial membranes, and cellular resistance is uncommon if TCS has a unique mechanism of action. Since the TCS inhibits () enoyl reductase (), the bisphenol has also been found to inhibit the enzyme from different bacteria such as () and (). TCS's inhibitory action on enoyl reductase was discovered, in and (), in (), in () and () have all been identified3, 4. and are TCS resistant, whereas is not. Similar inhibition of TCS fatty acid production was seen in higher lifeforms, including ), which causes malaria, and ()3, 5. TCS is easily photodegraded in the environment, despite its high chemical volatility and resistance to high and low pH. In the laboratory, they found eight photochemical by-products. Under various irradiation wavelengths, Latch .,6 reported TCS photoconversion to 2,8-dichlorodibenzo-p-dioxin (2,8-) with up to 12% output at pH > 8. The yield of 2,8-DCDD under laboratory settings (pure water) and river water treated with TCS was compared7. According to findings comparable to lab and field settings, TCS can be converted to 2,8-DCDD in sunlight irradiated water sources. According to Son .,8, radicals that enhance transitional dioxin degradation control TCS breakdown by titanium dioxide photocatalysis. Oxidative damage to lipid membrane, protein, and nucleic acid may result from insufficient reactive oxygen species (ROS) scavenging9. Reduced glutathione (GSH), catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), and glutathione reductase (GR) are examples of enzymatic and non-enzymatic antioxidants that defend against the harmful consequences of ROS. The peroxidation of cell membrane lipids may occur when organisms are exposed to ROS-producing contaminants. Malondialdehyde (MDA) is a biomarker for assessing cell membrane destruction that is produced as a result of membrane lipid peroxidation (LPO)10. After subchronic TCS treatment, the antioxidant mechanism of the liver may be unable to remove ROS produced by TCS, which might explain the elevated MDA levels. Antioxidant compounds are free radical scavengers because they prevent or delay-free the radical oxidation of substrates, resulting in significant LPO protection in biological systems11. Phenolic and polyphenolic chemicals are the most common natural antioxidants found in plants, foods, and beverages. The total antioxidant capacity (TAC) was calculated by reducing Mo (VI) to Mo (V) in the extract and forming a green phosphate/Mo(V) complex at an acid pH12. It evaluates overall antioxidant capacity, including both water and fat-soluble antioxidants. It has been suggested that electron donation is related to antioxidant activity, which indicates a decrease in bioactive chemical potency. Antioxidants may operate as reductants, and the deactivation of oxidants by reductants can be thought of as redox reactions in which one reaction species is reduced while the other is oxidized. Antioxidants have been found in the root of (), which may play a role in the plant's medicinal action9, 13. On the other hand, TCS interacts with (), causing structural changes and inhibiting adhesion to the AcrA promoter. TCS membrane association in human erythrocytes was also studied to see the underlying mechanisms of electrolytes channels. TCS induced K outflow and haemolysis, implying membrane breakdown while preventing hypotonic lysis, which might be mediated by membrane enlargement. TCS significantly decreased the enzymatic efficiency of membrane-bound K, Na, Mg-ATPase14. TCS affects erythrocyte osmoregulation, promotes membrane instability, and inhibits monovalent ion movement. According to studies on its impact on cell fate, TCS possesses estrogenic, proliferative, and apoptotic characteristics14. The cell cycle and death genes and proteins are especially susceptible to TCS regulation. TCS is cytotoxic to epithelial cells and gingival fibroblasts, suggesting that this may be a new apoptosis inducer in these cells. A research team used BG-1 ovarian cancer cells in various and studies to see how TCS affected the growth and proliferation of these cells. TCS promotes cell proliferation and raises the protein levels and expression of the cyclin D1 gene while decreasing the expression and protein levels of the p21 and Bax genes. After exposure to TCS, inflammation started via Toll-like receptor-4 (TLR-4)-mediated signalling mechanism through gut microbiota. Mustafa ,14 discovered TCS targets in human gingival fibroblasts, including interleukin-1 (IL-1), interferon- (IFN-), prostaglandin E - (PGES-), and major histocompatibility complex class II (MHC-II). Investigations into the subcellular localization of TCS have shown that nucleus accumulation takes priority over cytosolic accumulation14. Due to the greater initial absorption of cytoplasmic TCS, a substantial portion of cytosolic TCS was removed after each wash, whereas nuclear TCS was retained. This may explain why TCS has different inflammatory signals. However, it has been known to be a potential endocrine disruptor due to binding to androgen and oestrogen receptors15, 16, 17. In terms of TCS's androgenic properties, it was found that TCS inhibits testosterone-dependent transcription while increasing androgen-dependent transcription. TCS stimulates or inhibits a variety of signaling pathways, according to evidence on xenobiotic responses to TCS18. Although considerable progress has been made in TCS signaling, much remains unknown regarding TCS's modulatory effects on cellular physiology, especially in human-based systems. In the administration to the whole blood leukocytes, TCS inhibited TLR signaling. It leads to the downregulation of several signaling mediators, most notably NF-B inducing kinase (Nik) and C-jun. It explains the cells' cumulative lowered inflammatory response lipopolysaccharides (LPS). TCS's endocrine-disrupting properties, particularly its estrogenicity, has grabbed researchers' attention. TCS promoted proliferation in BG-1 ovarian cancer cells through the oestrogen-receptor (ER), as shown by Kim J-Y .19. TCS's mutagenic potential has been studied in prokaryotic and eukaryotic systems using and investigations. It looks for frame shift mutations, point mutations, clastogenic events, and recombination events20.

