* Reprinted with permission from Toxicol. Pathol. 23:701-714, 1995
INTRODUCTION
Over the years, human exposure to chemicals has increased. In an effort to control pests and increase food production, chemicals are employed on a daily, global basis. Chemicals are also utilized (a) to enable individuals to reach their workplace, (b) to generate products at their occupation, and (c) to enhance the current standard of living. Although the benefits derived from chemicals are clearly established, extensive use of compounds can result in inadvertent, toxic consequences. To assure safety, it is incumbent upon the manufacturer to conduct the appropriate required mammalian toxicity tests. The fact that the public demands the right to know the risk of toxicity to humans necessitates that studies be undertaken with a species that can be compared to humans. In the choice of a suitable species, the investigator must consider factors such as metabolism, excretion, absorption, and distribution of the test material. One of the species proven to be extremely useful in the conductance of toxicologic research is the rat. The advantages to the use of the rat in research include (a) the many similarities between the rat and human metabolic pathways and (b) the many similar anatomical and physiological characteristics that allow for comparisons in pharmacokinetics. In addition, the other factors to consider for the choice of rat are availability, cost, ease of breeding, small size, relatively docile nature, short life span, short gestation period, and large database. In the interpretation of the relevance of animal data for humans, reliance on a large database is essential.
Although the rat is certainly one of the species of choice in toxicologic research, it should be made abundantly clear that in the interpretation of the findings one must consider age, sex, physiologic status (e.g., pregnancy), nutrition, disease, and so on. In addition to these factors, the strain of rat utilized in research may ultimately influence the data generated. It should be noted that there are over 200 different rat strains available, each with a unique genotype and pattern of responsiveness (23, 37). Thus, it is essential to establish whether a particular rat strain genotype resembles that found in the human for the estimation of risk of toxicity. The aim of this review is to demonstrate the importance of strain in testing of chemicals and to provide a basis for the observed differences in responsiveness among strains.
CENTRAL NERVOUS SYSTEM
Several phosphate triesters, of which tri-O-cresyl phosphate (TOCP) is the most
notorious, induce a delayed neurotoxicity characterized by sensory disturbances and motor weakness,
flaccidity of limbs, and axonal and myelin degeneration (1). After several days to a few weeks, a
peak is reached followed by improvement in the functional disturbance; however, the recovery is
slow and not always complete. In contrast to organophosphate insecticides, TOCP is not used as an
insecticide and is not a potent inhibitor of acetylcholinesterase (AChE). Currently, TOCP is used
as a plasticizer for rubber products and as an additive to gasoline and synthetic lubricants as
well as in the manufacture of hydralic fluids (79).
The responsiveness of the central nervous system
(CNS) to TOCP is highly dependent on the strain of rat examined. In a series of studies, Abou-Donia
and co-workers (82, 92) demonstrated that TOCP failed to induce neurobehavioral and neuropathologic
alterations in Fischer-344 (F-344) and Sprague-Dawley (SD) rats, indicating that these two strains
were not sensitive to the delayed neurotoxic effects of this organophosphate ester, which is
opposite to the effect reported for Long-Evans (LE) rats (91). Subsequently, Carrington and
Abou-Donia (8) found that the TOCP-induced inhibition of brain neurotoxic esterase, believed to be
involved in delayed neurotoxicity, was equivalent in LE and F-344 rats with a 2-fold higher
concentration of chemical needed to produce an effect in SD animals. A similar pattern was noted
for brain AChE inhibition with SD rats being the least sensitive. It is well established that in
LE and W/SPF rats inhibition of neurotoxic esterase by organophosphorous compounds correlates with
histopathologic lesions (42, 62) and that a lack of enzymatic inhibition in SD rats is associated
with no apparent neurotoxicity. However, the findings that TOCP-induced inhibition of neurotoxic
esterase is associated with no evidence of neurotoxicity in F-344 rats suggests that metabolic and
pharmacokinetic differences between LE and F-344 animals might account for the observed discrepancy
(2, 8, 82). Because a metabolite of TOCP, 2-O-cresyl-4H-1:3:2-benzyldioxaphoran-2-one, was found to
induce delayed neurotoxicity in liver of an unspecified rat strain (20), it is conceivable that
F-344 rats, in comparison to LE animals, may not generate sufficient quantities of metabolite to
inhibit neurotoxic esterase; and even if the metabolite does reach the target tissue, the F-344 rat
seems resistant to any toxic manifestation (8). Data thus show that an outbred (SD) stock is not
sensitive to TOCP-induced delayed neurotoxicity. Within other stocks, there is a marked difference
in the neuronal responsiveness of rats to TOCP, with LE and Wistar displaying sensitivity whereas
in F-344 rats there is a lack of response, as summarized in
Table I.
This is not surprising based on an extensive study of 46 different rat strains by Glowa and Hansen
(27), who found a wide variation in responsiveness of about 9 to 1 in an acoustic startle stimulus
between strains. It is evident that there are phenotypic differences between strains, and these
genetic components contribute to variation in neuronal responsiveness.
