Mercury (Hg), a cumulative neurotoxin that is present in the environment through a variety of natural and anthropogenic sources, is of grave concern because of its cellular, cardiovascular, hematological, pulmonary, renal, immunological, neurological, endocrine, reproductive, and embryonic toxicological impacts, etc. [16,17,18,19,20,21,22]. Hg is a well-established and cumulatively neurotoxic agent that can have serious adverse effects on the development and functioning of the human central nervous system (CNS), and it is environmentally ubiquitous [20]. In nature, Hg is unevenly distributed in the marine environment, and exists as three chemical forms, i.e., elemental Hg (metallic Hg⁰), inorganic Hg (Hg⁺ and Hg²⁺ as salts) and organic Hg (MeHg: CH₃Hg⁺, etc.), which exist in sediment, water and the atmosphere (seen in Figure 1) [20,21,22,23,24,25]. In general, vapor Hg⁰ is readily absorbed from the lungs, and it can pass the blood–brain barrier (BBB) and placenta, resulting in high neurotoxicity, while liquid Hg⁰ is slightly absorbed from the gastrointestinal (GI) tract and does not appear to be toxic; inorganic Hg is concentrated in the kidneys and it cannot pass the BBB and placenta; and organic Hg is easily absorbed from the GI tract and it can pass the BBB, resulting in higher toxicity [26].

Hg circulates in aquatic systems in several ways [25]. On the one hand, anthropogenic activities (such as the use of Hg pesticides in agriculture and industrial waste) transfer Hg into groundwater through the soil layer, and Hg-containing wastes enter surface waters such as reservoirs through surface runoff, entering rivers, lakes or marine aquatic ecosystems. On the other hand, some natural causes can also carry elemental Hg into aquatic systems, and Hg that is naturally accumulated in atmospheric air and industrial emissions also enters into the atmosphere, eventually directly accumulating in surface waters, oceans, and other aquatic systems through wet and dry deposition. Moreover, the most common flow route of Hg deposition into marine ecosystems is standing surface waters, such as rivers, streams, and estuaries [27]. Hg is released from a variety of natural and anthropogenic sources into the three phases of natural water bodies, i.e., solid, aqueous and biological phases; it exists mainly in the forms of Hg²⁺, Hg(OH)₂, CH₃Hg⁺, CH₃Hg(OH), CH₃HgCl, and C₆H₅Hg⁺ in the aqueous phase, in the forms of Hg⁺, Hg⁰, HgO, HgS, CH₃Hg(SR), and (CH₃Hg)₂S in the solid phase, and in the forms of Hg²⁺, CH₃Hg⁺, and CH₃HgCH₃ in the biological phase. In natural water bodies, highly toxic methylmercury (MeHg) transformed through some hydrophytic microorganisms (i.e., bacteria) is a major source of Hg exposure to the general population of fish and causes bio-magnification which disrupts the aquatic food web [28]. Moreover, it is presumed that MeHg is the predominant form of Hg transmission through food chains [29,30,31]. Harris et al. (2007) mentioned that MeHg contamination in fisheries from centuries of industrial atmospheric emissions negatively impacts humans and wildlife worldwide, and they also found that atmospheric settled MeHg does not stay in water for long periods, but preferentially enters into fish bodies during feeding [32].

The reason why Hg accumulates in fish as MeHg lies in its absorption and the metabolic mechanism of fish. Most forms of Hg eventually convert to MeHg or dimethylmercury (DMM) in fish due to methylation by the action of relevant microorganisms (anaerobic microorganisms) [33]. For instance, inorganic Hg can be transformed into MeHg and DMM by alkylcobalamin [34,35]. In short, elemental Hg present in water molecules is converted to MeHg by the action of microorganisms, and it eventually enters into fish bodies mainly through enrichment in the food chain [36].

Hg, especially MeHg, is a typical compound that can experience biological amplification (i.e., bio-magnification) [37]. Regarding bio-accumulation, MeHg concentrations are magnified through the food chain, reaching concentrations in fish 10,000- to 100,000-fold greater than those in the surrounding water [38]. Being at the top trophic level, fish face serious risks of bio-accumulated contents of Hg through the food chain in water bodies [8]. Moreover, this bio-accumulation process is evident in fish species feeding at the higher trophic levels: Mediterranean tuna, anchovies, sardines and mackerel [39,40]. The observations at Lake Wisconsin in the USA found that the MeHg concentration (ng g⁻¹) and the proportion (%) of MeHg to total Hg (THg) in the organic matter of phytoplankton, zooplankton and small fish were 34 and 18, 53 and 57, and 485 and 95, respectively; hence, the MeHg concentration and the proportion of MeHg to THg in organisms gradually increase with increasing trophic levels [41].