TCS did not induce gene mutations within these systems, as shown by the negative findings of these reverse mutation studies and the host. studies of gene mutations of mammalian cells in mouse lymphoma, L5178Y cells with and without metabolic stimulation show that the potential for TCS to induce mutations in the thymidine kinase (TK) domain was examined21. Studies have proven that TCS exhibits anti-androgenic and anti-estrogenic properties, depending on species, tissues, and cell types22. A study in China had shown that prenatal TCS exposure in pregnant women led to higher cord testosterone levels in infants23. Another study revealed that TCS was higher in urine samples than 75% in all tested samples24. Here, we summarized findings from recent studies, which suggest tumorigenic effects of TCS. It has been reported in many studies that extensive usage of TCS can have cancerogenic potential. Recently, TCS has been demonstrated to cause colon-associated inflammation, which ultimately leads to colitis-mediated colon tumours. TCS is also associated with higher colitis symptoms, ultimately leading to colitis-mediated colon cancer25.

TCS's effects on breast cancer cells may be influenced by the concentration and other factors such as oestradiol (natural oestrogen). A smaller head circumference at birth, early breast development, antibiotic resistance, and hypersensitivity are all possible health consequences. TCS's presence in milk suggests that it has travelled through the human breast, raising concerns about its involvement in breast cancer development. A commonly used antimicrobial preservative in personal care products, TCS is an endocrine disruptor in hormone-dependent tissues. TCS increases vascular endothelial growth factor (VEGF) production, a chemical that promotes tumour growth via human prostate cancer stromal cells26. TCS's first specific action method in prokaryotic cells was identified just 20 years ago when it was revealed that TCS suppressed fatty acid synthesis (FAS) in 27. By replicating its native substrate , TCS permanently blocked the FAS enzyme enoyl-acyl carrier protein (Enoyl-ACP) reductase28. TCS resistance was also shown by a mutant or overexpressed ACP expressed by in bacteria.

As a consequence of these investigations, ACP was identified as an intracellular TCS target. Multiple studies supporting fatty acid formulation suppression as a novel strategy for chemotherapy have been inspired by the effectiveness of cerulenin, a mycotoxin that inhibits FAS . FAS appears and acts differently in normal and malignant tissues, with the latter having a higher therapeutic index28. Because of its long history of human usage and broad prevalence in consumer products, as well as promising results, TCS is a suitable choice for chemotherapy. TCS may enhance the proliferation of BG-1 ovarian cancer cells by modulating the expression of cell cycle and cell death genes via ER-based mechanisms, according to research29. TCS, like E2, was shown to have estrogenic properties via altering the appearance ofprotein kinase B (PKB), mitogen-activated protein kinase (MAPK), phosphorylated insulin receptor substrate-1 (pIRS-1), and extracellular signal-regulated kinase (ERK) proteins30. It also inhibited the protein synthesis of pIRS-1, PKB, MAPK, and ERK, which were all increased by E2 or TCS, and therefore had an antiestrogenic effect. As shown through its prevalence in various environmental media, human bodies, and animals, TCS is not effectively regulated. Its careless use and disposal may put people and the environment at risk. In cell-based studies, TCS is harmful to many cells14. The precise role of TCS in selecting antibiotic resistance genes and multidrug resistance genes in the environment is unknown. It is also necessary to establish the TCS level required for tolerance choice in environmental communities. Future research should concentrate on finding signaling molecules controlled by TCS in different ways and determining their involvement in harmful or protective effects in various cell types14.

TCS has been shown to reduce the viability and growth of Michigan Cancer Foundation-7 (MCF-7) and SKBr-3 cells in culture at a range of 2.5-20 µg/mL. It also lessened the binding affinity of inhibitors in human and goose type-1 fatty acids as well as the enoyl-reductase level31, 32, 33. All present new reports indicate that widely used TCS cosmetic agents can trigger cancer, as shown in animal and human models21, 34, 35, 36 as well as in clinical studies. Therefore, government policies should reassess TCS usage in cosmetic products to prevent its harmful effects on human health. This manuscript's main aim is to highlight that TCS causes oxidative stress, an estrogenic, mutagenic, cancer-causing agent, and genotoxic agent present in cosmetic products. A further aim is to attenuate the TCS toxicity via natural products.

BIOSYNTHESIS OF TCS

TCS is a broad-spectrum antibiotic that inhibits bacterial fatty acid biosynthesis at the (Enoyl-ACP) reductase37. TCS is generally considered a broad biocide that targets bacterial membranes, and cellular resistance is rare if TCS does not have a distinct mode of action. TCS has been found to inhibit enoyl reductase in various bacteria, including and , after discovering that it blocks the enzyme in 38. The enoyl-ACP reductase family produces noncovalent, high-affinity ternary compounds with TCS and NAD(P) that effectively limit the enzyme's participation in biosynthesis39. TCS inhibits enoyl reductase by attaching to a location close to the nucleoside cofactor's nicotinamide ring. The TCS phenol ring interacts with the nicotinamide ring directly and enables substantial activities40.

More enoyl reductase genes have been identified after discovering TCS's inhibitory effect on enoyl reductase, including in and , in in , and 41. Both and are TCS resistant, whereas is sensitive. Similar inhibition of TCS fatty acid biosynthesis was also observed in higher life forms, such as and which cause malaria42. Both of these species have a type II fatty acid synthase since they are apicomplexans. TCS was recently demonstrated to block a type I fatty acid synthase (a versatile human enzyme) in breast cancer cells, even though these enzymes are commonly thought to be antibiotic-resistant43.

DEGRADATION OF TCS

Antimicrobial compounds have shown a proclivity for bioaccumulation in underwater organisms, and they have been found to survive in aquatic environments for longer periods. The presence of TCS in the environment necessitates the monitoring of surface water. TCS was discovered in silt from Greifensee Lake in Switzerland deposited 30 years ago44. The survivability of TCS in sediment was confirmed in this investigation, and a breakdown of the TCS using various strategies. The TCS level in sediment has progressively enlarged since the early 1960s, when it was initially introduced, to the mid-1970s, indicating that its usage trends were becoming more widespread. This trend reversed from the mid-1970s to the early 1980s, with most wastewater treatment facilities introducing a different conventional treatment stage. TCS levels have risen since the early 1980s, owing to its rising popularity and use44.