The organophosphate insecticides bind to AChE in an
irreversible fashion, and inhibition of this enzyme may reflect the adverse effects on behavior and
CNS function including hypothermia and reduced motor activity (32, 33, 74). These disturbances in
CNS function and marked inhibition of AChE activity are not a feature of organophosphorous triester
toxicity described previously. In a recent study, Gordon and MacPhail (34) noted that rat strain
was a factor in diisopropyl fluorophosphate (DFP)-induced neurotoxicity. DFP inhibited the activity
of serum ChE in LE, SD, and F-344 rats; however, the inhibition seen in F-344 animals was
significantly less compared to the other strains
(Table I).
DFP produced hypothermia in LE and SD rats but no change in body temperature in F-344 animals.
Motor activity was reduced by DFP in LE rats at a low dose, whereas a high dose was required to
produce this effect in F-344 rats. The DFP-induced decrease in motor activity seen in SD rats was
dependent on the methodology used to test this parameter, but this strain in general was either
more sensitive or equal to F-344 in responsiveness. In a subsequent study, Gordon and Watkinson
(36) confirmed that DFP decreased body temperature and heart rate to the greatest extent in LE
compared to F-344 rats. Although DFP lowered body temperature in SD rats, this was associated with
a rise in heart rate, suggesting that autonomic function responses to this organophosphorous
compound are distinctly unique from thermoregulatory and behavioral functions. These results taken
together clearly demonstrate that the F-344 rat strain is most resistant and the LE rat is most
sensitive to DFP-induced neurotoxicity. Strain-related differences exist in the ability to detoxify
organophosphate pesticides. It was found that serum carboxylesterase activity, believed to
inactivate organophosphate pesticides, was highest in SD rat followed by LE and F-344 rats in
descending order, but in the presence of an organophosphate compound this enzyme was inhibited to
the greatest extent in F-344 rats (11). These findings would support the conclusion that F-344 rats
are more resistant to DFP-induced CNS changes and that rat strain should be considered in the
assessment of neurotoxicologic hazards of organophosphates.
Table I. Summary of strain-related differences in CNS responses
|
Strain |
||||||
|
Chemical |
Response |
SD |
F-344 |
LE |
Wistar |
References |
|
TOCP |
Neuropathologic alterations |
Absent |
Absent |
Present |
Not done |
82, 91, 92 |
|
Brain neurotoxic esterase activity inhibition (ED50 in mg/kg) |
458 |
209 |
288 |
Not done |
8, 62 |
|
|
Brain AChE activity inhibition |
1,007 |
408 |
420 |
Not done |
8, 62, 82 |
|
|
DFP |
Serum ChE activity inhibitiona |
3 |
1 |
2 |
2 |
33, 34 |
|
Brain AChE activity inhibition |
2 |
1 |
2 |
1 |
33, 34 |
|
|
Heart rate |
Increase |
Decrease |
Decrease |
Decrease |
36 |
|
|
Decreased motor activity |
2 |
2 |
2 |
2 |
3334 |
|
|
Decreased body temperature |
2 |
1 |
3 |
1 |
3234 |
|
|
Methanol |
Decreased body temperature within |
Not done |
Mild |
Marked |
Not done |
57 |
|
TMT |
Syndrome of tremor, hyperactivity, |
Not done |
Marked |
Mild |
Not done |
60 |
|
DSP-4 |
Reduction in noradrenergic terminals in neocortex and cerebellum |
Marked |
Not done |
Absent |
Not done |
75 |
Abbreviations: DSP-4 = N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine; ED = effective dose.
a Denotes severity in response: 1 = mild; 2 = moderate; 3 = severe, as adapted from Gordon and Watkinson (36)
MAMMARY GLAND
The susceptibility of mammary tissue to chemical-induced carcinogenesis was reported in the 1940s and is still a subject of concern today. One of the difficulties associated with chemical-induced mammary tumorigenesis lies in the lack of a universal strain-dependent response and subsequent correlation between observed effect with relevant risk to humans. Exposure to the aromatic hydrocarbon, 7,12-dimethylbenz(a)anthracene (DMBA) was shown to cause a marked induction of mammary tumors in SD rats, whereas the incidence was low in LE rats (7, 85). The fact that a single injection of DMBA-induced mammary tumors in SD rats but that multiple chemical administrations for a prolonged period was needed for LE rats clearly demonstrated a strain-related difference in responsiveness. In addition, mammary tissue was excised from SD or LE rats and incubated with DMBA. Subsequently, DMBA-treated mammary tissue was grafted to its host with a resultant 3-fold greater incidence in mammary carcinoma in SD than in LE rats, indicating an inherent difference in mammary tissue sensitivity between these strains. The factor of inheritance in the susceptibility to DMBA-induced mammary carcinoma is supported by the findings in Table II. DMBA was effective in induction of mammary tumors in mating studies where either female or male or both sexes of SD rats were used, but this effect was virtually absent or similar to spontaneous background incidence in LE females mated to LE males. It is of interest that when a hybrid SD female was mated with a LE male, DMBA failed to produce mammary tumors. It is evident that the hybrid SD, which is susceptible to DMBA mammary tumorigenesis, may become more resistant when crossed with the LE strain. Sexual development and endocrine function varies between rat strains (Table III). It is important to note that first estrus occurs between days 39 and 57 in SD rats but takes place considerably later (between days 71 and 104) in LE rats (85). Hence, strain-related differences in hormonal function may be responsible for variation in susceptibility to DMBA-induced mammary carcinoma.