As top predators of the pelagic food web, some large fish and predatory fish naturally bio-accumulate Hg. The Hg concentrations in these fish are high, and the size of a fish is a determining factor of its Hg burden [42]. This is further supported by data from a survey of THg concentrations in Chinese marine fish, and the data from this study show that Hg levels in different fish species ranged from high to low: carnivorous fish (median: 58 ng g⁻¹, range: 2.4–330 ng g⁻¹), followed by omnivorous fish (median: 24 ng g⁻¹, range: 6.0–155 ng g⁻¹) and herbivorous fish (median: 16 ng g⁻¹, range: 2.5–123 ng g⁻¹) [43]. In addition to marine fish, the researchers also investigated freshwater fish, and the results showed the same trend [43,44]. Hg concentration is high in some long-living and predatory fish that simultaneously have higher opportunities for accumulating Hg [45,46,47].

Hg levels vary widely among different types of fish, and its concentration is affected by the specific physiological and ecological characteristics of different fish species [48]. In general, the Hg concentration in carnivorous fish is greater than that in omnivorous species [49], and there are high Hg concentrations in long-living predators (e.g., rockfish and sharks) [45]. Moreover, higher trophic-level fish (i.e., piscivores and carnivores) and benthic fish have higher mean THg concentrations [50,51]. Additionally, larger predatory fish contain the highest Hg concentrations, and Hg levels are positively correlated with body length, weight and age of the fish [52]. Vieira et al. (2021) indicated that carnivorous species presented higher Hg contents (range 0.03–0.88 μg g⁻¹) when compared to omnivorous fish (range 0.003–0.19 μg g⁻¹), demersal fish exhibited higher Hg levels (range 0.01–0.88 μg g⁻¹) than pelagic species (range 0.003–0.38 μg g⁻¹), and Zeus faber presented high Hg levels (0.68 ± 0.07 μg g^-1) above the maximum limit (0.5 μg g^-1) established for human consumption [53]. While several factors affect the Hg levels in fish, including nutritional level, size, and age of the fish, the Hg levels are generally higher in fish with high nutrient levels [41,54,55], and a significantly increasing trend in Hg concentration with fish size has been observed for all species (except for European anchovy), suggesting Hg bio-accumulation throughout the life cycle [56]. Dang and Wang (2012) indicated that biokinetic variation could explain the size-dependent Hg accumulation in fish, and both size-related g (growth rate constant) and k_e (efflux rate constant) were the key drivers [57].

Among the different fish tissues, muscle was a major reservoir for Hg and contained the highest ratio of MeHg/THg, liver was the second important organ for Hg accumulation in most fish species, and intestine was a critical organ for Hg bio-transformation, with the proportion of MeHg to THg differing greatly among different fish species [58]. Additionally, the Hg concentration in fish muscle correlated with the length and weight of the studied fish species of Sander lucioperca and Esox lucius linnaeus (carnivorous), Cyprinus carpio and Carassius auratus gibelio (omnivorous) [49]. It was indicated that the average Hg level (0.17 ppm wet weight) in fish muscle was within the range known to adversely affect sensitive birds and mammals, and only 4% of Pacific cod samples contained more than 0.5 ppm of Hg [52]. Additionally, the regression models in a study of cod (mostly from the Pacific Ocean) showed that 27% of the Hg variation was due to tissue examination and the age of fish, and the Hg levels in muscle were significantly higher than those in liver [52]. Moreover, although male fish not only ingest Hg at a higher rate than females, they also eliminate Hg at a higher rate than female fish [59]. Thus, sex, in contrast, did not influence Hg levels, suggesting that female and male fish have similar feeding habits [42].

