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TERATOLOGY

the study of monsters - from the greek TERATOS.

so it's the study of embryonic malformations and how they occur if that 
is known.

development even though it depends on closeknit interdependent events 
usually goes well. nevertheless, some embryos do not make it or do not 
make it NORMALLY. so today we'll look at some reasons why these teratos 
or terata are caused or formed. the chemical or other agents responsible 
are called TERATOGENS.

the causes of embryonic malformation can be either

GENETIC
ENVIRONMENTAL
or
a combination of both.

today we'll look at environmental causes of teratos.

genetic: trisomy 21, arabian foal cerebellar hypoplasia, etc...most of 
these are controlled by BREEDERS not vets. the environmental aspect is 
more under the control of the practicing vet. 

IONIZING RADIATION:

it's obvious from say hiroshima and nagasaki that this can cause birth 
defects and developmental abnormalities. xrays can cause this also, so 
when you buy an xray machine you make sure it's a newer one because you 
can use shorter exposure time with the new ones, and also that the 
machine is well collimated.

obviously if the animal is of reproductive age or possibly pregnant 
always weigh risks of xray vs possible consequences...

BACTERIA/VIRUSES:

have been known to cause abortions and congenital malformations. 
brucellosis is caused in cows by brucella abortis, and in swine by 
brucella suis, and this gram neg rod is associated with preemie births, 
abortions, and many developmental abnormalities.  bacteria can pass 
placental barrier under some circumstances. usually only stuff less than 
1000 mw can pass through - some bacteria can bind to plasma membranes and 
get through that way. w/viruses, need to be most careful giving modified 
live or live viral vaccines. killed virus vaccines unlikely to cause a 
problem. but the modified lives can cause problems. pregnant ewes early 
in gestation were given a live vacc for blue tongue dz - 50% Mortality 
occured, and surviving lambs had CNS defects.

pregnant swine, mod live hog cholera vacc- 38% had craniofacial 
abnormalities or other abnormalities.

another interesting case reported...cattle get common dz BVD-MD - this is 
enzootic, in 50-75% of world's cattle. this dz is bovine viral diarrhea 
mucosal dz, and many of these cases you need to recall dont' cause 
problems for the mother - signs may be insignificant or absent. but 
significant problems for fetus! only 5-10% of cows with bvd-md are really 
"sick". but if herd is infected during 108-180 d gestation range, there 
is a high abnormality rate of cerebellar hypoplasia.  also interesting to 
note that 130-160 days in cattle is when cerebellum becomes developed - 
so the time fits. so this virus bvd-md is associated w/cerebellar defects 
if the infxn takes place at the right time. 

NOTE: what this does is it points out some general principles of 
teratology - namely, for every one of these agents there is a critical 
period - eg, when you give the drug or have the radiation exposure or 
whatever, there is a critical period when it will hav maximum effect - 
usuall first third of gestation - because that's when you see 
organogenesis. these tissues have high mitotic rate. many of these agents 
affect the mitotic rate. if the tissue is done dividing, damage less. eg, 
radiation causes dna breaks. but that isn't important anywhere but in a 
germ cell - eg, if cells are already fully differentiated, it's ok that 
the dna breaks.

in dog critical period between 8-20 days.

DRUGS (including antibiotics):

most drugs are less than 1000 mw so they do pass the placental barrier 
pretty easily. some drugs involved are endocrine preps eg progestogens, 
which can cause masculinization of external genitalia of female fetus. 
CORTISONE - can cause cleft palate in several mammals, rodents, dogs, 
cats. other preps eg antibiotics - given in clinical doses w/no 
deleterious effect on adult - SULFA drugs used in UTIs can in higher 
doses be teratogenic. TETRACYCLINE, PEN-STREP (pen-strep together often 
correlated with the appearance of syndactyly), STREPTOMYCIN alone 
implicated in prenatal damage to the acoustic nerve. SEROTONIN is a 
potent vasoconstrictor and it can cause hypoxia to the fetus by cutting 
blood flow to the fetus. GRISEOFULVIN: antifungal used to tx ringworm. 
old protocol was to give it at 1000 mg/wk for for weeks. this was 
discovered and written up to show teratogenicity when cats treated like 
this in first third of pregnancy. the cat colony kittens had cyclopia 
(one eye) and other craniofacial abnormalities. likely this drug works as 
an antimitotic and affects the fetus preferentially. another 
antihelmentic PARBENDAZOLE is a very useful drug but the teratogenic dose 
is too close to the clinical dose. 30 mg/kg is therapeutic dose, and 
teratogenic dose is only 60 mg/kg. and farmers tend to overestimate the 
weight of the sheep. also, this drug is given by dosing gun and guns like 
that are not very accurate so to treat sheep you really need better 
separation of teratogenic and therapeutic doses. 
also: CHEMOTHERAPEUTIC drugs - these drugs specifically target fast 
growing tissues...so they tend to preferentially attack the cells of the 
embryo.