Table II. Role of strain in DMBA-induced mammary tumors
|
|
|
|
Mammary tumor (%) |
Mean day detected after DMBA |
|
b F-SD Χ M-SD |
38 |
38 |
100 |
43 |
|
b F-SD Χ M-LE |
29 |
21 |
72 |
78 |
|
b F-LE Χ M-LE |
2S |
4 |
16 |
74 |
|
b F-LE Χ MID |
26 |
20 |
77 |
80 |
|
(F-SD Χ M-LE)F1b Χ M-SD |
29 |
29 |
100 |
SO |
|
(F-SD Χ M-LE)F1b Χ M-LE |
20 |
20 |
8 |
L 10 |
a
F = female: F1 = female hybridTable III. Strain differences in reproductive cyclea
|
Time (mo) |
|||||||
|
Parameter |
Strain |
1 |
9 |
12 |
15 |
18 |
24 |
|
Days in estrous (%) |
F-344 |
25.0 |
25.0 |
22.0 |
20.0 |
10.0 |
6.0 |
|
Plasma estradiol (pg/ml) |
F-344 |
3.4 |
15.3 |
13.9 |
9.0 |
3.7 |
0.2 |
|
Plasma progesterone (ng/ml) |
F-344 |
7.8 |
16.3 |
41.6 |
45.3 |
36.9 |
10.9 |
|
Incidence of mammary tumors over a 105-wk interval (number of tumor-bear- |
F-344 |
7/125 |
|||||
a Data adapted from Wetzel et al. (94)
Variation in the susceptibility of rat
strains to aromatic amine-induced mammary tumors has also been reported. A much higher incidence of
mammary tumors was recorded in Wistar rats ingesting 2-acetylaminofluorene than in LE animals (4).
Intraperitoneal administration of N-hydroxy-2-acetylaminofluorene resulted in greater
susceptibility to mammary tumor induction in SD than in F-344 rats, and this was associated with
enhanced mammary arylhydroxamic acid acyltransferase activity in SD animals (49, 54). Data thus
suggest that there are strain-related differences in metabolism within this tissue. It is of
interest that topical administration of parent compound or metabolite to mammary tissue resulted in
tumorigenesis in SD but not F-344 rats. These findings support the view that inherent properties of
mammary tissue rather than pharmacokinetic characteristics are responsible for differences in
susceptibility to mammary tumors. The finding that the herbicide 1,4-bis(4-fluorophenyl)-2-propynyl-N-cyclooctyl
carbamate was equally effective in the induction of small intestine and Zymbal gland carcinomas in
SD and F-344 rats but only produced mammary gland adenocarcinomas in the SD strain again emphasizes
the unique characteristic of this strain (93). A chemical-mediated induction of mammary carcinoma
in a highly susceptible, unique rat strain is an important observation, but the relevance as a
potential risk to humans would be enhanced if the phenomenon could be initiated in an additional
strain. The ability of a chemical to induce mammary gland tumorigenesis in SD rats should be
utilized as a signal that examination of the effects of this agent should also be conducted with
F-344 or LE rats.
The mammary tissue-specific response to chemicals
is not the sole factor to account for strain-related differences in tumorigenesis. The development
and function of mammary tissue is dependent on the endocrine hormonal system. Alterations in the
normal endogenous hormonal balance of estradiol (E2) and prolactin also have a profound
effect on mammary tumor development in control rats. Major strain differences exist between SD and
F-344 rats in the stability of the estrous cycle and reproductive competence (19). The central
control mechanism regulating the sensitive balance and secretion of reproductive hormones in the
SD strain is easily interrupted while the same mechanism in F-344 rats is very stable (18). The SD
rat enters the first phases of reproductive senescence as early as 6 mo of age whereas the F-344
has very stable ovulatory cycles for 1518 mo of age (18, 53). Reproductive senescence in the SD
rats starts with episodes of prolonged proestrus/estrus associated with delayed ovulation. This
progresses in later phases of senescence to periods of anovulation and constant estrus with ovaries
devoid of corpora lutea, which may persist for the remainder of the animal‐s life. During
these delayed ovulatory or anovulatory periods, ovarian follicles are continuously recruited, grow,
and produce moderately elevated sustained levels of E2 which in turn stimulates
prolactin secretion by the pituitary. This sequence of events contributes to increased mammary tumor
incidence through greater exposure to endogenous E2 and prolactin in SD rats (16, 18).