Hg levels in fish vary widely from place to place, and a significantly positive relationship between the mean total Hg (THg) in fish and the latitude of the sampling site was observed in 40 different water bodies located in 26 countries [50]. High Hg levels occur near sources of Hg release from industrial (e.g., Minamata) and natural (e.g., Cinnabar) mines in the Mediterranean, and volcanic sources near Madeira. The Mediterranean basin contains large amounts of cinnabar sediment, which is why marine organisms here have a higher Hg burden than the same species living in other oceans [60]. Over time, it was experimentally determined that tuna caught in the Mediterranean had three to four times as much Hg as tuna from the Atlantic [60]. Moreover, significant differences were observed in the Hg levels of Scomber australasicus, S. japonicus, Trachurus trachurus, Decapterus punctatus and Paralichthys olivaceus between the Pacific Ocean and the Sea of Japan [61].

In China, Hg in fish is generally accumulated at a low level, but significant geographical differences were evident and formed hot spots from the north to the south [43]. For terrestrial aquatic ecosystems in China, the Hg content in fish is high in the north and low in the south, which may be related to the relatively high Hg emissions in Northern China [21]. However, the Hg content in most river fish did not exceed the national standard of China (0.3 mg/kg) or the international standard of WTO (0.2 mg/kg). Moreover, in terms of marine ecosystems, the fish in the Southern Sea contained higher Hg content than those in the North Sea, and the Hg content in sea fish (0.09–0.36 mg/kg) was generally higher than that in river fish (less than 0.1 mg/kg) [21]. In addition, data on Hg levels in fish from other regions of the world clearly demonstrated that the Hg content in sea fish was below 10.9 µg g⁻¹ in North America [62], between 50 and 3100 ng g⁻¹ in the Mediterranean, and between 10 and 1240 ng g⁻¹ in the Western Indian Ocean [63]. This shows that there is some variability in Hg levels in fish from different regions.

In summary, the differences in Hg levels in fish are related to the differences in fish species and the different positions of fish in the biological food chain (mainly reflected in the level of Hg bio-accumulation in fish), but also depend on the differences in the nutritional status and age of individual fish, which are less dependent on the levels of Hg contamination in the environment [64,65].

4. Toxic effects of mercury (Hg) contaminated fish food on pregnant women and fetuses

4.1. Background of the toxic effects of Hg contamination in fish on fishes and humans

For fishes, Hg markedly affects their physiological health even at lower exposure level, and this is manifested microscopically in the genetic mutations, tissues and physiology, and macroscopically in the survival, growth and developmental status of fish [48]. In addition, Hg exposure can produce teratogenic and neurotoxic effects, and reproductive toxicity, and these effects can then cause harm to cells, tissues, proteins and genes, and ultimately, the survival, growth and behavior of marine fish [48]. There are distinctly individual differences in the factors known to influence the hazard levels of Hg exposure [66]. Thus, there might be non-negligible differences in the effects of Hg toxicity on different individuals, species and life stages of fish [67]. On the other hand, humans can be exposed to Hg, i.e., organic Hg (MeHg/ethyl-Hg) via consumption of fish food and poultry products, and use of insecticides, fungicides and pesticides, in the forms of air pollution, medical equipments (e.g., thermometers and dental amalgam), certain vaccines etc. [68]. The Hg that people usually ingest through feeding fish is organic Hg [25,48]. The most important source of exposure to organic Hg in human beings seems to be the consumption of fish contaminated with MeHg [69]. MeHg bioaccumulates to differing degrees in various fish species and can have serious adverse effects on the development and functioning of the human central nervous system (CNS), especially during prenatal exposure [70]. And the harm of MeHg mainly lies on its toxicity to human nerves, and specifically brain which are most vulnerable to Hg [71]. The World Health Organization (WHO) estimates that the critical blood Hg concentration for MeHg poisoning is 200 μg·L^-1 [72]. High level exposure to Hg can result in significantly neurological and behavioral disorders, including tremors, memory loss, neuromuscular changes, renal and thyroid disorders, and even death [73]. And body burden of Hg has been linked to hypertension in populations exposed to high Hg levels, and a significantly positive association between Hg and hypertension, and between Hg and blood pressure (BP) was identified respectively [74].