Nonetheless, the comparatively large level of TCS found in a 30-year-old sedimentary layer from 1970 to 1971 indicated that TCS breakdown was highly sluggish in the sediment45. A parallel timeline pattern for TCS in estuary sediments in the United States was also documented. Antimicrobial chemicals can subdivide into sediments and withstand breakdown mechanisms under anaerobic circumstances, as evidenced by TCS's environmental survival in sediments. Furthermore, sediments are the last sink for the aqueous ecosystem. TCS persistence in this medium would be risky since bioturbation generated by animals or human excavation might push it back into the aqueous ecosystem46.

Despite its strong chemical volatility and resilience to both high and low pH, TCS has been discovered to be easily destroyed in the atmosphere due to photodegradation. Scientists found eight photochemical pathway subproducts in laboratory testing47. Researchers found TCS photoconversion to 2,8-DCDD with an output of up to 12% at pH > 8, using varied illumination intensities. Under the laboratory conditions (purified water), the production of 2,8-DCDD yield was compared to river water spiked with TCS. According to similar results across laboratory and real-world scenarios, TCS could transform into 2,8-DCDD in sunshine irradiated water sources48. TCS that persists in the secondary discharge after sediment processing may be chemically transformed after disposal. In the United States, sodium hypochlorite, a sterilizing oxidant and a producer of free chlorine is extensively used for various applications and may interact with TCS. In certain instances, the TCS phenol carbons may be chlorinated in either ortho- or para-positions, yielding three chlorinated TCS derivative (CTD) transitional compounds49. Direct photolysis is ineffective at degrading dioxin derivatives of TCS, so they are therefore not a public health problem6.

Similarly, chloramination of TCS results in CTDs comparable to those formed by the free method50. Chlorinated TCS derivatives like 4-Cl-TCS, 6-Cl-TCS, and 4,6-Cl-TCS have been found in sewage discharge51. CTDs have been discovered at the apex of marine biological chains and as biomethylated equivalents in fresh water, specimens taken downstream of a sewage discharge, and in carps that live in it due to the spread TCS-containing effluents in streams52. According to these findings, CTDs are either generated via TCS during water purification using free chlorine or are synthesized without passing through the conventional treatment processes. As a result, CTDs are regarded as a significant environmental concern since they have the potential to preserve or perhaps enhance the antibacterial and endocrine-disrupting properties of TCS. Furthermore, under spontaneous photochemical circumstances, CTDs such as 6-Cl-TCS, 4,6-Cl-TCS, and 4-Cl-TCS have been shown to release dioxins in water53.

Buth JM .,54 investigated the history of TCS dioxin photoproducts and their chlorinated counterparts in Mississippi River sedimentary basins. Sunlight irradiation of CTDs, which produces chlorinated dioxins, is another conceivable cause of TCS-derived pollutants. The photochemical breakdown of TCS occurs until by-products are subjected to ultraviolet rays after interaction with chlorinated water, 2,4-dichlorophenol (2,4-DCP), and 2,8-DCDD are formed. The chlorination of 2,4-DCP yields 2,4,6-trichlorophenol55. The transitional chlorophenols are then converted to chloroform and trihalomethanes56. The ways by which CTDs are converted to chlorophenols, chloroform, and trihalomethanes. TCS can be chlorinated by frequent exposure to chlorine at water treatment plants. A wastewater treatment plant discharges chlorinated TCS, which can be converted into more harmful dioxins by sunlight57. 2,4-DCP is a contaminant of concern according to the United States environmental protection agency and is hazardous to fish and other aquatic life58. 2,4-DCP is a chemical that is used to make insecticides, disinfectants, and antiseptics.

Furthermore, upon exposure to the sun's rays, the 2,4-DCP decomposes even more, perhaps resulting in more strongly chlorinated dioxins59. Due to low levels of ROS in natural rivers and the ineffectiveness of straight photolysis of TCS, research by Latch .,6 found that dioxin chemicals produced from TCS are not a public health risk. Microorganisms like , , and may degrade chlorine and CO under natural circumstances60.

According to Son et al. (2009)61, radicals that stimulate the destruction of transitional dioxins control TCS degradation by titanium dioxide photocatalysis. Furthermore, hydrogen peroxide enhances the oxidative process. TCS is stable at 50°C when it is kept separate from biotic contact and kept at a pH of 4–9. TCS degrades more rapidly in an aqueous medium at 25°C and pH 7, reaching 50 % in around 41 minutes. Within 4 hours after therapies, primarily 2,4-DCP is generated. TCS is easily degraded in aquatic environments by photolysis, with a half-life ranging from 1 hour in abiotic settings to roughly 10 days in freshwater sources62. Furthermore, depending on the reactivity of TCS with photochemically generated hydroxyl radicals, its aerial half-life has been predicted to be 8 hours63. Even while the current amounts of TCS and its by-products in the atmosphere are not dangerous, continued deposition of TCS into the atmosphere could approach a threshold value, affecting all categories of animals in the food chain64.

OXIDATIVE STRESS MECHANISM

If not adequately scavenged, these “two-edged sword” molecules, ROS, may disrupt the cellular redox equilibrium, resulting in oxidative harm to protein, lipids membranes, and nucleic acid65. When the dynamic balance in the synthesis and removal of ROS in typical circumstances is disturbed, "oxidative stress" is used66. The antioxidant defence mechanism, including CAT, SOD, GPx, GR, GSH, Glutathione disulphide (GSSG), and glutathione S-transferase (GST), works to counter the potentially harmful effects of ROS. As a result, ecologists may measure antioxidant levels to monitor the amount of oxidative damage induced in organisms treated with particular substances67.