In contrast, F-344 rats have a very stable estrous
cycle and maintain a physiological estradiol-prolactin balance until late in life (1518 mo)
(Table IV).
Reproductive senescence and estrous cycles in the F-344 rats are characterized by prolonged periods
of diestrus, lengthened corpora luteal life, and elevated progestin level. Mammary gland
responsiveness is reflective of cycles dominated by progestins and remains largely unstimulated
until 1518 mo when some degree of lobulo-alveolar development is accompanied by secretory activity,
which becomes evident due to prolonged diestrus cycles associated with elevated progesterone and
prolactin level (15, 16, 18).
Differences in susceptibility to chemical-induced
alterations in hormonal balance may account for the presence or absence of tumors in certain
strains. Atrazine, a broad-leaf herbicide, administered chronically at doses at or above the
maximum tolerated dose (MTD) significantly increased the incidence and onset of mammary tumors in
SD but not in F-344 rats (83). The observed increase in atrazine-induced mammary tumorigenesis at
the MTD in SD rats was associated with a lengthening of the estrous cycle, a greater incidence of
galactocele, and an elevation in endogenous plasma prolactin and E2 (15). The early
onset of neuroendocrine imbalances in SD rats dominated by elevated or sustained E2
levels correlated with the early appearance of mammary neoplasms in this strain (15, 16). In
contrast, atrazine failed to disturb the hormonal balance in F-344 rats, supporting the view that
chemical-mediated estrogen-related mammary tumorigenesis is dependent on the rat strain utilized,
but the relevance of this observation for risk assessment of humans must be addressed
(Table IV).
It is of interest that a hormonal imbalance was also shown to be involved in strain-associated
differences in cadmium-induced lethality. Pretreatment of male F-344 rats with progesterone
followed by subcutaneous cadmium injection resulted in 53% mortality; however, this treatment
regimen did not produce mortality in WF rats (78). These studies stress the importance of strain
selection in drug or chemical testing. Compounds should be assessed for their ability to alter the
reproductive neuroendocrine control mechanism. This can be easily done in short-term rodent dose
range finding studies by histomorphologically determining the phase of the estrous cycle to ensure
that the ovaries, vagina, uterus, and mammary glands are in proper hormonal synchronization.
Disruption of the cycle with prolonged periods of proestrus/estrus may be an early indication of
future mammary gland stimulation and mammary tumor development caused by an imbalance of endogenous
reproductive hormones. The important question arising from differences in strain responsiveness to
chemical-induced mammary carcinoma, in particular if the neoplasm is hormone-related, is which
observation is reflective of changes in humans. It should be noted that the incidence of
spontaneous mammary tumors with aging is common in SD, F-344, and LE rats but the type of neoplasm
is quite different. In the case of SD rats, the spontaneous tumor incidence was approximately 40%
with 22% fibroadenomas and 21 adenocarcinomas (29). The incidence of spontaneous mammary tumors in
F-344 rats was predominantly fibroadenomas (24%) and only 2% adenocarcinomas (29), whereas a 5%
incidence of fibroadenomas was found in LE rats (77). Clearly, SD rats are more susceptible to
mammary adenocarcinomas in particular and all types of mammary cancers in general. Hence, in
reporting mammary carcinoma in rat strain, a distinction between spontaneous versus
chemical-mediated effects may be clouded if one neglects to consider both the type and total
incidence of carcinoma. Physiologically, the endocrine changes in aging SD and F-344 rats are
markedly different
(Tables III) and
IV)
and may account for the enhanced susceptibility to mammary carcinogenesis in SD animals. The
physiological alterations noted in SD rats such as low progesterone level resulting in unopposed
estrogens are not similar to those in humans. Hence, the occurrence of chemical-induced mammary
carcinoma in F-344 rats should be considered of more grave concern for humans. Data thus indicated
that there were strain differences in the response to estrogenic compounds and potential risk to
humans is significant when mammary carcinoma occurs in a strain with a spontaneous low incidence of
this neoplasm. A summary of the strain-related differences in chemical-induced mammary tumorigenesis is given in
Table V.
