Page 479 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

446 SECTION | V Metals and Micronutrients

VetBooks.ir 1997; Malecki et al., 1999; Aschner et al., 2002; Neuronal uptake of Mn involves transferrin (Suarez and
Eriksson, 1993) and utilization of specific transporter sys-
Fitsanakis and Aschner, 2005). This chapter describes
tems, such as the dopamine transporter (Chen et al.,
deficiency and toxicity of Mn in animals.
2006a; Anderson et al., 2007). At the subcellular level,
Mn preferentially accumulates in mitochondria, where
PHARMACOKINETICS/TOXICOKINETICS
it disrupts oxidative phosphorylation and increases
Absorption of Mn is via oral and inhalation routes. the generation of reactive oxygen species (ROS) (Gunter
Absorption of Mn through the skin is negligible. Apparent et al., 2006).
absorption of orally administered 54 Mn has been esti- Rodent studies of enhanced CNS uptake during
mated to range from 1% to 5% in rats, humans and live- development have been contradictory. While one study
stock (Hurley and Keen, 1987; Davis et al., 1993). In indicates that the amount of Mn that crosses the pla-
young rats, Mn absorption has been reported to be 8%. centa was not increased by enhanced maternal exposure
Absorption of Mn appears to occur by a low-capacity sat- via diet (Jarvinen and Ahlstrom, 1975), another study
urable process and by diffusion (Garcia-Aranda et al., indicated increased neonatal brain Mn following
1983; ATSDR, 2000). Uptake and retention of dietary Mn chronic high-level exposure of the dam to Mn in drink-
was found to be greater in suckling than postweaning rats ing water throughout gestation (Kontur and Fechter,
(Keen et al., 1986). In cattle, using MnSO 4 as 100% avail- 1985). Other studies also showed that, when compared
able, MnO is 58%, MnO 2 is 33% and MnCO 2 is 28% with adults, neonatal rodents attained higher brain Mn
available (Puls, 1994). Mn is more available from hay levels following similar oral exposures (Kontur and
to cattle than from silage. It is important to note that Fechter, 1985; Dorman et al., 2000). This tendency of
newborn calves absorb and retain more dietary Mn than neonates to attain higher brain Mn concentrations may
adults. reflect a less than optimal BBB, markedly reduced bili-
Absorption of Mn can be influenced by various dietary ary Mn excretion rates, and/or increased placental Mn
factors such as iron, calcium, phosphorus, phytate, and concentration (Aschner and Aschner, 2005; Austinc
amino acids. Henry (1995) estimated the relative bioavail- et al., 2016). However, an increase in the placental con-
ability of Mn to poultry was 0.55 from manganese carbon- centrations does not necessarily mean higher placental
ate, 0.3 from manganese dioxide and 0.75 from manganese transfer of Mn to the fetus or higher fetal exposure
monoxide, when the bioavailability of manganese from (Dorman et al., 2005; Yoon et al., 2009a). Furthermore,
manganese sulfate and manganese chloride was considered brain Mn concentrations are higher in developing
to be 1. Manganese from manganese carbonate, dioxide animals, suggesting that high amounts of Mn are
and monoxide (relative bioavailabilities were 0.3, 0.35 and required for normal brain development in infants (Keen
0.6, respectively) was even less available to sheep than et al., 1986; Takeda et al., 1999). Therefore, whether
manganese sulfate (relative bioavailability was 1). the relatively higher net increase in brain Mn observed
Following absorption, Mn can be distributed to many in neonates compared to adults would pose an increased
organs. The average adult human has about 12 mg of Mn, risk for neurotoxicity requires further understanding of
of which about 43% resides in the skeletal system and the the Mn requirements for normal brain development
rest in soft tissues including the liver, pancreas, kidneys, (Yoon et al., 2009b).
and central nervous system (CNS). Such information The absorbed Mn can be excreted via urine and
about Mn is not available for animals. It is interesting to bile. Excretion of Mn through urine is minor. Bile is
note that in dogs, the pancreas accumulates 3 60 times the major excretory route of injected or ingested Mn.
more Mn than other soft tissues. Furthermore, colored Rats excreted 15% 40% (Ballatori et al., 1987)and
hair has higher Mn levels than noncolored hair. calves excreted 21% (Abrams et al., 1977) of injected
After absorption from the gut, Mn is transported to the doses of Mn in bile. In humans, Mn is eliminated
liver by α2-macroglobulins and albumin (Andersen et al., almost entirely with feces, and only 0.1% 1.3% of
1999). This protein-bound Mn is efficiently cleared in the daily intake through urine. Klaassen (1974) observed
liver and is bound to transferrin. Transferrin is believed to that rats excreted proportionately more Mn into bile
be the primary transporter of Mn across the blood brain than rabbits and dogs. Following ingestion, effective-
barrier (BBB) and Mn is taken up into astrocytes and ness of the gut in preventing excess absorption blunts
neurons in the brain. Astocytes serve as the major the effect of biliary excretion (Abrams et al., 1977;
homeostatic regulator and storage site for Mn in the Davis et al., 1993; Malecki et al., 1996). Calves
brain (Aschner et al., 1992; Sidoryk-Wegrzynowicz and excreted 0.2% of a duodenal dose of Mn into bile in
Aschner, 2013). Increased accumulation of Mn in astro- one study (Abrams et al., 1977), and 2.1% 3.6% of
cytes may alter release of glutamate and elicit high levels of Mn infused intraduodenally in another
excitatory neurotoxicity (Erikson and Aschner, 2003). study (Symonds and Hall, 1983).