Catalase (CAT)

Adult zebrafish livers treated to different dosages of TCS, SOD, CAT, and GPx enzyme activity were assessed. When the antioxidant defence fails to resist this ROS, the overwhelming generation of ROS is a potential source of enzyme inactivation. ROS elimination is caused by the change of radicals without oxygen into hydrogen peroxide molecules by SOD, further reduced into HO by CAT and GPx68. As a result, if these critical first-line defences become less active, HO and its degradable compounds may accumulate69. SOD activities were inhibited in all treatment groups relative to the control group, according to the research. At the lowest dose of 50 g/L, though, the caused suppression of SOD was significant (p < 0.05) when compared to the control70. The lower concentrations of SOD activity in the treatment groups' liver tissue may be related to the ROS generated by TCS treatment. The CAT and the GPx enzymes must maintain intracellular redox equilibrium and HO degradation68.

The activity of CAT followed a parallel path to that of SOD in the liver. There was a substantial decrease in CAT activity between the treatment and control groups (p < 0.05). The reduction of CAT activity in the liver varies considerably between treatment groups at p < 0.05, with the effect of suppression being most noticeable at the lowest dose (50 g/L)71. The apparent decrease in CAT behaviour implies that the produced HO may not be quickly destroyed by CAT, indicating a redox imbalance in the cell. The pattern toward reduced CAT activity was lower in the liver72. Poor regulation of antioxidant enzyme activity may result in an increased amount of ROS, thus reducing the antioxidant system's efficiency. This theory is supported by the idea that increasing ROS produced the reduction in SOD, resulting in a loss in enzyme efficiency and function73.

CAT plays a vital role in the progression of ROS due to TCS toxicity (Figure 1). After subchronic treatment with TCS, the enzyme activity of SOD and CAT was assessed in the brain of adult zebrafish74. CAT activity was reduced to control across treatment groups. There was a statistically significant difference in CAT activity between the control and increased TCS exposure (100 g/L and 150 g/L). TCS may alter the zebrafish brain's antioxidant system due to the reduction of CAT and SOD activities. Despite this, mean SOD activity in the brain was significantly greater than in the liver for both TCS treatments, whereas mean CAT function in the brain was significantly lower. The various physiological roles of the organs may describe the discrepancy in numerical ranges of antioxidant enzymatic activity74.

ESTROGENICITY

TCS, an antibacterial molecule, has a negative impact on human genotoxicity, and its antiandrogenic capability damages DNA. TCS has induced IP at a dosage of 15 mg/kg for two days in a row. TCS therapy results in a substantial reduction in testicular hormones (testosterone FSH and LH)139. TCS's impact on the environment and human health. TCS is prooxidant and cytotoxic in a variety of ways, according to cell research. TCS is involved in both estrogenicity and anti-estrogenicity in cancer development140. TCS research on surface water and wild fish. TCS and a binary combination with BE2 had a negative impact on testicular growth and reproduction in fish at a dosage level of TCS 117.9 mg/L141.

MUTAGENICITY

The mutagenic capability of TCS has been studied in several ways, including and tests that look for point mutations, recombination events, and frame shift mutations in prokaryotic and eukaryotic systems. On TCS, microbial reverse mutation tests (Ames Assays) were performed14. Various strains, with or without S9 metabolic stimulation, were employed tests using TCS. Muller D .,142 also investigated the mutagenicity of TCS in a bacterial reverse mutation test using intrasanguineous hosts. All findings from these reverse mutation tests and host were negative. It showed that TCS did not induce gene mutations143.

Gene mutation investigations in mammalian cells via model suggested that metabolic stimulation of mouse lymphoma L5178Y cells with and without TCS has shown the ability to produce mutations in the TK region of a gene144. In host-mediated research in mice, Müller D .,145 investigated the mutagenicity of TCS at the TK gene in mouse lymphoma L5178Y cells, finding no treatment-related changes in malformation rate. There was no rise in the mutant rate at doses that did not cause cell death (up to 20 g/ml without S9 and up to 15 g/ml with S9).

However, De Salva ,146 and Bhargava .,147, continue to believe that TCS is not a mutagen, and antimicrobial individual care items are not harmful to one's health. Despite the positive results of the mammalian spot test, most of these tests revealed that TCS had no mutagenic ability. Fahrig R .,148 was the first to conduct the mammalian spot test and yielded a positive result, but was later replicated by Russell (1980)149 yielded negative results. Fahrig R ,148 have been challenged, claiming that the optimal TCS dosage could produce maternal toxicity, preventing offspring evaluation. It's unclear why these two types of research, which used the identical methodology, produced such disparate findings. Fahrig R .,148 employed a larger dosage of TCS soluble in hank's balanced salt solution (HBSS). In contrast, Russell LB, and Montgomery C. .,149 found TCS insoluble in HBSS and consequently applied methanol to dissolve the antibiotic. Russell LB and Montgomery C.149 assumed that the Fahrig R .,148 investigation was unsuccessful in inserting one of the TCS dams because the absorption of the TCS in HBSS was restricted, explaining the toxicity at 50 mg kg. It was extremely hazardous to embryos149. Many scientists appear to endorse this study observations149 as TCS safety reviews.