Table IV. Comparison of reproductive senescence among SD and F-344 rats and humans
|
Parameter |
SD |
F-344 |
Human |
|
Start of senescence |
2530% |
6070% |
6070% |
|
Principal cause of senescence |
Hypothalamic failure to stimulate leutiniz- |
Hypothalamic failure to control prolactin surges |
Depletion of ovaries, oocyte content |
|
Leutinizing hormone surge capability |
Lost |
Maintained |
Maintained |
|
Predominant cycle pattern |
Persistent estrus |
Prolonged diestrus (pseudopregnancy) |
Menopause (diestrus) |
|
Estrogen secretion |
Elevated/prolonged |
Reduced |
Reduced |
|
Estrogen/progesterone ratio |
Elevated |
Reduced |
Reduced |
|
Prolactin secretion |
Persistently elevated |
Episodical |
Reduced |
|
Prolactin effect on corpora lutea |
Luteotrophic |
Luteotrophic |
No effect |
|
Prolactin effect on mammary gland |
Alveolar/lobular growth and secretion |
Alveolar/lobular growth and secretion |
Lactation |
|
Principal factors that increase mammary tumor risk |
Prolactin, estrogen, chemical mutagens |
Prolactin, estrogen, chemical mutagens |
Family history, parity, diet, body weight |
Table V. Strain-related differences in mammary tumorigenesis
|
Strain |
|||
|
Compound |
Resistanta |
Susceptible |
References |
|
DMBA |
LE |
SD |
7,85 |
|
COP |
Wistar |
58 |
|
|
AAF |
LE |
Wistar |
4 |
|
F-344 |
SD |
54 |
|
|
FPOC |
F-344 |
SD |
93 |
|
Atrazine |
F-344 |
SD |
15, 83, 94 |
Abbreviations: AAF = 2-acetylaminofiuorene; FPOC = 1,4-bis(4-fluorophenyl)-2-propynyl-N-cyclooctyl carbamate
a Resistant does not imply a lack of effect but, rather, a significantly lower responsiveness than susceptible.
One of the factors that must be considered with respect to human breast cancer is the role of lipid. In an extensive study, Falck et al. (21) examined human breast fat tissue from women with mammary carcinoma with a comparison to fat tissue of women who had benign disease. The concentration of polychlorinated biphenyls, 1,1,1-trichloro-2,2-bis(p-chloroethane), and its metabolite DDE were significantly elevated in the mammary fat samples of women with breast cancer than in tissue obtained from women with mammary benign disease. It should be noted that SD rats upon aging to 24 mo become obese (24% mean body fat) whereas F-344 rats remain lean (15% mean body fat) (29). Based on fat content, it is thus conceivable that SD rats would accumulate a greater concentration of contaminants in fat and, as observed, be more susceptible to induction of mammary neoplasms. At present, a correlation between mammary fat content and the incidence of human breast cancer induced by chemicals has not been established. Furthermore, the association between human breast cancer and body fat is not known; thus, the relevance of the findings in SD rats is difficult to extrapolate to humans.
GASTROINTESTINAL TRACT
Chemicals induce carcinogenesis in various segments of the gastrointestinal tract; however, the
susceptibility can vary among strains. Dietary ingestion of the antioxidant catechol 0.8% for 104
wk produced glandular adenocarcinomas in 67 and 77% Wistar and SD rats but in only 10% of the WKY
strain (87). Further forestomach papillomas and squamous cell carcinomas were noted in only SD rats.
Treatment with 1,2-dimethylhydrazine produced a markedly higher incidence and number of tumors per
rat of colonic adenocarcinomas in LE than in Wistar rats (86). It is of interest that male rats
were more susceptible than females to chemical-mediated colon carcinoma
(Table VI).
Similarly, the administration of methyl(acetoxymethyl)nitrosamine (DMN) produced a significantly
higher incidence of intestinal tumors in male SD and F-344 than in female rats of both strains (3).
However, the susceptibility of SD rats to DMN-induced intestinal carcinomas, regardless of sex, was
markedly greater than in F-344 animals. Testosterone was found to increase dimethylnitrosamine
metabolism in the kidney to yield a carcinogenic metabolite (56), which would support the view that
a higher concentration of carcinogen is present in males. It is worthy to note that the
administration of testosterone to females, initially not responsive to chloroform, subsequently
developed renal damage (10, 68). Furthermore, a female SD rat injected with male
a2u-globulin developed hyalin droplet nephropathy in the presence of decalin; however,
this effect did not occur when decalin was given to normal SD females (72). The
a2u-globulin is not present in females and, thus, provides a resistance to
decalin-induced nephropathy. Evidence thus indicates that hormonal factors play a role in strain
different susceptibility to chemical-mediated intestinal tumorigenesis.
In a comparative study of 3 rat strains, Roebuck
and Longnecker (73) found that F-344 rats were least (10%) responsive to azaserine-induced atypical
acinar cell nodules of the pancreas. In contrast, the incidence of pancreatic tumors was 90100%
in Wistar and LEW rats administered azaserine. While the incidence of pancreatic tumors was not
significantly different between sexes in F-344 rats, there was a marked 2-fold higher incidence in
male Wistar or LEW than in female rats of these strains. Although the role of sex was not examined,
Hoffmann et al. (40) found that administration of N-nitrosoguvacoline (NG) at a
concentration of 1.9 mmol/animal induced a significant incidence of exocrine pancreatic tumors in
F-344 rats. An increase in the NG concentration to 4.4 mmol/animal failed to produce pancreatic
tumors in female SD rats (51), indicating that strain is a factor in susceptibility to
chemical-mediated pancreatic tumorigenesis.
