MISCELLANEOUS SMALL MAMMAL BEHAVIOR

DAN H. JOHNSON , in Exotic Pet Behavior, 2006

Natural History and Behavior

The short-tailed opossum Monodelphis domestica is native to eastern and central Brazil, Bolivia, and Paraguay. They are found in forests, open areas, and high moisture areas close to water sources. Nests are usually built in hollow logs, in fallen trees, along streams, and among rocks. Short-tailed opossums are also commonly found in dwellings, where they are a welcome means of pest control, as they eat rodents, insects, spiders, and scorpions. 52

In the tropical extent of its range, short-tailed opossums are able to breed continuously, having up to four litters per year. Short-tailed opossums reach sexual maturity at 4 to 5 months of age. Gestation is 14 to 15 days, and litter size ranges from 5 to 12. Neonates are dependent on the mother for approximately 50 days; offspring cling to the nipple initially and hang onto the mother's back and flanks later on. Short-tailed opossums may live up to 4 to 6 years. 35, 37

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Techniques of Experimentation

Michael R. Talcott , ... Robert P. Marini DVM , in Laboratory Animal Medicine (Third Edition), 2015

F Other Mammals

The laboratory opossum (gray short-tailed opossum, Monodelphis domestica ) may be repeatedly bled via cardiac puncture under anesthesia (Robinson and VandeBerg, 1994). The common opossum (Didelphis marsupialis virginiana) may be bled from a number of sites, including the heart, lateral and ventral tail veins, femoral vessels, and pouch veins. Moore (1984) has described a method for obtaining blood from the brachiocephalic veins in a fashion similar to that used to bleed swine from the anterior vena cava. Daily samples ranging from 0.5 to 3.0   ml have been obtained from unanesthetized nine-banded armadillos (Dasypus novemcinctus) via puncture of the caudal tail vein between the second and third, or the third and fourth, bony tail segments. A modified piece of polyvinyl chloride (PVC) pipe is used for restraint (Herbst and Webb, 1988).

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Anesthesia and Analgesia in Other Mammals

Jeff Wyatt , in Anesthesia and Analgesia in Laboratory Animals (Second Edition), 2008

I. MARSUPIALIA: MARSUPIALS

Marsupials have short gestations, undeveloped neonates, extended development and lactation in the pouch, metabolic rates 26–35% lower than those of equivalently sized eutherian mammals, and lower core body temperatures, making them uniquely interesting for biomedical research applications (Holz, 2003; Pye, 2001). The marsupials most commonly used in biomedical research are found in four families including relatively small species compared to the more familiar macropod kangaroos and wallabies found in zoos.

Order Marsupialia

Family Didelphidae (New World opossums)

Didelphis virginiana (Virginia opossum)

Monodelphis domestica (short-tailed opossum)

Family Phalangeridae (Australian opossums)

Trichosurus vulpecula (brushtail opossum)

Family Potoroidae

Potorous tridactylus (long-nosed potoroo)

Bettongia gaimardi (Tasmanian bettong)

Family Petauridae

Petaurus breviceps (sugar glider)

A. Family Didelphidae

1. Virginia Opossum—Didelphis virginiana

The Virginia opossum, North America's only marsupial, is nocturnal and weighs 3.7–6.4 kg (Fig. 17-1). They play dead or "possum" when threatened by a predator. Their gestation is of 13 days with a 95–105-day pouch life (Newell and Berg, 2003). The Virginia opossum is used for studies of gastric banding (O'Rourke et al., 2006), parasitism (DeStefani et al., 2006; Dubey et al., 2000), infectious disease (Fitzgerald et al., 2003), metabolism (Weber and O'Connor, 2000), snake venom toxicity (Neves-Ferreira et al., 2000), neuron regeneration (Wang et al., 1999), and toxicology (Liapis et al., 1997).

Fig. 17-1. Virginia opossum—Didelphis virginiana.

Photo credit: American Society of Mammalogists, Mammal Images Library.
2. Short-tailed Opossum—Monodelphis domestica

The short-tailed opossum is a small marsupial (90–155 g) found throughout the forests of Brazil, Bolivia, Argentina, and Paraguay. Their gestation is of 14–15 days with postpartum attachment to nipples for 3–4 weeks (Moore and Myers, 2006). The short-tailed opossum has a rudimentary flap of abdominal skin instead of a pouch (Johnson-Delaney, 2006). The short-tailed opossum is used in studies of exercise metabolism (Schaeffer et al., 2005), developmental anatomy and physiology (Kraus and Fadem, 1987; Robinson and Van de Berg, 1994; Stolp et al., 2005), ultraviolet radiation–induced melanoma (Robinson and Van de Berg, 1994), and cytogenetics (Kraus and Fadem, 1987). There is no orbital sinus for blood collection (Kraus and Fadem, 1987).