The researchers have carried out three-wide genomic DNA (0.2T-AMX, 0.2T-CHL, and 0.2T-TET) sequencing for reproduced mutants induced by TCS (n = 6) and for wild strain (n = 2) to find important genetic modifications of antibiotic resistance caused by TCS. When compared to non-treated , sequencing of 6 resistant mutants produced following treatment of TCS at 0.2 mg/L showed 14 genetic modifications in 11 genes and 9 alterations in intergenic regions. The +A insertion in the insB-1 gene was seen in all sequenced mutants, along with substitution alterations in the genetic code150. Because TCS interacts with the enoyl reductase , which is expressed by the chromosome, genetic variations in the chromosome may impair TCS effectiveness by altering the shape of the targeted protein151. Apart from the typical mutations, several strain-specific mutations have been discovered. The (A346T), (L65R), and (R20S) substitute alterations, for example, were detected solely in the 0.2T CHL strains. In comparison to other strains, the 0.2 T-TET strain contains a 1 bp frameshift in the insl-1 genetic coding and a replacement variation in the chromosome (T72P)152. At the same time, transcriptional analysis was used to identify the molecular processes behind TCS-induced antibiotic resistance. Complete genome Illumina RNA sequencing was used to see how three mutant kinds (n = 9) and wild-variant (n = 3) responded to the 8-hour 0.2 mg/L TCS treatment. Acute TCS treatment leads to typical transcript alterations between mutants and wild-kind compared with untreated wild-kind (n = 3)151. In contrast, the cellular antioxidant genes and the membrane encoding porin gene have decreased153. TCS induces oxidative stress in at a concentration of 0.2 mg/L, while simultaneously reducing the regulation of genes that encode antioxidants, activating the SIM response to DNA deterioration152.

TCS-induced genetic changes may have enhanced antibiotic tolerance by modulating the genetic code's appearance concerning antibiotic resistance. Since the promoter of the gene encoding beta-lactamase overlaps the gene space in K-12154. The alteration observed in 0.2T-AMX mutants could have impacted the supporter endurance155, resulting in greater expression (log2 fold change (LFC) = 5.4) and elevated beta-lactam antibiotic tolerance156. Furthermore, gene alteration may cause a spike in expression157, leading to a rise in efflux via boosting regulation158. As a result of the overexpression of the many drugs exporter channel, multiple antibiotic resistance is likely to occur159. Mutations in the gene may have reduced adhesion capacity in 0.2T-TET mutants, resulting in upregulation of genes that control overall multidrug resistance160. As a result, may have sparked the development of an antibiotic resistance genes cascade, including and 161.

CARCINOGENICITY

TCS is a diverse antibiotic negotiator often used in cosmetics, toothpaste, and other consumer goods. Queries have been expressed about the blend's wide-ranging use in customer goods and its recognition in bosom milk, pee, and sera. It’s possible linked to a variety of human health effects16. The compound's extensive use in consumer goods, as well as its presence in bosom milk, pee, and sera, has sparked worries about its possible link to a variety of human health effects. Recent data put forward that TCS can serve a part in cancer growth, possibly due to its estrogenic properties or propensity to suppress fatty acid production16.

The most common mechanism of endocrine disturbance by exogenous substances is the suppression of the internal secretion (hormones) from attaching its receptor sites by trying to compete for sense-organ linkage locations with the competitor140. This is one of the mechanisms via which TCS causes endocrine dysfunction26. It is well established that when a ligand binds to a receptor site, it induces conformational changes in the sense-organ, resulting in the synthesis of transcription factors essential for the representation of internal secretion sensitive genes162. Hypospadias, cryptorchidism, and cancer are uncontrollable physiological outcomes of the antagonist's representation of oestrogen-sensitive genes140.

Carcinogenicity and precocious puberty might be interpreted as a result of receptor overstimulation, presumably caused by the high TCS level, or as a result of TCS occupying the receptor's ligand engaging domain33. More research is needed to link TCS concentrations in the environment with observed physiological consequences in animals, such as unfavourable fertility impacts. However, the toxicity of TCS has not been established accurately, noticeable concentrations of the substance in exposed humans' body fluids. TCS bio-accumulates and is widely dispersed in human tissues, as evidenced by the increased TCS levels in tissues compared to ambient levels26.

There have been reports of human beings developing allergic responses to TCS. Extensive usage of TCS-containing hand detergents has been linked to dermatitis or subsequent exposure to sunshine163. Similarly, after extended usage of toothpaste containing TCS, lesions have been reported to occur in the oral cavity and on the lips of human patients164. Elevated TCS concentrations in urine have been linked to immunological malfunction, allergic responses, and the development of asthma in children165. TCS has been shown to modify the structure of human serum albumin166. Endogenous molecules are obstructed by toxic substances attached to serum albumin and alter the shape of the protein molecule, thereby impairing its function or even altering its physiological activity. Researchers found that greater urinary concentrations of TCS were associated with lower fecundity in women88.

Xenoestrogens are oestrogen-like chemicals widely present in cosmetics, insecticides, and plastic bottles. Xenoestrogens interact with oestrogen attachment to oestrogen receptors in the human body, resulting in oestrogen-dependent health consequences such as maturation, reproductive health, and fertility167. TCS is a less well-known xenoestrogen with antimicrobial properties often found in cosmetic products, toothpaste, detergent, and other consumer goods. The ubiquitous usage of TCS, along with its presence in pee, sera, and in women's bosom milk, has prompted concerns about its link to various health consequences, including cancer168. According to an existing study, TCS can be estrogenic and anti-estrogenic33. Recent evaluations imply that TCS is estrogenic at lower concentrations because it promotes female sex hormone-sensitive bosom cancer cells. TCS inhibits the development of these cells at increasing concentrations, implying that higher doses may have an anti-estrogenic impact169.

