Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 22 Trace Minerals
Perhaps the most striking effect of a marginal prenatal
Zn deficiency is on the ontogeny of the immune system.
In both mice and rhesus monkeys, marginal prenatal
Zn deficiency impairs immunoglobulin M production and
decreases sensitivity to a number of mitogens. Of particular
interest are the observations that these immune defects
can persist well into adulthood despite the introduction of
Zn-replete diets at birth. Immune defects associated with
postnatal Zn deficiency include reduced thymic hormone
production and activity, impaired lymphocyte, natural
killer cell and neutrophil function, and impaired antibodydependent
cell mediated cytotoxicity. Postulated defects
include impaired cell replication, gene expression, and cell
motility and alterations in cell surface recognition sites
( Cousins, 1998 ; Fraker and King, 2004 ).
There can also be a reduction in glucose utilization in
Zn deficiency that has been linked to increased lipid metabolism.
It is secondary to reduced insulin release, increased
insulin degradation via glutathione insulin transhydrogenase,
and an increase in peripheral insulin resistance. As
with Cu and Mn, Zn deficiency can result in marked alterations
in lipoprotein metabolism. A Zn deficiency-induced
hypercholesterolemia has been demonstrated in rat models.
This hypercholesterolemia is primarily due to a decrease in
HDL cholesterol; the HDL isolated from Zn-deficient animals
is enriched in apo E and low in apo C content ( Fekete
and Brown, 2007 ; Hughes and Samman, 2006 ).
In addition to lipoprotein metabolism, Zn deficiency
has been shown to affect essential fatty acid metabolism,
and many of the signs of Zn deficiency mimic essential
fatty acid deficiency. For example, the delta-desaturation
of linoleic acid is markedly elevated in Zn-deficient rats,
and Zn deficiency has consistently been shown to increase
tissue arachidonic acid levels ( Fekete and Brown, 2007 ;
Hughes and Samman, 2006 ). In addition, Zn deficiency
is associated with a reduction in growth hormone production
and output. This defect can be secondary to the Zn
deficiency-induced reduction in food intake rather than
resulting from a direct role in growth hormone synthesis
and release. The growth retardation associated with Zn
deficiency is refractory to growth hormone therapy, however,
unless Zn therapy is also instituted, suggesting that
Zn is required for growth hormone uptake, or that reduction
is required for growth hormone uptake, or that reduction
in cellular Zn is the rate-limiting step with regard to
cell growth ( O’Dell and Sunde, 1997 ). A classic sign of Zn
deficiency in humans is hypogonadism. In Zn-deficient animals,
the testes are significantly reduced in size with atrophy
of the seminiferous epithelium. The resulting testicular
hypofunction affects both spermatogenesis and output of
testosterone by Leydig cells. Current evidence suggests
a primary defect in Leydig cell function with a secondary
effect of Zn deficiency per se. There are also specific
effects of Zn deficiency on prostate, epididymal, and
seminal vesicle size that are independent of the reduction
in food intake, suggesting a defect in testosterone’s target
cell response. Tissue and circulating levels of hypothalamic
pituitary hormones are consistent with a primary
failure of Leydig cell function. Levels of LHRH, FSH, and
LH have all been reported to be normal or elevated with Zn
deficiency. Prolactin, thyroid hormone, and corticosterone
metabolism have all been reported to be either unaffected
or affected by Zn deficiency.
At least five genetic errors in Zn metabolism that mimic
Zn deficiency have been identified in mammals. They are
Adema disease (inherited parakeratosis) of cattle, chondrodysplasia,
congenital Zn deficiency (lethal acrodermatitis) in
bull terriers, acrodermatitis enteropathica (AE) in humans,
and lethal milk syndrome in mice. Bovine hereditary Zn
deficiency, Adema disease, is an autosomal recessive disorder
that results in inadequate amounts of Zn being absorbed
from the gastrointestinal tract and leads to a number of clinical
abnormalities. The first clinical manifestation is diarrhea,
followed by skin lesions, poliosis, and a decreased ability to
sustain a suckle reflex ( Watson, 1998 ). It is similar in many
respects to acrodermatitis enteropathica in humans. The oral
administration of Zn acetate caused a reversal of all clinical,
biochemical, and histological abnormalities in affected
calves. Adema disease occurs predominantly in black pied
cattle of Frisian descent. Affected calves are born “ normal, ”
but the signs of the disease usually appear 30 to 60 days
after birth; in addition to diarrhea, other signs include dry
scaly coat, alopecia, hyperkeratotic conjunctivitis, diarrhea,
poor weight gain, immunological dysfunction (in particular
severe thymic atrophy), and death at 3 to 4 months of age.
An additional sign of the disease is delayed sexual maturation.
Mature dwarfs produce spermatozoa with 45% acrosomal
defects compared to 5% in controls. Significantly, this
defect in spermatozoa can be corrected by dietary Zn supplementation.
Of interest, many of these same signs occur
in humans with acrodermatitis enteropathica ( O’Dell and
Sunde, 1997 ). Lethal milk syndrome is an autosomal recessive
disorder caused by a mutant gene in the C57BL/6 J(B6)
mouse strain. Phenotypic characteristics of this genotype are
similar to some signs observed in AE and Adema diseases.
Offspring, which suckle from affected dams, exhibit stunted
growth, alopecia, dermatitis, immune incompetence, and
rarely survive past weaning ( Keen et al. , 2003 ).
Lethal acrodermatitis (congenital Zn deficiency) is an
autosomal recessive disorder in bull terriers ( Colombini,
1999 ; McEwan et al. , 2000 ). The syndrome is clinically
characterized by growth retardation, progressive acrodermatitis,
chronic pyoderma, diarrhea, pneumonia, and
abnormal behavior. Laboratory findings include nonregenerative
anemia, neutrophilia, low serum alkaline phosphatase,
and hypercholesterolemia. Pathological findings
include parakeratosis, hyperkeratosis, and a reduction in
lymphocytes in the T-lymphocyte areas of lymphoid tissue.
Overall, the expression of lethal acrodermatitis in bull
terriers is similar to experimental Zn deficiency in dogs.