B. Family Phalangeridae

1. Brushtail Opossum—Trichosurus vulpecula

The brushtail opossum weighing 1.2–4.5 kg is an arboreal, nocturnal marsupial found commonly throughout Australia and Tasmania and is considered an agricultural pest (Fig. 17-2). Their gestation is of 18 days with a 16-week pouch life (Meyer, 2000). The brushtail opossum is used for studying oxytocic and vasopressor neurohypophyseal peptides (Bathgate et al., 1992).

Fig. 17-2. Brushtail opossum—Trichosurus vulpecula.

Photo credit: American Society of Mammalogists, Mammal Images Library.

C. Family Potoroidae

1. Long-nosed Potoroo—Potorous tridactylus

The potoroo is a rabbit-sized marsupial common to Australia and Tasmania weighing up to 1.8 kg with a 38-day gestation and 130-day pouch life (Landesman, 1999). They are used for studies of nonshivering thermogenesis (Nicol, 1978), metabolism (Umminger, 1975), parotid salivary gland function (Beal, 1992), respiratory physiology (Baudinette et al., 1993; Nicol et al., 1977; Ryan et al., 1983), and sperm anatomy and motility and reproductive toxicology (Bryant and Rose, 1985).

2. Tasmanian Bettong or Rat Kangaroo—Bettongia gaimardi

The Tasmanian bettong is a 1.2–2.3-kg nocturnal marsupial, extinct in Australia after introduction of the red fox but fairly common in Tasmania. Their gestation is of 21 days and pouch life of 14 weeks (Lundrigan and Gallego, 2005). They are used for studying thyroid function (Rose and Kuswanti, 2004), nonshivering thermogenesis (Rose et al., 1999), reproductive endocrinology (Rose and MacFayden, 1997), and muscle physiology (Ye et al., 1995).

D. Family Petauridae

1. Sugar Glider—Petaurus breviceps

The sugar glider is a small (80–140 g) Australian, arboreal marsupial gaining popularity in the U.S. pet trade. They have a gliding membrane extending between the fore and hind limbs. They become torpid at cool temperature extremes. The gestation is of 16 days with a 70-day pouch life (Passata, 1999). They are used for studies of thermoenergetics (Holloway and Geiser, 2001a, 2001b), aerobic metabolism (Holloway and Geiser, 2001a, 2001b), depression (Jones et al., 1995), metabolism (Bradley and Stoddardt, 1990), angiography (Buttery et al., 1990), gliding physiology (Endo et al., 1998), and transthyretin expression (Duan et al., 1995).

E. Manual Restraint

The small marsupials used in biomedical research may be firmly gripped behind the head and the tail base or hind legs for placement in an anesthetic induction chamber or administration of intramuscular injections (Holz, 2003; Pye, 2001; Wallach and Boever, 1983). Sugar gliders may be restrained in a bag with head exposed for mask induction with isoflurane or leg exposed for IM injection (Pye, 2001).

F. Chemical Restraint

Isoflurane is the agent of choice for both induction via mask (3–5%) or chamber as well as maintenance (1–3%) for adults and neonates (Carpenter, 2005; Hernandez-Divers, 2004; Holz, 2003; Pye, 2001; Shima, 1999; Wallach and Boever, 1983) and is the technique recommended by the author. Premedication of sugar gliders with butorphanol (0.2 mg/kg IM) contributes to a smooth induction when using a chamber or face mask for delivery of isoflurane (Hernandez-Divers, 2004). Enflurane and sevoflurane may be used to effect (Carpenter, 2005). Preanesthetic fasting of 4–6 hours is recommended, since regurgitation under anesthesia is possible (Holz, 2003). Other injectables provide adequate anesthesia for minor procedures or endotracheal intubation (Table 17-1). Premedication with atropine 0.02–0.05 mg/kg IM, IV, SQ (Carpenter, 2005; Holz, 2003) or glycopyrrolate 0.01–0.02 mg/kg IM, IV, SQ (Carpenter, 2005; Shima, 1999) can aid in control of hypersalivation (Tables 17-2 and 17-3).