Table VI. Strain-related differences in chemical-induced responses
|
Strain |
|||
|
Parameter |
Resistanta |
Susceptible |
References |
|
DMH-inducedb colonic carcinoma |
Wistar |
LE |
86 |
|
DMN-inducedb intestinal carcinoma |
F-344 |
SD |
3 |
|
Cadmium-induced lethality in progesterone-pretreated rats |
WF |
F-344 |
78 |
|
Azaserine-induced2 pancreatic tumors |
F-344 |
LEW |
73 |
|
NG-induced pancreatic tumors |
SD |
F-344 |
40, 51 |
|
Catechol-induced stomach carcinomas |
WKY |
SD |
87 |
|
BBN-induced urinary bladder tumors |
LEW |
AC1 |
44 |
|
BBN-induced renal pelvis |
F-344 |
SD |
59 |
|
NMD-induced urinary bladder tumors |
SD |
F344 |
52 |
|
Mercury-induced autoimmune disease |
LEW |
BN |
50 |
|
ME-induced immunosuppression |
F-344 |
WF |
81 |
|
HQ-induced renalb dysfunction |
SD |
F-344 |
17 |
|
Decalin-inducedb hyalin droplet nephropathy |
NBR |
F-344 |
72 |
|
AAF-inducedb cirrhosis and carcinoma |
Marshall |
F-344 |
70 |
|
DCB-induced hepatotoxicity |
SD |
F-344 |
24, 84 |
|
Diquat-induced hepatic necrosis |
SD |
F-344 |
39 |
|
Carbon disulfide-induced hepatic necrosis |
AGUS |
LEW |
89 |
|
Carbon tetrachloride-induced hepatic carcinomas |
OM |
Wistar |
71 |
|
Carbon tetrachloride-induced hepatic necrosis |
SD |
F-344 |
45 |
|
TCDD-induced toxicity |
HW |
LE |
66, 67, 90 |
|
Light hydrocarbon (paraffin-induced renal dysfunction) |
SD |
F-344 |
64 |
Abbreviations: AAF = 2-acetylaminofluorene; DCB = 1,2-dichlorobenzene;
DMH = 1,2-dimethylhydrazine; HQ = hydroquinone; ME = 2-methoxyethanol; NG = N-nitrosoguvacoline
a Resistant does not imply a lack of effect but a significantly lower responsiveness than susceptible.
b In studies where both sexes were studied, the male was found to be more sensitive than the female within the same strain.
IMMUNE SYSTEM
Although differences in immune system responsiveness to toxicants are well documented among
species (48, 80}, recent studies have demonstrated that rat strain plays a role in the
susceptibility to chemical-mediated effects. Bigazzi (5) demonstrated that SC administration of
mercury produces an autoimmune disorder in Brown Norway (BN) rats. Mercury-induced autoimmunity in
BN rats was associated with a decrease in peripheral RT6+ T lymphocytes, particularly
in lymph nodes, and the appearance of circulating autoantibodies to renal antigens such as laminin
(50). In contrast, mercury failed to markedly affect peripheral RT6+ T-lymphocyte levels
in LEW rats, suggesting that this strain was resistant to the autoimmune actions of this heavy
metal. It is noteworthy that in human insulin-dependent diabetes mellitus a decrease in
RT6+ T lymphocytes occurs and environmental factors are believed to play a role in this
disease (26, 76). Although the basis for the differences in susceptibility to mercury-induced
autoimmune disorders remains to be established, the strain-specific responses may be used to
elucidate mechanisms involved in initiation of diabetes mellitus.
The immunosuppressive effects of the glycol ether
solvent 2-methoxyethanol (ME) and its metabolite 2-methoxyacetic acid (MAA) are also strain-related.
With the use of trinitrophenyl-lipopolysaccharide antibody plaque-forming cell response as an
index of immune function, ME and MAA were effective in preventing this response at a low
concentration in LEW and WF rats (81). Although SD and F-344 rats appeared to be resistant at low
concentrations of solvent exposure, a 4-fold increase in ME and MAA produced immunosuppression in
these strains in descending rank order of WF = LEW > SD > F-344. The basis for the
differences in sensitivity of the immune system of rat strains to various chemicals is not known;
however, recent evidence indicates that there are strain-related differences in macrophage cytokine
formation in response to the lipopolysaccharide conclavin, an index of fibrosis (46). Furthermore,
it is known that amiodarone increased the white blood cell count in F-344 but not Wistar rats (95),
supporting the view that strain is a factor to consider in chemical-induced effects on immune function.
