Tin - Toxicology of Metals - page 833

triorganotins inhibit P-450 monooxygenase ethox-
yresorufi n o -deethylase, as well as aromatase and
dehydrogenase, which convert estrone to estradiol
and androstenedione to testosterone (Lavado et al .,
2004; Nebbia et al ., 1999; Thibaut and Porte, 2004).
These effects of organotins suggest the possibility of
alterations in steroid hormone metabolism. Indeed, it
has been shown that tributyltin inhibits testosterone
metabolism, which is associated with elevated testo-
sterone levels in gastropods (Oberdorster et al ., 1998).
Gastropod imposex, an irreversible syndrome when
male genital tracts are imposed on female organisms,
is typically induced by very low concentrations of
tributyl- or triphenyltin compounds (Horiguchi et al .,
1997; Morcillo et al ., 1999; Sole et al ., 1998). However,
aromatase activity is not decreased in gastropods
exposed to tributyltin, even in those exhibiting clear
evidence of imposex (Morcillo et al ., 1999). Recently,
it has been shown that trisubstituted organotin com-
pounds act as agonists of retinoid X and peroxisome
proliferator-activated receptors, which play an impor-
tant role in the development of gastropod imposex
(Kanayama et al ., 2005). The effective concentration
of receptor inhibition is approximately 10 −8 mol/L. In
fi sh yolk sac fry stage has been also shown to be the
most sensitive to the toxic effects of tributyltin com-
pounds (de Vries et al ., 1991). Studies of reproduction
in rats by administration either in food or oral dosing
have demonstrated that triphenyltin at dose of 1 mg/
kg and triphenyltin hydroxide at a dose >6 mg/kg
cause death to pups at birth, but there was no reduced
fertility or in utero lethality (Golub and Doherty, 2004).
Winek et al . (1978) reported that rats fed triphenyltin
hydroxide at 20 mg/kg became sterile. Diphenyltin at
16.5 mg/kg and greater administered on days 0-3 of
pregnancy causes embryonic loss mediated through
reduction of progesterone and suppression of uterine
decidualization (Ema and Miyawaki, 2002). Triphe-
nyltin acetate or chloride reduces the number of gam-
etes at various stages of the sperm cycle, and rats can
become completely sterile after administration of
20 mg/kg for 20 days (Pate and Hays, 1968; Snow and
Hays, 1983). Moreover, triphenyltin can cause reduc-
tion in relative ovarian and uterine weight in guinea
pigs fed 20 mg/kg and rats treated with 20 and 50 mg/
kg (Newton and Hays, 1968; Verschuuren et al ., 1966).
Trialkyltin compounds are toxic to the CNS of new-
born and adult rats at doses of 3-7 mg/kg (Harry
and Tilson, 1981; Swartzwelder et al ., 1981). Prenatal
administration of triphenyltin acetate causes abnor-
malities in spontaneous locomotor activity and con-
ditioned avoidance in rat pups (Lehotzky et al ., 1982a).
Tributyltin and triphenyltin compounds are potent
stimulators of placental hCG production and suggest

that the placenta is a potential target organ for trialkyl-
tin compounds (Nakanishi et al ., 2002). Triphenyltin
can induce hyperglycemia and hypertriglycemia in
hamsters but not in rats (Matsui et al ., 1984; Ohhira and
Matsui, 1996). Trimethyltin and triethyltin are neuro-
toxic and can cause neuronal necrosis primarily affect-
ing the hippocampus and endocrinal cortex (Bouldin
et al ., 1981; Winship, 1988). Triphenyltin compounds
show relatively low neurotoxicological effects even
at high doses compared with triethyltin, trimethyltin,
tributyltin, and tripropyltin (Bouldin et al ., 1981; Wada
et al ., 1982). Severe swelling of the brain accompanied
by hind limb paralysis was observed in rats exposed to
20 mg/kg triethyltin for 3 weeks (Barnes and Magee,
1958). Unlike triethyltin treatment, oral exposure to tri-
methyltin in a single dose of 10 mg/kg caused severe
and permanent damage in the CNS in rats as charac-
terized by neuronal necrosis rather than intramyelinic
edema (Bouldin et al ., 1981). Trimethyltin at a single dose
of 4.5 mg/kg produces neurodegeneration in the hip-
pocampus, especially in CA1 stratum radiatum (Scallet
et al ., 2000). The toxic effects of trimethyltin include
inhibition of transmembrane gradient of K+ in astro-
cytes with release of glutamate and aspartate into the
extracellular fl uid on release from astrocytes (Aschner
et al ., 1992). The lack of ability to maintain a transmem-
brane gradient triggers a destructive cascade of events
that results in swelling of astrocytes (Matthews et al .,
1991). Tributyltin and dibutyltin inhibit various param-
eters of cholinergic activity (Kobayashi et al ., 1996).
These compounds suppress K+-induced release and
synthesis of acetylcholine in cortex, as well as inhibit
the activity of choline acetyltransferase. Because orga-
notins are diffi cult to eliminate from the central nerv-
ous system, exposure to these compounds can lead to
permanent neurological defi cits.
Neurotoxicity of organotin compounds is accom-
panied by impairment of liver function (Manzo et al .,
1981). Signifi cant depression of hepatic microsomal
aminopyrine demethylase and aniline hydroxylase
activities has been observed in rats fed with triphenyl-
tin at dose 1 mg/kg for 3 days (Di Nucci et al ., 1986).
However, triphenyltin did not affect bile fl ow and liver
weight. The administration of tributyl- and dibutyltin
cause hepatotoxicity in mice at doses >180 or 60

mol/
kg, respectively (Ueno et al ., 1995). Monobutyltin does
not cause liver injury even at 7 mmol/kg. Both tri- and
disubstituted butyltin compounds have been shown to
induce infl ammation of the bile duct associated with
hepatic lesions (Krajnc et al ., 1984). Tributyltin com-
pounds reduce cyclic AMP production, change cal-
cium metabolism, and also suppress hormone-induced
calcium response in primary hepatocytes (Snoeij et al .,
1986).

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