Hg-toxic effects will differ depending on whether it has been caused by exposure to elemental, inorganic (as salts) or organic Hg compounds, and each form of Hg has a unique toxicological profile and differs in the mechanisms of transport and disposition in human bodies. Exposure to inorganic and organic Hg can lead to the adverse effects including developmental toxicity, immunotoxicity, neurotoxicity and teratogenicity, and especially cytotoxicity, cardiovascular toxicity, hepatotoxicity and nephrotoxicity, and disrupting endocrine systems and metabolic effects for human beings, and all these possible adverse outcomes with Hg exposure may depend on the doses and length of Hg exposure and the Hg forms, and the age and sex of the exposed humans [17-19]. Both MeHg and vapor Hg are highly reactive and interacting mainly with thiol-based-proteins (-SH) in human bodies, and MeHg exerts some toxic effects through altering protease activity, and both metallothioneins and glutathione appear to have a strong relation with the cytotoxicity caused by inorganic and organic Hg, respectively [75]. Moreover, MeHg plays a role affecting several biological processes, including increased lipid peroxidation, reactive oxygen species (ROS) generation and glutathione (GSH) depletion, reduced cell membrane integrity, altered cell signaling and mitochondrial impacts, changed DNA repair and immunomodulatory impacts, affected the regulation of Ca²⁺, caused glutamate and calcium dyshomeostasis, and changed the DNA methylation etc., which in turn cause adverse effects on humans [17]. Balali-Mood et al. (2021) also indicated that Hg can disrupt cellular events including growth, proliferation, differentiation, damage-repairing processes and apoptosis, and the mechanisms of their action reveal to induce toxicity including ROS generation, weakening of antioxidant defense, enzyme inactivation and oxidative stress, and apoptosis, caspase activation as well as ultrastructural changes in the hepatocytes have also been seen due to Hg exposure [18]. Renu et al. (2021) indicated that Hg can induce apoptosis in liver, and the epigenetic mechanism is that Hg can cause DNA methylation and disruption in the post-transcriptional modifications [19]. And Bridges et al. (2017) indicated that modulation of neurotransmitters including dopamine and serotonin in brain may result in changes of behavior related to Hg exposure [76]. Furthermore, high exposure to Hg can deplete the amount of cellular selenium available for the biosynthesis of thioredoxin reductase and other selenoenzymes that prevent and reverse oxidative damage, which, if the depletion is severe and long-lasting, results in brain cell dysfunctions that can ultimately cause death [77]. Although multiple mechanisms of toxic action of Hg were discussed in [16-19,75], however, many aspects are still far from being understood satisfactorily.

4.2. Toxic effects of Hg contamination in fish food on pregnant women and fetuses

It is undeniable that the intake of fish during pregnancy is beneficial for the body health due to the diverse nutrients it contains. Numerous studies have shown that fish is rich in long chain omega-3 polyunsaturated fatty acids (LCn-3PUFAs), and vitamins A, D and B₁₂, which play an important role in the physiological metabolism [78-79]. However, aquatic organisms, mainly fish, are contaminated with numerous toxic substances, including Hg and other heavy metals and drug residues, which may have adverse effects such as teratogenicity [80-81]. Numerous statements have been made in the medical literature and by WHO in the past, recommending limiting seafood intake by pregnant women to avoid exposure of this population to the potential toxicity of aquatic products [9]. Hg exposure in pregnancy has been associated with both pregnancy complications and developmental problems in infants [82]. In pregnant women, Hg passes through the placental membrane, which can cause spontaneous abortions, premature births, congenital disabilities and retardation of fetus development [83]. And even small amounts of fish consumed by mothers during pregnancy can cause elevated Hg levels and affect children's neurobehavioral development, including basic skills such as listening, reading, and writing [84,85]. Meanwhile, in contrast, no negative effects of maternal fish consumption during pregnancy on local children's neurobehavioral development were found in the Republic of Seychelles [86,87]. However, relevant indicators showed that the population of the Faroe Islands, which consumes mainly whale meat and blubber, contained approximately 10 times more MeHg in their samples at 1.6 ppm than Seychelles fish [87]. The difference in MeHg content undoubtedly contributes to the difference in findings, which also confirms in a comparative way the risk of MeHg in fish for the fetus in pregnant women. Moreover, researchers measured blood Hg levels using atomic absorption based on 200 cases of deliveries in a Chinese hospital, and the incidence of fetal malformations, adverse pregnancy outcomes, hypertensive disorders of pregnancy, intrauterine growth retardation, and fetal distress were found to be higher in the group with elevated blood Hg than in the group with normal blood Hg [88].