KIDNEY
The biotransformation processes and function of renal tissue are uniquely different among
rat strains. There are marked strain differences in the metabolic activation and/or detoxification
of various chemicals and cytochrome P-450 isozymes between SD and F-344 rats (46). Furthermore,
F-344 rats are more susceptible to a severe, progressive renal disease compared to other strains
(29). Acute administration of hydroquinone, the reducing agent used in photographic developer
formulations, produced renal dysfunction in F-344 but not in SD rats, as evidenced by glycosuria,
pronounced enzymuria, and an increased number of urinary epithelial cells (6). It is of interest
that female F-344 rats were markedly more sensitive to hydroquinone-induced nephrotoxicity compared
to male F-344 rats. Surprisingly, in a chronic 2-yr study, English et al. (17) found that
hydroquinone induced an increased incidence of renal tubule adenomas, enzymuria, and tubular d
egeneration, measured histopathologically, in male but not female F-344 rats. SD rats were also
resistant to the acute and chronic nephrotoxic actions of hydroquinone. It is not surprising that
F-344 rats are more susceptible to chemical-induced nephrotoxicity as a similar pattern or renal
toxicity was noted in the case of aminoglycosides (69) and acetaminophen (55, 88). Although it is
difficult to ascertain the basis for the reversal in toxicity in F-344 rats from acute
nephrotoxicity seen in female vs. chronic toxicity seen in males, it should be noted that male
F-344 rats are more susceptible to chemical-induced intestinal carcinoma (3, 86) and
chloroform-induced nephrotoxicity (68). Because the male F-344 rat in general is more sensitive
than the female to carcinogens (29) and tumorigenesis is seen in male rats chronically administered
hydroquinone (17), it would appear that susceptibility to nephrotoxicity is reversible in the
female and that sensitivity increases with age in the male F-344 rat. It would be of interest to
determine the role of testosterone in hydroquinone-induced nephrotoxicity.
Strain and sex also play an important role in
hyalin droplet nephropathy. Administration of decalin to male F-344, SD, Buffalo, or BN rats
increased Ξ±2u-globulin content associated with hyalin droplet formation (72). In
contrast, female F-344, SD, Buffalo, and BN rats showed no evidence of hyalin droplet formation or
accumulation of a2u-globulin. It is of interest that both male and female NCl-Black-Reiter
(NBR) rats resembled female responsiveness, as there was no hyalin droplet nephropathy (72).
Clearly, the decalin-induced hyalin droplet nephropathy is strain-related, but the role of male
hormones is difficult to decipher due to the lack of response noted in NBR male rats. However,
there are marked differences in endogenous circulating testosterone levels among strains (10),
and this may account for the differences between NBR and other strains. It is also conceivable
that NBR male rats, unlike SD or F-344, lack the gene necessary to synthesize a2u-globulin (77).
LIVER
The genetic variation and differences in the biotransformational enzyme processes controlled
by these genes have been well documented among strains (77). In an early study on the
hepatotoxicity of the insecticide N-hydroxy-2-acetylaminofluorene, Irving (43) demonstrated
that female SD rats were resistant to lethality compared to Wistar or F-344 rats. The ability to
produce toxicity was related to hepatic N-hydroxy-2-aminofluorene sulfotransferase activity
with greater activity in female F-344 and Wistar rats and markedly less in SD liver, indicating
that a metabolite may be responsible for toxicity. In a subsequent study, Reuber (70) found that
male F-344 and ACl rats treated with N-2-fluorenyldiacetamide developed cirrhosis and
carcinoma of the liver, whereas Marshall strain rats were resistant. As in the case of
chemical-induced renal and intestinal damage, the male was markedly more susceptible to
acetylaminofluorene-induced hepatotoxicity.
Dichlorobenzenes are used as intermediates in the
manufacture of dyestuffs, herbicides, and degreasers. F-344 rats were found to be more sensitive to
the hepatotoxic action of dichlorobenzene than SD animals, as evidenced by greater glutathione
depletion and elevated plasma alanine aminotransferase activity in the F-344 strain (84).
Furthermore, liver slices from F-344 rats had a higher rate of dichlorobenzene metabolism than
slices from SD rats (24). Recently, it was suggested that the release of reactive oxygen species
from Kupffer cells plays a role in dichlorobenzene-induced hepatotoxicity in F-344 rats (38). This
metabolic phenomenon may occur to a limited extent or be absent in SD animals. It is of interest
that differences in reactive oxygen species may also be associated with variation in strain
responsiveness to the herbicide diquat. Treatment with diquat was reported to produce hepatic
necrosis associated with an increase in biliary N-acetylglucos-aminidase activity, non-heme
iron, and protein carbonyl excretion in F-344 rats (39). It was suggested that the biliary protein
carbonyls represented oxidized cellular proteins that required the presence of iron for their
generation. In contrast, diquat failed to markedly increased biliary non-heme iron excretion in SD
rats; consequently, there was no evidence of elevated protein carbonyl levels and hepatic necrosis.
It should be noted that hepatocytes express a transporter P-glycoprotein, which is a plasma
membrane transporter involved in the excretion of drugs from liver cells through a pumping
mechanism into the biliary canaliculus (47). In a recent study, Chieli et al. (9) demonstrated
that dexamethasone suppressed P-glycoprotein expression in F-344 rat hepatocytes to a greater
extent than in SD and Wistar rats. These findings indicated that F-344 rats displayed a decreased
ability to extrude chemicals and may be more prone to liver toxicity. It is also conceivable that
the strain-related differences in diquat-induced hepatotoxicity are associated with biliary release
of iron in F-344 rats, which interferes with the pumping mechanism, a phenomenon not seen in SD rats.