The impacts of TCS on bosom cancer cells may be affected by concentration and other variables like oestradiol (natural oestrogen)170. Untimely bosom development, antimicrobial opposition, and hypersensitivity are possible health consequences171. However, the existence of TCS in milk indicates that it has passed through the human bosom, raising worries about its potential role in developing bosom cancer170. Plasma and sewage from people indicate the systemic transfer of TCS to humans, although local absorption from cosmetic goods applied to the bosom region is another exposure mechanism. TCS is a type 1 FAS enoyl-reductase blocker that is impactful against the bosom cancer cell lines MCF-7 and SK Br-3 in cultured cells172. The disruption of human FAS through a different method and at various active sites reinforces the idea that type 1 FAS could be a chemotherapeutic goal. It also implies that inhibiting any of this multipurpose enzyme's activity could be useful31. When a substance is so widely diffused in the aquatic environment, it can induce an endocrine disruption in aquatic animals, which is a reason for concern. The early investigations in medaka fry () indicated that TCS could be slightly androgenic based on alterations in fin size and sex ratio fluctuations173. TCS has been demonstrated to bind to proteins in other investigations. In North American bullfrogs, it binds to thyroid hormone receptors and disrupts their endocrine system174. TCS can potentially cause endocrine disruption by raising thyroid hormone levels. Thyroid hormone levels above a certain threshold may indicate a greater chance of getting bosom cancer175. Thyroid dysfunction is more common in bosom cancer patients than in healthy people, although no clear link has been discovered176.

Environmental chemicals may harm human health and induce carcinogenesis, according to accumulating data. TCS enhances the release of the VEGF, a substance that promotes tumour development177. This process involves the direct stimulation of a membrane ion channel which causes an elevation in intracellular calcium levels. In primary cultivated human prostate cancer, stromal cells show that ecologically significant levels of TCS activate a TRP family, TRPA1 (Transient Receptor Potential Ankyrin 1), using calcium imaging and electrophysiological approaches. TRPA1 activation of TCS raised baseline calcium in stromal cells, boosted VEGF production, and enhanced epithelial cell proliferation178. Immunofluorescence labelling of prostate tissue in formalin fixation and paraffin embedding revealed that the TRPA1 channel was expressed only in prostatic adenocarcinoma stromal cells179. Although the tumour’s androgen reliance has long been known, epidemiological studies imply that elements from a Western lifestyle can also take part in its growth180. Prostate cancer growth and development are thought to be influenced by epithelial-stromal interconnections181. Carcinomas are two interconnected parts: neoplasia epithelia cells and the supportive tumour stroma, which secretes cytokines and growth factors to control key procedures such as tumour propagation, vasculature, and penetration182.

GENOTOXICITY

TCS and triclocarban effect on the () inhibit with 24 h EC values of 1063 and 295 g/L. Respectively both TCS and TCC significantly damage DNA183. The study of TCS on goldfish for 28 days results in TCS damage the erythrocyte tail DNA184. The dose of 0.125 mg/L did not affect the size and shape of the cell. But the dose of 0.5 mg L affects sexual reproduction and damages dependent DNA standards184. The broad spectrum TCS study on the zebrafish had a ratio of 0, 17, 34, 68 g/L TCS for 42 days. Antioxidant-related gene at 34 the gills were significantly down-regulated as compared to 68 g/L. In the 34 and 68 g/L TSC groups, the gene was substantially up-regulated in the ovary. In zebrafish, a greater dosage of TSC may induce oxidative damage in the gills and ovaries, as well as a faster ROS-dependent ovary opposite185.

The pharmaceutical, personal care products found in the aquatic ecosystem for a decade have a potent biological effect in the non-target organism. TCS genotoxicity increased dose-dependent at different dose levels TCS 0.1, 0.15, 0.2, 0.3 M used to prevent the effect of antibacterial TCS and antibiotic trimethoprim (TMP). Significant DNA damage at extremely low levels affects haemocyte functioning186. The trail TCS was conducted on goldfish () the dose level (control, DMSO control, and ½, ¼ and 1/8 LC) effect of genotoxicity and micronucleus (MN) and nuclear abnormalities (NA) frequencies in peripheral blood. TCS 96 h median lethal concentration was 1111.9 g/L significantly increase MN and NA frequencies TCS cause oxidative stress and a genotoxicity response in goldfish9.

Different doses of TCS response increased in the proliferation of MCF7 DOS cells elicited by E1. The TCS is at 76 – 87 % and 68 — 95% at the maximum level. MCF7 Bos cell significantly increased by PFOS and 0.01 and 30 kg.ml proliferative response of 116% of the maximum E233. According to research, TCS at 0.5 mg/L reduced the development of the unicellular alga Closterium ehrenbergii and caused DNA damage187. The MN test TCS caused substantial DNA genetic damage in single-cell gel electrophoresis at all doses (1, 2, 3 M)187. TCS increases hepatocyte proliferation-induced fibrogenesis, produces oxidative stress, and boosts inflammatory response, according to and studies using different biomarkers188.

The smear was fixed in absolute methanol for 10 minutes, air-dried, and stained with 10% Giemsa stain for 8 minutes in a study of MN and NA. MN and NA rates were significantly different in the TSC-treated group190. The haemocytes' genetic damage was substantial at all three TCS doses, and it followed a concentration- and time-dependent pattern. The comet test in Artemia salina was also used to assess TCS's genotoxicity191.

Concentration of TCS	Effects	References
0.0028 – 28.9 µg/ml	Estradiol antagonism	26
0.00002 – 28.9 μg/mL	Cell proliferation, estradiol antagonism	170
0.002 – 200 μg/mL	Cell proliferation, estradiol antagonism, cytotoxicity	33
0 – 20 μg/mL	FAS inhibition, reduced cell viability	3566
0 – 100 μg/mL	FAS inhibition reduced cell viability non-toxic to normal cells	36, 32
1 µM	Activate transient receptor potential Ankirin-1 (TRPA-1) in human prostate cancer stromal cells	178
0.1 – 10 µM	Proliferation and anti-apoptosis inhibit ROS production	109
10 – 6 M	Up regulate pIRS-1, PKB, and MAPK in breast tumor growth	192
10, 100 and 200 mg/kg	Induce mouse liver tumor via CAR and PPARα activation	147
10 - 5 – 10 - 7 M	Induce proliferation of breast cancer cells through ER pathway and activated CXCR4 receptor involved in metastatic behavior	29