For pregnant women, the blood levels of Hg often exceed acceptable international levels, and the average Hg levels in the blood of mothers with premature births, low birthweight and spontaneous abortions were 30% higher in comparison with unexposed women, and a significantly increased risk of premature birth and birth of children with low body weight and spontaneous abortions was also found when the Hg concentration exceeded 2 µg/L of plasma [89]. MeHg is usually absorbed by the body through the skin mucosa, respiratory and digestive tracts, and the most important route is the digestive tract [90]. As a common food item on the human table, the entry of MeHg into the body of pregnant women through the gastro intestinal route is often an important cause of Hg hazards [88]. After entering the bloodstream, Hg binds to the sulfhydryl group of hemoglobin and enters the organs of the body, subsequently the amount of MeHg in the organs and tissues remains relatively constant [91]. It is noteworthy that the toxic effects of MeHg on the liver and kidneys are lower, although the Hg levels in the organs or tissues are in descending order: liver>brain>kidney>blood [90]. And the toxic effects of MeHg in the brain and the nervous system are relatively high [92]. The reason for this is, on the one hand, that brain tissue is rich in lipid-like substances that have a strong affinity for MeHg, which can easily enter brain tissue through blood flow; On the other hand, MeHg is strongly bound to the carbon-Hg chains in the molecular structure of MeHg, so MeHg can remain in brain cells for a long time and cannot be easily excreted [92]. The clearance of MeHg from brain is delayed by 20% compared to other parts of the body, and MeHg accumulation in brain is higher than that in sensory and motor areas, especially in the posterior lobe of the brain [92]. The mechanism of Hg following injury to the mother involves several complex aspects of the body's metabolism. Hg readily binds to sulfhydryl groups and enzymes in proteins leading to dysfunction of several enzymes in the body, including ATPase, lactate dehydrogenase, cytochrome oxidase and alkaline phosphatase, leading to severe enzyme inactivation [91]. Hg can also disrupt the structural integrity of genetic material by binding to multiple groups (e.g., hydroxyl and amino groups) in genetic materials (e.g., DNA and RNA), which can lead to DNA breakage and mutation in severe cases [88]. And Hg exposure often leads to visual field contraction, motor ataxia, dysarthria, tremor and cardiovascular diseases etc. [93,94]. Hg and MeHg can cause mitochondrial dysfunction, decrease ATP synthesis, deplete glutathione, increase phospholipid, protein and DNA peroxidation [95]. The vascular effects of Hg also include many aspects, such as increased oxidative stress and inflammation, and decreased oxidative defenses, mitochondrial dysfunction, depolarization and autoxidation of inner mitochondrial membranes and inactivation of oxygen phosphatase [71].

For the fetus, once incorporated into the body, MeHg easily penetrates the blood-brain barrier (BBB) and causes damage to the central nervous system (CNS) [20]; and high blood Hg levels can increase the incidence of intrauterine growth retardation and fetal distress [96]. In general, Hg can pass placenta into unborn infant, and the early exposure to Hg is correlated to infant health effects, such as neurological, developmental and endocrine disorders [97]. The teratogenicity of MeHg and its effects on fetal growth and development have also been confirmed in a trial of singleton pregnancies [88]. Gilbertson (2004) indicated that the perinatal exposure to MeHg was known to result in severe neurological effects on the developing fetus and infant, including cerebral palsy, mental retardation and seizures [98]. Simultaneously, Hg exposure is also extremely harmful to the fetus, causing cardiovascular disease, hypertension and changes in heart rate variability [99,100]. Since cardiac rhythm and function are controlled by the autonomic nervous system, and it has been hypothesized that the neurotoxic effects of Hg may also affect cardiac autonomic function [101]. Exposure to Hg may have long-term effects on cardiac parasympathetic activity of children, and the intrinsic mechanism why elemental Hg is so damaging to the nervous and cardiovascular systems is due to the high affinity of Hg for sulfhydryl and selenium groups, which are present in glutathione precursors such as cysteine [101].