A marked strain-related variation was noted in the
hepatotoxic effects of carbon disulfide. Histologically, carbon disulfide produced marked hepatic
centrilobular vacuolar degeneration accompanied by focal coagulative necrosis (89). The inbred LEW
strain was most susceptible while AGUS rats were least affected. Other inbred strains including
F-344 and WA as well as an outbred Porton strain exhibited responses between these extremes. The
degree of severity of carbon disulfide-induced hepatotoxicity was related to loss of total liver
cytochrome P-450 content being highest in LEW and least in AGUS rats. It is thus conceivable that
the rate of carbon disulphide metabolism or detoxification of reactive intermediates may be
responsible for the observed strain-related difference in chemical-induced liver pathology.
As early as 1970, Reuber and Glover (71)
demonstrated strain-dependent variation in the responsiveness of liver to carbon tetrachloride. SD
rats were most susceptible to carbon tetrachloride-induced cirrhosis followed by Wistar higher than
Osborne-Mendel (OM) strain rats. Carbon tetrachloride produced a higher incidence of hyperplastic
nodules and hepatocellular carcinomas in Wistar than in OM rats at 68 wk of treatment. Because SD
rats died by week 18 of carbon tetrachloride administration, hepatic carcinoma was not noted in
this strain. In a comparative study between F-344 and SD rats, carbon tetrachloride produced more
severe hepatotoxicity in F-344 rats, as evidenced histopathologically by necrosis and cellular
degeneration and functionally as an increase in serum sorbitol dehydrogenase (45). It is important
to note that the susceptibility to carbon tetrachloride-induced hepatotoxicity was greater in age-
or weight-matched F-344 rats. Because F-344 rats are leaner (29), the use of weight-matched SD and
F-344 rats in a study would involve the utilization of younger F-344 animals, a factor that is
generally not considered in strain comparison experiments. However, the aging process does
influence susceptibility to chemicals and must be borne in mind, especially with respect to
potential risk for humans.
The relationship between chemical-induced
peroxisomal proliferation and rat strain is not clearly defined. Administration of trichloroacetic
acid increased hepatic cyanide-insensitive palmitoyl coenzyme A (PCO), a peroxisome proliferator
marker, to 650% of control in Wistar rats (14). In F-344 rats, trichloroacetic acid was found to
elevate PCO hepatic activity 284% of control (13, 28). However, the trichloroacetic acid-induced
rise in liver PCO activity was only 20% higher in SD rats (63). Data thus suggest that there are
strain differences with respect to trichloroacetic acid-induced peroxisomal proliferation; however,
these studies were conducted in different laboratories using different vehicles, water, and corn
oil. Indeed, DeAngelo et al. (13) demonstrated that the vehicle does play a role in the observed
effect of trichloroacetic acid on peroxisomal proliferation. It should be noted that the
trichloroacetic acid-induced peroxisomal proliferation is markedly less in rats than mice and that
carcinogenesis has thus far only been reported in mice (13).
DIOXINS
Extensive studies have been carried out in Finland on the most susceptible (LE) and most resistant Hanover/Wistar (HW) strain rats to various dioxin congeners. Pohjanvirta et al. (66) reported that the acute LD50 value for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PCDD), and 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (HCDD) in LE rats was 9.817.7 µg/kg for TCDD, 2060 µg/kg for PCDD, and 120360 µg/kg for HCDD. In contrast, the LD50 values in the resistant HW strain for TCDD was greater than 7,200 µg/kg for TCDD, greater than 1,620 µg/kg for PCDD, and 1,871 µg/kg for HCDD. TCDD-induced lethality is associated with the appearance of a wasting syndrome, as reflected by a prominent weight loss (67). In LE susceptible strain rats, TCDD produced a significant body weight loss accompanied by a decrease in plasma b-endorphin-like imm
unoreactivity material, an increase in plasma tryptophan, and enhanced brain serotonin turnover, factors involved in the control of food intake (90). TCDD did not markedly alter these parameters or body weight in the HW resistant strain. In a recent study, Fan and Rozman (22) demonstrated that SD rats were more susceptible to TCDD-induced toxicity than LE rats. This is reflected by the fact that much higher d oses of TCDD were required to produce a decreased food intake, an increase in serum tryptophan as well as a reduction in the activities of hepatic tryptophan 2,3-dioxygenase and γ-glutamyl transpeptidase in LE rats, indicating that these metabolic differences may account for the strain-related differences in susceptibility to TCDD. In contrast to the mouse, where lethality is associated with hepatic Ah receptor induction, TCDD induced an equivalent amount of Ah receptor binding sites in LE, SD and HW strain rats (65), demonstrating that in rats the correlation between TCDD-induced toxicity and Ah receptor binding is lacking. When administered to pregnant LE rats, TCDD produced cleft palate in the fetuses and increased the incidence of resorptions (41); however, in the resistant HW strain rats given TCDD in pregnancy, there was an unexpected rise in fetal hydronephrosis and gastrointestinal hemorrhaging, phenomena not seen in LE rats. Clearly, rat strain sensitivity to TCDD is also dependent on the developmental stage and age of the animal.REFERENCES
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