TABLE 17-1. INJECTABLE ANESTHETICS FOR MARSUPIAL

Species Drug dosage and route References
All opossums a Ketamine 20 mg/kg IM plus xylazine 10 mg/kg IM Holz, 2003
Tiletamine/zolazepam 5–10 mg/kg IM Holz, 2003; Pye, 2001; Wallach and Boever, 1983
Tiletamine/zolazepam 1–3 mg/kg IV Pye, 2001
Short-tailed opossum Ketamine 40 mg/kg IM hind limb Robinson and Van de Berg, 1994
Potoroos Ketamine 30 mg/kg IM plus xylazine 6 mg/kg IM Holz, 2003
Tiletamine/zolazepam 3.3–19.1 mg/kg IM Pye, 2001
Tiletamine/zolazepam 14.7 mg/kg IM Schobert, 1987
Ketamine 30 mg/kg IM (1 hour duration) Pye, 2001
Bettong Pentobarbital 60 mg/kg IP for terminal perfusion Ye et al., 1995
Sugar gliders b Ketamine 30 mg/kg IM plus xylazine 6 mg/kg IM Holz, 2003
Ketamine 20 mg/kg IM followed with isoflurane Carpenter, 2005; Pye, 2001
Tiletamine/zolazepam causes neurologic syndromes and death at 10 mg/kg Carpenter, 2005; Pye, 2001
Virginia opossum Tiletamine/zolazepam 10–20 mg/kg IM supplemented with ketamine 10–25 mg/kg IM or 5–10 mg/kg IV (do not supplement with tiletamine/ zolazepam due to prolonged recovery) Shima, 1999
Brushtail opossum Ketamine 50 mg/kg IM plus xylazine 10 mg/kg IM Bathgate et al., 1992
Tiletamine/zolazepam 10 mg/kg IM Pye, 2001
Tiletamine/zolazepam 7.7–11.5 mg/kg IM Schobert, 1987
a
Reversal with yohimbine 0.2 mg/kg IV or atipamezole 0.05–0.4 mg/kg IV.
b
Provided with heat during anesthesia to prevent torporous state.

TABLE 17-2. SEDATIVES AND TRANQUILIZERS—SHORT-TAILED OPOSSUM, VIRGINIA OPOSSUM, SUGAR GLIDER

Drug Dosage and route References
Diazepam 0.5–2 mg/kg IM, PO, IV Johnson-Delaney, 2006
Butorphanol 0.1–0.4 mg/kg SQ, IM q 6–8 hours Johnson-Delaney, 2006
Medetomodine 0.05–0.1 mg/kg IM with ketamine 2–3 mg/kg IM Johnson-Delaney, 2006
Diazepam (sugar glider) 0.5–1.0 mg/kg IM Carpenter, 2005

TABLE 17-3. ANALGESICS FOR SMALL MARSUPIAL SPECIES

Species Drug Dosage and route References
Short-tailed opossum Buprenorphine 0.01 mg/kg SQ, IM q 8 hours Johnson-Delaney, 2006
Butorphanol 0.1–0.5 mg/kg SQ, IM q 6–8 hours Johnson-Delaney, 2006
Carprofen 1.0 mg/kg PO, SQ q 12–24 hours Johnson-Delaney, 2006
Meloxicam 0.2 mg/kg PO SQ q 24 hours Johnson-Delaney, 2006
Virginia opossum Buprenorphine 0.1 mg/kg SQ, IM q 8–12 hours Johnson-Delaney, 2006
Butorphanol 0.1–0.5 mg/kg SQ, PO q 6–8 hours Johnson-Delaney, 2006
Carprofen 1.0 mg/kg PO, SQ q 12–24 hours Johnson-Delaney, 2006
Meloxicam 0.2 mg/kg PO, SQ q 24 hours Johnson-Delaney, 2006
Sugar glider Buprenorphine 0.01 mg/kg SQ, IM q 6–8 hours Johnson-Delaney, 2006
0.01–0.05 mg/kg IM q 8–12 hours Pye, 2001
Butorphanol 0.2–0.5 mg/kg IM q 8 hours Pye, 2001
0.5 IM mg/kg Pollock, 2002
0.5 IM mg/kg q 8 hours Carpenter, 2005
Butorphanol 1.7 mg/kg plus acepromazine 1.7 mg/kg, both given PO to prevent self-trauma at incision site Carpenter, 2005
Ketamine 10 mg/kg plus acepromazine 1 mg/kg, SQ to prevent self-trauma at incision both given site
Morphine 0.1 mg/kg SQ, IM q 6–8 hours Johnson-Delaney, 2006
Carprofen 1.0 mg/kg PO, SQ q 24 hours Johnson-Delaney, 2006
Meloxicam 0.2 mg/kg PO, SQ q 24 hours Johnson-Delaney, 2006
Flunixin meglumine 0.1–1.0 mg/kg IM q 12–24 hours Carpenter, 2005

G. Vascular Access

The jugular, femoral, lateral coccygeal, and cephalic veins are accessible for blood collection or catheterization (Holz, 2003; Wallach and Boever, 1983). The ventral tail vein of the Virginia opossum may be used for blood collection as well as catheterization (Johnson-Delaney, 2006; Wallach and Boever, 1983).