4.3. Interactive toxic effects of Hg contamination in fish food on pregnant women and fetuses

The main reason for the widespread concern about fish intake by pregnant women is the vulnerability of the pregnant woman and the fetus itself, and the hazard extent of Hg exposure [102]. The fetus is relatively vulnerable to adverse external factors, and the incomplete development of the fetal liver results in the inability to excrete toxic substances and pollutants in a timely and effective manner [103]. The dangers of Hg are also passed between the pregnant woman and the fetus and affect each other [102]. On the one hand, the pregnant women who consumed a large amount of fish might have elevated blood Hg levels, and Hg level in cord blood is much higher than that in maternal blood [9]. Kim & Kim (2006) also indicated that the blood Hg content in the umbilical blood is substantially higher, and this may lead to higher blood Hg levels in neonates [9]. Higher Hg concentration in the fetus compared to that in the mother may affect immature fetal organs [104]. And the placenta in pregnant women does not present a barrier to Hg and the fetus has a high accumulation capacity for MeHg with 1.8 - 4.0 times of MeHg content in brain, liver, kidney, heart or lung than that of normal adults [105]. On the other hand, MeHg has lipolytic properties with a strong affinity for lipid-like substances and can easily pass through membranous tissues, such as the placental barrier and the blood-brain barrier (BBB), and it is easy to cause direct all-round damage to the fetus [20]. Because of its lipid solubility and short-chain hydrocarbon structure, Hg can rapidly pass through the placenta and be oxidized into ionic complexes that bind with high affinity to fetal hemoglobin and cannot be returned to the pregnant women's blood circulation [38,83]. Moreover, Hg easily binds to sulfhydryl groups, so proteins and enzymes containing sulfhydryl groups (e.g., ATPase and lactate dehydrogenase) are disturbed or even inactivated by the binding of Hg [91]. And genetic material containing amino and phosphate groups (e.g., DNA) can be damaged by Hg binding [88].

Based on the toxic effects of Hg contaminated fish food on pregnant women and fetuses, and in combination with the reviewed multiple mechanisms of Hg-toxic action on humans [16-19,75], the action model of high exposure to Hg for pregnant women and fetuses through consumption of Hg contaminated fish food was elucidated in Figure 2, which was adapted from Balali-Mood et al. (2021) [18]. It is elucidated that high exposure to Hg for pregnant women and fetuses is harmful and has many adverse effects on various organs (especially liver, kidney and brain), and disruption of the antioxidant system may play an important role in the Hg toxic effects, simultaneously signaling transduction, protein or/and enzyme activity, and gene regulation are involved in mediating toxic and adaptive response to Hg exposure. The information of mechanism involved in Hg toxicity is growing, but knowledge gaps still exist between the adverse effects and mechanisms of action, especially at the molecular level.

Figure 2. Action model of high exposure to mercury (Hg) for pregnant women and fetuses through consumption of Hg contaminated fish food (Note: ADS-Antioxidant Defense System (including various enzymatic and nonenzymatic antioxidants); ES-Endocrine Systems (i.e., Glands) produce and release different hormones; CNS-Central Nervous System, and Hg can inhibit the formation of myelin to prevent nerve sheaths from forming properly; Blood and brain-Forming the blood-brain barrier (BBB) against toxic chemicals, and MeHg easily penetrates BBB and causes CNS damage particularly in fetuses; Liver-Hg can induce apoptosis in liver through DNA damage with disrupting DNA methylation and disruption in the post-transcriptional modifications. Adapted from Balali-Mood et al. (2021) [18])

 

5. Recommended fish diet for pregnant women based on toxic effects of Hg contamination in fish food

Fish is considered as a healthy food with exceptional properties rich in vitamins, minerals and high quality proteins and essential 3FAs [1-5]. During pregnancy period, pregnant women need more nutritional supplements than ever before. However, given the toxic effects of Hg contained in fish products, there is often a “trade-off” for them in fish consumption to achieve a relatively favorable ratio [6,104,106-107]. The rational consumption of fish is a mustin terms of nutrient intake, ensuring the health safety and concerns of pregnant women [11,108]. On the one hand, more innovative and new fish products need to be developed to better suit the seafood intake needs of pregnant women. On the other hand, the proper understanding of fish consumption needs to be further promoted and popularized in general, especially for pregnant women. Some researchers recommend regular fish oil supplementation during pregnancy [109]. Although many reports elucidated the benefits of fish oil [110-111], some studies have concluded that it is not beneficial or have even reached the opposite conclusion [112-114]. Given the effects of high doses of cod liver oil on hypertension in pregnancy [113] and some adverse effects of MeHg arising from the consumption of regular fish oil [115], the rational recommendation of dietary fish intake is a must due to the complex interplay between MeHg and fish oil-derived fatty acids [116]. Fish oils come from different fish species and involve some variation in the contamination status and purification level of the origin, and therefore the most conservative recommendation is to consume a variety of low Hg contaminated fish food for health benefits [117].

