Introduction of Methylmercury

1. 1
Methylmercury (MeHg)
By Waqar Ahmad Khan
Mercury (Hg) is an environmental pollutant that is of major public concern due to its ubiquitous
nature. Hg that has been released into aquatic environments from anthropogenic sources becomes
readily methylated by sulfate and iron-reducing bacteria giving rise to MeHg [1]. MeHg then bio-
accumulates up the aquatic food chain. Consumption of large seafood such as tuna or swordfish is
the primary source of exposure to humans [2]. MeHg can readily cross the blood–brain barrier.
This in part is due to its ability to bind thiol groups on proteins and amino acids. In particular,
MeHg binds to cysteine, and therefore mimics the structure of methionine, thus enhancing its
likelihood to be taken up by amino acid transporters [3]. MeHg can accumulate in human bodies
with a biological half-life in the blood of 2–3 months [4]. Exposure to MeHg is detrimental,
particularly for the developing brain. MeHg has been reported to induce deformities and
neurological impediments in the fetus, as well as cause stillbirths. In addition, it can cause visual,
auditory, and speech impairment and ataxia [5]. MeHg induced neurodegeneration has been
examined in a variety of animal models including C.elegans, rats, and monkeys [6–8]. While many
studies have focused on the role of MeHginduced oxidative stress, recent studies are focused on
other mechanisms underlying its neurotoxicity, such as autophagy. In an in vitro study by Chang
et al. [9], human neural stem cells exposed to chronic doses of MeHg (0.01–1 lM) exhibited
decreased mTOR protein levels in a dose-dependent manner. As previously mentioned, mTOR is
a negative regulator of autophagy. Therefore, loss of mTOR may suggest that MeHg-induces
excessive autophagy, resulting in the conversion of the recycling nature of the autophagic system
to a degenerative process. It has yet to be investigated how MeHg decreases mTOR expression.
Increase in Atg6/Beclin-1 protein levels was also observed, suggesting a possible upregulation in
autophagic activity. Finally, an increase in the microtubule-associated protein 1 light chain 3
(LC3)-II–LC3-I ratio was detected subsequent to exposure. The conversion of LC3-I (cytosolic
form)– LC3-II (lipidated form that binds to the autophagosome membrane) is a widely used marker
to assess the autophagy induction in mammalian cells [10]. The increased ratio of LC3-II–LC3-I
in cells exposed to MeHg indicated higher autophagic activity. Transmission electron microscopy
further verified that more autophagic vacuoles existed in the cells after MeHg exposure [9].

2. 2
Yuntao et al. [11] examined autophagic biomarkers in rat astrocytes treated with MeHg. They
observed the presence of autophagosomes post-exposure, increased LC3-II–LC3-I ratio, and an
increase in Beclin-1 protein, indicating enhanced autophagy in astrocytes. Inducing autophagy
with rapamycin led to cytoprotection, whereas suppression of autophagy with chloroquine
exacerbated cytotoxicity post-MeHg exposure [11], suggesting that autophagy is protective against
MeHg-induced cytotoxicity. The study also showed that the protective effect of autophagy is
possibly through attenuating cell apoptosis. To date, the mechanisms underlying MeHg-induced
autophagy upregulation remain unclear. As previously mentioned, MeHg binds thiol groups on the
proteins and may lead to protein destabilization and/or functional changes which possibly serve as
an autophagy inducer. MeHg also triggers oxidative stress as indicated by ROS generation [12].
Oxidative stress has been shown to activate the autophagy-signaling pathway. Due to the continued
exposure of the general public to MeHg and the very limited literature on the role of autophagy in
the mechanisms of its neurotoxicity, further investigation in this area is warranted.Minamata
disease, sometimes referred to as Chisso-Minamata disease, is a neurological syndrome caused by
severe mercury poisoning. Symptoms include ataxia, numbness in the hands and feet, general
muscle weakness, narrowing of the field of vision and damage to hearing and speech. In extreme
cases, insanity, paralysis, coma and death follow within weeks of the onset of symptoms. A
congenital form of the disease can also affect fetuses. Minamata disease was first discovered in
Minamata City in Kumamoto prefecture, Japan in 1956. It was caused by the release of
methylmercury in the industrial wastewater (point source pollution) from the Chisso Corporation's
chemical factory, which continued from 1932 to 1968. This highly toxic chemical bioaccumulated
in shellfish and fish in Minamata Bay and the Shiranui Sea, which when eaten by the local populace
resulted in mercury poisoning. While cat, dog, pig and human deaths continued over more than 30
years, the government and company did little to prevent the pollution.As of March 2001, 2,265
victims had been officially recognized (1,784 of whom had died) and over 10,000 had received
financial compensation from Chisso. By 2004, Chisso Corporation had paid $86 million in
compensation, and in the same year was ordered to clean up its contamination. Lawsuits and claims
for compensation continue to this day.A second outbreak of Minamata disease occurred in Niigata
Prefecture in 1965. Both the original Minamata disease and Niigata Minamata disease are
considered two of the Four Big Pollution Diseases of Japan[13]. As soon as the investigation
identified a heavy metal as the causal substance, the wastewater from the Chisso plant was