NOVEL TREATMENT STRATEGIES

Normal cells can convert into cancer cells due to a variety of genetic and environmental factors. It causes them to develop abnormally and propagate to many other body areas by disrupting regular cellular mechanisms such as DNA synthesis, cell division, and suicide, resulting in fatal disorders193. The basic cancer treatments are surgery, radiotherapy, chemotherapy, and adjuvant medicines such as biological gene or hormone therapies194. TCS's initial particular action strategy in prokaryotic cells was only discovered twenty years ago when it was shown that TCS inhibited fatty acid production in 195. By replicating its native substrate , TCS blocked the fatty acid manufacturing enzyme enoyl–ACP reductase permanently (Figure 2). TCS resistance in the bacteria was also conferred by a mutant or overexposed ACP expressed by . ACP be identified as an intracellular TCS goal as a result of these studies. Cerulenin, mycotoxin effectiveness that inhibits fat formation in inhibiting tumour development has inspired multiple papers in favour of fat formulation suppression as a new approach for chemotherapy196. FAS appearance and action vary in normal and cancerous tissues, with the latter being increased, implying a potentially high therapeutic index. TCS is a good option for chemotherapy because of its long history of human use and widespread presence in consumer goods, as well as promising outcomes197.

Phytoestrogens generated from vegetables and fruits have long been considered alternative remedies for human disorders as natural chemicals. Phytoestrogens as hormone replacement therapy (HRT) are used in protracted therapies to prevent oestrogen-responsive malignancies, such as bosom cancer198. Polyphenolic substances, such as flavonoids, have been shown and to limit bosom cancer cell proliferation by challenging with 17β-oestradiol (E2) for ER attraction sites199 as shown in Figure 2. Further comprehensive underlying mechanisms have to be researched as interest in phytoestrogens' positive effects rises200. Flavonoid-based phytoestrogen kaempferol occurs mainly in fruit and plants like apples, tomatoes, and green tea29. The anti-cancer and osteosarcoma effect of kaempferol has been described in current studies192. It has been reported in many studies that extensive usage of TCS can have cancerogenic potential, as shown in Table 1. Significant research has also highlighted the mechanisms involved in kaempferol anticancer action associated with the cell cycle, cell death and angiogenic, inflammatory reactions, and oxygen radicals production201. In U-2 OS human osteogenic sarcoma cells, kaempferol also reduced the appearance of ERK, JNK, and p38202. Kaempferol inhibited the PI3K/Akt signal transduction by adhering directly to P­­I3K and inhibiting the capabilities of AP-1, and protein kinase b (NF-β), which affect a variety of cellular activities such as growth, angiogenesis, and death203. According to an study, TCS can enhance the growth of BG-1 ovarian cancer cells by modulating the expression of cell cycle and death genes19.

To investigate for signalling-related genes in MCF-7 cells treated with Dimethyl sulfoxide (vehicle), E2 (109 M), TCS (106 M), and a blend of kaempferol (50 M) and TCS, we conducted western blotting on specimens of proteins recovered from the cells204. Given the discoveries, E2 was up-regulated. IRS-1, PKB, MAPK, and phosphorylated versions of IRS-1 are all expressed in phosphorylated forms (Figure 2). The major proteins of insulin-like growth factor type (IGF-1R) signalling are the ERK proteins. E2 stimulates MCF-7 cell growth through both the ER and IGF-1R signalling pathways. E2 and TCS were used to see how they affected IGF expression (Figure 2). TCS, like E2, was found to exhibit an estrogenic effect by modulating the protein appearance of pIRS-1, PKB, MAPK, and ERK. Kaempferol also had an antiestrogenic impact by inhibiting the protein production of pIRS-1, PKB, MAPK, and ERK, which were all induced by E2 or TCS30. As previously stated, changes in the result of TCS therapy are primarily dependent on the experimental setup. Furthermore, limited evidence from animal research suggests that TCS treatment exacerbates the disease in the existence of a previously established tumour29.

FUTURE PERSPECTIVE

TCS is not effectively controlled, as seen in numerous environmental media, human bodies, and wildlife. Its reckless usage and disposal may endanger humans and the ecology as a whole. TCS has been demonstrated to be harmful to a variety of cells in cell-based investigations. Cell-based assays are time-limited and so cannot rightly examine the consequence of persistent expose. TCS recognition in human fluid or tissue may not have been a reliable predictor of the extended period because the evidence on its bioaccumulation in the flesh is lacking205.

Furthermore, TCS is considered to block enzymes involved in its decomposition206. There is currently a scarcity of information about TCS's pharmacokinetics and pharmacodynamics. Enough knowledge would allow for more flexibility in determining TCS's toxicity. However, its anti-growth influence has been noted in certain malignant cells, the toxicological importance of TCS' inhibitory impact on human FAS is not fully grasped104. TCS has been found in significant amounts in mammalian tissues, raising the likelihood that the molecule has an adverse effect on mammalian anatomy. Its negative impact on birth resistance has been documented, as clinical reports claim it can treat human allergic skin conditions207.

TCS's exact function in selecting antibiotic resistance genes and many drugs protection genetic codes in the surroundings remains resolute. The level of the TCS needed for ecological tolerance choices also needs to be determined. The correlation between TCS introduction and bioaccumulation in an earthly organism is still unclear208. More research is needed, such as the movement of soil-based TCS processing and earth organisms absorption, including Invertebrates and slug, essential to crop production and diet208. TCS increased MCF-7 bosom cancer reproduction via modulating cell division, death, and tumour-linked genetic codes through nongenomic ER signalling linked to IGF-1R signalling.