Additionally, some researchers recommend eating small fish because they have low levels of bio-concentration of toxic substances such as Hg in their bodies [44,57]. And avoiding specific species (mainly carnivorous fish), limiting the intake of fish for pregnant women and avoiding intake of fish that survive from heavily polluted waters, and selective intake of aquatic products (e.g., shellfish and shrimp) is also recommended. The importance of fish food should not be overlooked because of the toxic effects of harmful substances (including Hg), and the benefits of important nutrients need to be properly and widely disseminated to the consumer community, especially pregnant women. In a study on the effects of fish consumption and fetal neurodevelopment in women of childbearing age, the authors stated that fish consumption in dietary intake should focus on nutrients, such as docosahexenoic acid (DHA) as mentioned by Mendivil (2021) [4]. The population of pregnant women is encouraged to consume fish with high DHA and low MeHg, such as anchovy, arctic char, atlantic mackerel, catfish, cod, haddock, herring, perch, pollock, salmon, sardines, shellfish, tilapia, trout and tuna etc., and strictly avoid consuming fish with high MeHg levels (such as bluefish, croaker, eel, king mackerel, shark, swordfish, tilefish and weakfish etc.) (as described in Table 1).

Table 1. Choice guidelines of the species and types of fish based on the Hg contamination, as daily fish food for pregnant women.

Choices	Level of Hg contamination	Types of fish	Species of fish	Cited references
Right	Low Hg/MeHg	Freshwater fish, herbivorous fish, small fish etc.	Anchovy, arctic char, atlantic mackerel, catfish, cod, haddock, herring, perch, pollock, salmon, sardines, shellfish, tilapia, trout and tuna etc.	42-47, 49- 53, 107, 118, 119
Wrong	High Hg/MeHg	Marine fish, piscivores and carnivores, benthic fishes, large fish, predatory fish etc.	Bluefish, croaker, eel, king mackerel, shark, swordfish, tilefish and weakfish etc.

 

As for the frequency and amount of fish consumption, the relevant safety and health authorities have given different recommendations based on different countries or regions. For instance, in March 2004, the Department of Health and Human Services (HHS) and the Environment Protection Agency (EPA) of the USA published a report entitled “What You Need to Know about Mercury in Fish and Shellfish" which showed that nearly all fish and shellfish contain trace amounts of Hg. Thus, to avoid Hg contamination, in 2010, the U.S. Department of Agriculture (USDA) and the U.S. Department of HHS recommended the public to consume not more than 8 ounces (227 g) of a variety of seafood per week, which equates to an average daily intake of 250 mg of fatty acids, including DHA [120]. In addition, the US EPA recommended that the total blood Hg concentration should remain lower than 5.8 µg/L for women of childbearing age [121]. The British Food Standard Agency (FSA) recommended that pregnant women, women of childbearing age and children under 16 years of age should avoid consuming swordfish and tuna (which are higher ranking in ocean food chain) because of the high Hg content and recommended that pregnant women and women of childbearing age should avoid consuming more than two tuna steak per week [72, 122-123].

Many documents have also presented fish consumption views and guidelines for pregnant women [6,52,106]. However, these recommendations tend to be generalized in nature. Specifically, for individuals, the amount of fish recommended per week depends on the frequency and portion size of fish a person eats, the individual's physical condition such as the individual's sensitivity to toxicity, his or her own body weight, etc. More precise recommendations can be obtained from national or local public health departments [118]. In addition, based upon the study on the awareness of fish Hg and in compliance with WHO’s enforcement of fish consumption among pregnant women, researchers found that women with higher incomes and education and those living in coastal states were more likely to be aware of Hg in fish food, suggesting that information about safe fish consumption is not being communicated equally to all groups [124-125].