also remember embryo also at risk due to the fetal kidney being unable to 
conjugate and excrete the drugs like the adult kidney can and the fetal 
liver doesnt have the full complement of detoxifying enzymes until very 
late in term.

so in essence you see an abnormal buildup of the drugs in the fetus more 
so than in the mother. 


ANESTHETICS:
(inhalational)
most of the problems can be predicted because of the size of anesthetics 
and what they do, but few controlled exp'ts done. logically they're less 
than 1000 mw and can pass placental barrier easily. they are lipophilic, 
so easily pass placental barrier.  and in the fetus the Hb concentration 
is 50% higher than in mother. and Hb is lipophilic. so there is a natural 
storehouse and concentration mechanism for these anesthetics.

eg, if you give trichloroethylene to preg sheep, within 16 min there is 
more anesth in fetal blood than in maternal blood. with CYCLOPROPANE - it 
tends to sequester itself 2.5x more in RBCs than in plasma. knowing fetus 
has 50% more Hb than this is another natural concentration point.

tricholoroethylene, cyclopropane, and methoxyfluorane (he says that 
metofane is the most popular small animal anesthetic - really??? I have 
only ever seen it in labs, clinicians are using halothane and 
isofluorane)


NATURAL AGENTS:

locoweed- probably teratogenic....has major effect on adult, let alone 
fetus.
VERATRUM CALIFORNICUM:this plant grows in high wet elevations in meadows 
in sierras and rockies. also called CORN LILY. it's eaten by ruminants 
that roam freely and these animals about 45 yrs ago had high incidence of 
intrauterine death, craniofacial abnormalites, and cyclopia. this 
cyclopia seemed to be fairly indicative of their proximity to the 
veratrum californicum. so they ground up the plant and fed it as an 
experiment, at diff times during gestation. they found that at day 14 in 
sheep if you feed this stuff you will get cyclopia - this was 
reproducible. if you fed it later you got long bone problems, or 
intrauterine death. but this effect at 14 days was very reproducible.   
[god, i am falling asleep again....]
how does this happen? recall neural plate, where future brain is 
flat...there is an eye field centrally in the neural plate and what 
happens is it separates to give two primordia that will become the eyes. 
at the 14th day, this is not quite separated yet. this plant causes it to 
stick at this stage, causing cyclopia. so they tried to isolate the 
teratogen...they got cyclopamine, an alkaloid, which would induce the 
cyclopia. cyclopamine is converted to veratramine easily. veratramine is 
not teratogenic.  so they thought about this more. only ruminants are 
affected by the plant. if you feed veratrum to other animals you do not 
see abnormalites. now, the conversion occurs under acid conditions. so 
they hypothesized that maybe when ruminnant eats plant, it stsays around 
in stomach too long - is absorbed into blood BEFORE being acidified in 
glandular abomasum. other animals, ingesta goes into the stomach right 
away and meets acid. they tried feeding cyclopamine and tums to rabbits 
and rats, which caused them to develop the teratogenic effects of the 
drug.


there are some others but they "don't have much relevance" to veterinary 
practice per Dr. McD.


mode of action of most teratogens is NOT KNOWN. lots of implications but 
it's not really possible to make firm statements about this...

this is uesful to give us pause as we are practicing vet med, use caution 
and remember reproductive status of the patient. every administration of 
a drug or whatever during first 3rd of gestation is an uncontrolled expt 
in teratology.

the truth is out there.


ABOUT THE FINAL: will follow format of midterm. will be longer. as a 
class we did exceptionally well on the midterm. will be 1hr 15 min. will 
start at 10 am. and go til 11:15. class split in two rooms. Adams to Kerr 
rm 13; Knighton to W in MDL 12  [ok, hillary - remember it's in rm 13]

practical similar to midterm. divided into three sections. will begin at 
3 pm 
will id 5 structures. recall this includes 2nd part of circulatory 
system, nervous system, and UG system.

exam is NOT cumulative. will likely be a question from dean kelleys 
lecture but dr mcd will be making the question.

both are on 12/16 one week from today, monday.

final will be 60% of grade.


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