3. 3
immediately suspected as the origin. The company's own tests revealed that its wastewater
contained many heavy metals in concentrations sufficiently high to bring about serious
environmental degradation; these metals included lead, mercury, manganese, arsenic, selenium,
thallium and copper. Identifying which particular poison was responsible for the disease proved to
be extremely difficult and time consuming. During 1957 and 1958, many different theories were
proposed by different researchers. Initially, manganese was thought to be the causal substance due
to the high concentrations found in fish and the organs of the deceased. Thallium, selenium and a
multiple contaminant theory were also proposed but it was not until March 1958, when visiting
British neurologist Douglas McAlpine suggested that Minamata symptoms resembled those of
organic mercury poisoning, that the focus of the investigation centered on mercury. The 1971 Iraq
poison grain disaster was a mass methyl mercury poisoning incident that began in late 1971. Grain
treated with a methylmercury fungicide and never intended for human consumption was imported
into Iraq as seed grain from Mexico and the United States. Also ingestion probably began in
October-November 1971 , and the first patient with severe poisoning were admitted to the hospital
at thee end of December 1971 . This incidence developed into the most catastrophic epidemic ever
recorded with 6,530 people hospitalized by March 27 of the following year , of whom 459 died in
the hospital[14].
References
1.Parks JM, Johs A, Podar M, Bridou R, Hurt RA Jr, Smith SD, Tomanicek SJ, Qian Y, Brown
SD, Brandt CC, Palumbo AV, Smith JC, Wall JD, Elias DA, Liang L (2013) The genetic basis for
bacterial mercury methylation. Science 339:1332–1335
2. Sheehan MC, Burke TA, Navas-Acien A, Breysse PN, McGready J, Fox MA (2014) Global
methylmercury exposure from seafood consumption and risk of developmental neurotoxicity: a
systematic review. Bull World Health Organ 92:254F–269F

4. 4
3. Kerper LE, Ballatori N, Clarkson TW (1992) Methylmercury transport across the blood–brain
barrier by an amino acid carrier. Am J Physiol 262:R761–R765
4. Jo S, Woo HD, Kwon HJ, Oh SY, Park JD, Hong YS, Pyo H, Park KS, Ha M, Kim H, Sohn SJ,
Kim YM, Lim JA, Lee SA, Eom SY, Kim BG, Lee KM, Lee JH, Hwang MS, Kim J (2015)
Estimation of the biological half-Life of methylmercury using a population toxicokinetic model.
Int J Environ Res Public Health 12:9054–9067
5. do Nascimento JL, Oliveira KR, Crespo-Lopez ME, Macchi BM, Maues LA, Pinheiro MdCN,
Silveira LC, Herculano AM (2008) Methylmercury neurotoxicity & antioxidant defenses. Indian
J Med Res 128:373–382
6. Martinez-Finley EJ, Caito S, Slaughter JC, Aschner M (2013) The role of skn-1 in
methylmercury-induced latent dopaminergic neurodegeneration. Neurochem Res 38:2650–2660
7. Cao B, Lv W, Jin S, Tang J, Wang S, Zhao H, Guo H, Su J, Cao X (2013) Degeneration of
peripheral nervous system in rats experimentally induced by methylmercury intoxication. Neurol
Sci 34:663–669
8. Shaw CM, Mottet NK, Body RL, Luschei ES (1975) Variability of neuropathologic lesions in
experimental methylmercurial encephalopathy in primates. Am J Pathol 80:451–470
9. Gimenez-Xavier P, Francisco R, Platini F, Perez R, Ambrosio S (2008) LC3-I conversion to
LC3-II does not necessarily result in complete autophagy. Int J Mol Med 22:781–785
10. Chang SH, Lee HJ, Kang B, Yu KN, Minai-Tehrani A, Lee S, Kim SU, Cho MH (2013)
Methylmercury induces caspase-dependent apoptosis and autophagy in human neural stem cells.
J Toxicol Sci 38:823–831
11. Yuntao F, Chenjia G, Panpan Z, Wenjun Z, Suhua W, Guangwei X, Haifeng S, Jian L, Wanxin
P, Yun F, Cai J, Aschner M, Rongzhu L (2014) Role of autophagy in methylmercury-induced
neurotoxicity in rat primary astrocytes. Arch Toxicol. doi:10. 1007/s00204-014-1425-1
12. Farina M, Rocha JB, Aschner M (2011) Mechanisms of methylmercury-induced neurotoxicity:
evidence from experimental studies. Life Sci 89:555–563
13.https://www.bu.edu/sustainability/minamata-disease/#:~:text=August%202019-
,Minamata%20Disease,damage%20to%20hearing%20and%20speech.

5. 5
14.https://www.researchgate.net/publication/330958073_1971_Iraq_Poison_Grain_Disaster_and
_Methylmercury_Hawraz