On the other hand, Kaempferol showed an anti-proliferative effect against bosom cancer by inhibiting TCS and E2-induced cancer growth by serving as a competitor for ER and IGF-1R signaling. It's the first research to demonstrate that kaempferol has anticancer action against the pro-cancer action of endogenous oestrogen and xenoestrogen in bosom cancer. It also recommends kaempferol as a major drug to modify TCS-induced malignancy hazard30. Future research should concentrate on recognizing TCS-controlled signaling molecules and their responsibility for poisonous or preventive effects of different cell types. The information obtained from such revelations will be invaluable in validating therapeutic strategies or developing potential TCS adjuvants or blockers209. In ongoing studies, animal and human growth investigations and mammalian experiments with susceptible endocrine/reproductive outcomes should be included. Systematic evaluations of these areas, particularly through deriving human health risk inferences from TCS consequences, can enable upcoming studies and regulations to safeguard people's health more efficiently210.

CONCLUSION

TCS is a synthesized antimicrobic that has been used in humans for a long time. Humans are subjected to TCS as a result of environmental and consumer good consumption. TCS exposure can cause various problems, including thyroid dysfunction, liver tumorigenesis, endocrine disruption, growth issues, muscle weakness, and oxidative stress. It is also necessary to estimate the TCS level required for tolerance choice in environmental groups. Precocious puberty and carcinogenicity could be produced by receptor overstimulation, presumably caused by the high TCS level. TCS has been linked to allergic reactions in people, according to certain research. TCS is a type 1 FAS enoyl-reductase inhibitor that has been proven to be effective in cultured cells against the MCF-7 and SK Br-3 bosom cancer cell lines. Because of its long history of human usage and ubiquitous prevalence in consumer items, as well as promising results, TCS is a viable alternative for chemotherapy.

According to extensive studies, the kaempferol anticancer effect has also been linked to the cell cycle, cell death and angiogenic, inflammatory reactions, and the formation of oxygen radicals. By adhering directly to PI3K and limiting the capacities of protein kinase b (NF-β) and AP-1, kaempferol suppressed the PI3K/Akt signal transduction, which affects a range of cellular activities such as growth, angiogenesis, and death. TCS's environmental survivability in sediments demonstrates that antimicrobial compounds can spread and endure breakdown mechanisms in anaerobic conditions. In addition, hydrogen peroxide speeds up the oxidation process. This system contains enzymatic and nonenzymatic antioxidants such CAT, SOD, GPx, GR, GSH, and GST. As a result, ecologists may examine the amount of oxidative stress caused in organisms exposed to specific substances by measuring antioxidant levels. The current study's lower GSH/GSSG levels might be explained because GSH could not be restored to its standard concentration in the liver after introducing TCS concentrations due to impaired GPx and GR actions.

Abbreviations

2,4-DCP: 2,4-dichlorophenol; 2,8-: 2,8-dichlorodibenzo-p-dioxin; A. difformis: Anchomanes difformis; A. tumefaciens: Agrobacterium tumefaciens; APND: aminopyrine N-demethylase; AR: androgen receptor; : ; β-hCG: β-human chorionic gonadotropin; CAT: Catalase; COX-1: cyclooxygenase-1; CTD: chlorinated TCS derivative;: ; : ; Enoyl-ACP: acyl carrier protein; EE: ethinylestradiol; EMT: epithelial-to-mesenchymal transition; ER: estrogen-receptor; ERK: extracellular signal-regulated kinase; EROD: ethoxyresorufin-O-deethylase; ERND: erythromycin N-demethylase; FAS: enoyl-fatty acid synthesis; FSH: follicle-stimulating hormone; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GPx: Glutathione peroxidase; GR: Glutathione reductase; GSH: Glutathione; GSSG: Glutathione disulfide; GST: glutathione S-transferase; HBSS: hank's balanced salt solution; HRT: hormone replacement therapy; HS: hidradenitis suppurativa; hsp-70: heat shock protein 70; IL-1β: Interleukin-1β; JNK: Jun N-terminal kinases; LFC: log2 fold change; LH: luteinizing hormone; LPO: Lipid peroxidation; LPS: lipopolysaccharides; : ; M. tuberculosis: ; MAPK: mitogen-activated protein kinase; MCF-7: Michigan Cancer Foundation-7; MDA: Malondialdehyde; MHC-II:Major histocompatibility complex class II; miRNA: MicroRNA; MN: micronucleus; MMP-13: matrix metalloproteinase-13; NA: nuclear abnormalities; Nik: NF-B inducing kinase; NMR: nuclear magnetic resonance; : ; : ; PGES-1Prostaglandin E synthase- PGE2: prostaglandin E2; PGI2: prostaglandin I2; PI3K: phosphoinositide 3-kinase; pIRS-1: phosphorylated insulin receptor substrate-1; PKB: protein kinase B; PLA2: phospholipase A2; PTH: parathyroid hormone; : Rhodospirillum rubrum; ROS: Reactive oxygen species; RyR1: ryanodine receptor type 1; : ; S. pneumoniae: ; : ; SAM: S-adenosylmethionine; SOD: Superoxide dismutase; : ; : ; TAC: Total antioxidant capacity; TCS: Triclosan; TK: thymidine kinase; TLR-4: Toll-like receptor-4; TMP: trimethoprim; TPO: thyroid peroxidase; TRPA1: Transient Receptor Potential Ankyrin 1; TSN: Testosterone; UTI: urinary tract infection; VEGF: vascular endothelial growth factor.

Acknowledgments

The authors concede the support of the Cholistan University of Veterinary & Animal Sciences-Bahawalpur, Pakistan, during the write-up.

Author’s contributions

Kamal Niaz: Conceptualization, outlines and editing; Furqan Shafqat, Shafeeq Ur Rehman, and Muhammad Usman: Data curation, writing- original draft preparation and drawing figures; Kamal Niaz: Supervision, reviewing and editing. All authors read and approved the final manuscript.

Funding

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Availability of data and materials

Not applicable.

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Not applicable.

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Not applicable.

Competing interests

The authors declare that they have no competing interests.