However, there have been many studies on the toxicity of MeHg in fish, which have drawn opposite conclusions. The risk of Hg content caused by moderate fish intake is less than the beneficial effects of fish nutrients on human body, and they maintain a positive attitude towards fish intake as a whole [126]. Gale et al. (2008) indicated that as oily fish is a major dietary source of 3FAs, it is possible that low intake of fish during pregnancy may have adverse effects on the developing fetal brain [127]. And many experiments have shown that Hg does not affect pregnant women and fetuses in small amounts [10,108,128-129]. No significant conversion of Hg species was also observed after fish cooking treatment, while an overall loss of up to 33% of Hg species in fish was observed after frying and most of the Hg lost during the cooking procedure came from CH₃Hg⁺, so it was concluded that the fish diet was neutral especially after cooking treatment [130]. There is no consensus on the effects of fish containing MeHg on pregnant women and the neurological effects on the fetus. Persistent chemical pollutants may bio-accumulate and have the potential to achieve teratogenic or other adverse effects. In addition, the ultimate consequences of exposure to toxic chemicals (including Hg) in pregnant women, especially in the long term, are uncertain [131]. Therefore, some studies concluding that exposure to low levels of chemical toxins (including Hg) during pregnancy has no long-term effects are incomplete and inappropriate, and more high quality precise and scientific researchers are warranted.to further carry out in the future.

The researchers hitherto found low-Hg dietary intake of fish per week, where almost all women consume less than 6 ounces which is equivalent to WHO’s recommendation of 170.1 g as per week, is the current existing scenario, however the average fish intake for the female population ranged from 89 g to 120 g (2 to 3 ounces) per week or less. The overall fish consumption pattern of females is followed as pregnant women > postpartum women > normal group of women [128]. This finding is similar to the FDA’s analysis of fish consumption, which estimated that average fish consumption of all women aged (16-45) to be 13.4 g per day (i.e., 93.8 g per week), and the 2003-2004 NHANES results estimated that women aged 16-45 years averaged 10.3 g fish per day [132]. These data respond to a phenomenon that indicates a deficit in the promotion of fish consumption. The predominantly pregnant and postpartum women appear to be following national or local safety and health organization recommendations of "no eating" rather than maintaining a regular intake of low-Hg fish, this results in pregnant women not consuming enough low-Hg fish to benefit for their health [125,128]. Therefore, education and media coverage for pregnant women needs to be further improved, and the government and society need to take measures to avoid extreme attitudes toward fish consumption among pregnant women, i.e., total ban or no concern at all. Agencies need to adequately communicate the benefits of consuming adequate amounts of low-Hg fish food while in the meantime raising awareness among pregnant women about the dangers of Hg contamination in fish and other fish products, as per described in this review. Moreover, both metallothioneins and glutathione appear to have a strong relation with inorganic and organic Hg cytotoxicity respectively [75]. And hair is considered as an index of Hg exposure since MeHg is accumulated there (the average ratio of hair to blood concentrations of MeHg is about 250:1) and Hg is excreted in urine and feces [76]. So the hair, urine and feces, and some specific proteins of pregnant women can be used as special biomarkers as early warning of Hg contamination for the daily intake of fish in the diet.

6. Conclusion and perspectives

As one of the top ten chemicals or groups of chemicals of major public health concern, Hg has been continuously discharged from natural sources and industrial activities, and the health effects of Hg contamination on humans, especially pregnant women (including fetuses) susceptible to Hg (especially MeHg) exposure even though at low levels become a worldwide concern. This review paper introduced the Hg forms in the nature and fish bodies, and the bio-accumulation of Hg in fish through food chains in water ecosystem, and further reviewed the interactive toxic effects and action mechanisms of Hg-contaminated fish food on pregnant women and fetuses. Based on the mechanisms that inorganic Hg cannot pass the blood brain barrier (BBB) and placenta, and liquid Hg⁰ is just slightly absorbed from the gastrointestinal (GI) tract, so these two forms of Hg does not appear to be toxic as accidentally contacting small amounts, while vapor Hg⁰ and organic Hg (including MeHg) have high toxic even at low levels because they can pass the BBB (blood-brain barrier) and cause CNS (central nervous system) disorder. Because there are species-specific and geographical difference of Hg bio-accumulation in fish, this review paper provides practical recommendations for people, especially pregnant women to select right species and specific tissues of fish and seafood with low concentrations of Hg in fish and suggest cooking fish diet. In this review paper, it was addressed this important public health dilemma for pregnant women to eat or not eat fish exposed to mixtures of healthful nutrients and Hg contamination. In the future, based on the accurate measurement of the Hg content in different species of fish in the corresponding waters of different regions and the detailed classification of different populations of Hg-contaminated fish in the region, the local governments and health organizations should further provide more accurate and personalized fish dietary intake recommendations for specific populations of childbearing-age women who might become pregnant, are pregnant, and nursing mothers, and young children under 16 years of age, so as to ensure the maximum benefits of fish dietary intake.

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