H. Fluid Therapy

For marsupials used in research, 50–100 ml/kg/day of crystalloid fluids may be administered subcutaneously using a butterfly catheter (Johnson-Delaney, 2006). A femoral intraosseous catheter may be used for fluid replacement in sugar gliders, short-tailed opossums, and Virginia opossums by first anesthetizing the animal and aseptically preparing the hip area as if for surgery. After an optional local skin block (2% lidocaine), a 1 in., 18–22-gauge hypodermic or spinal needle is placed into the proximal aspect of the femur through a small skin incision. After taping the needle in place, administer warmed fluids at 5 ml/h. Avoid fluids with glucose since marsupials develop cataracts and hepatic lipidosis with dextrose-containing fluids (Johnson-Delaney, 2006).

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Reproduction, Mating Strategies and Sperm Competition in Marsupials and Monotremes

D.A. Taggart , ... G. Shimmin , in Sperm Competition and Sexual Selection, 1998

11 Didelphidae

There is a general paucity of data available on the social structure of species in the Didelphidae. The species for which most information is available are the Virginia and grey short-tailed opossums (Didelphis vir-qiniana and Monodelphis domestica , respectively). Most species studied are seasonal breeders, polyoestrus and polytocous although, the grey short-tailed opossum may breed for most of the year in Brazil (Streilein 1982; Fadem and Rayve 1985; Baggott et al. 1987; Perret and M'Barek 1991). In captivity, at least, female grey short-tailed opossums will mate with 2–3 males during the one oestrus (Taggart and Moore unpublished observations). Relative testes mass and sperm tail length of the two didelphid species examined are average for body mass, as is relative epididymal sperm number in Monodelphis. Prediction of whether intermale sperm competition occurs in these species is made difficult owing to a number of confounding factors, in addition to the lack of data on social organization. For example, epididymal sperm pairing, a characteristic of all didelphids, directly affects sperm motility (Biggers and Creed 1962; Biggers and De Lamater 1965; Phillips 1972; Temple-Smith and Bedford 1980; Taggart et al. 1993a,b; Moore and Taggart 1995), sperm transport in the female tract is highly efficient (Bedford et al. 1984), and, as indicated earlier, sperm storage occurs in the lower oviduct (Bedford et al. 1984). In Monodelphis, when all these factors are taken into account, in combination with copulatory behaviour and a strongly male-orientated sexual dimorphism in body mass, the occurrence of intermale sperm competition appears to be likely.

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Sun Protection in Man

Elaine L. Jacobson , ... Myron K. Jacobson , in Comprehensive Series in Photosciences, 2001

34.2.1 Erythema

Post-UV erythema is the consequence of a variety of concomitant phenomena triggered by UV on cells and tissues. Ronald Ley pointed out in 1985 that the stimulation of DNA repair in marsupials had an effect on the minimal erythemal dose [19]. Monodelphis domestica were exposed to increasing doses of UV-B, and subsequently untreated or exposed to a dose of UV-A. Since marsupials have photolyase, exposure to UV-A triggers photoreactivation, a DNA repair process that does not generate nicks. The results of the experiments were that the dose of UV-B necessary to provoke the appearance of erythema was larger when UV-B irradiation was followed by UV-A irradiation, and that the number of pyrimidine dimers was smaller in UV-B- and UV-A-irradiated animals than in animals irradiated only with UV-B. This was the first experiment to link DNA damage and erythema.

This observation has led to the following hypothesis. UV-B generated DNA damage is repaired by endogenous DNA repair systems. In placental mammals, this system generates nicks (placental mammals such as humans and guinea pigs do not have photolyase) and nicks activate PARP-1. PARP-1 consumes NAD, and when the damage is significant, the cells secrete pro-inflammatory signals and trigger an inflammatory process, clinically characterized by an erythema. If this model holds, then the intensity of the erythema could be lessened by optimizing cellular NAD in skin after erythemal UV-B irradiation. Because NAD molecules carry two negative charges at physiological pH, NAD would not be expected to cross the cell membranes unless it is encapsulated in liposomes or analogous vehicles that facilitate crossing of membranes by charged molecules. NAD encapsulated in non-ionic liposomes or in liposomes, or dissolved in phosphate buffered saline (PBS) was applied to the back of hairless guinea pigs after exposure to 2 MED and the erythema was assessed 4 and 24 h after the irradiation. The results are reported in Table 1 [35]. The addition of NAD in non-ionic liposomes as well as in other vehicles dramatically reduces the intensity of UV-B induced erythema [20], similar to indomethacine. It should be noted that indomethacine inhibits erythema by blocking the generation of pro-inflammatory signals. Further studies are needed to determine the precise mechanism by which optimizing NAD blocks UV-induced erythema, but a prediction is that cells are protected either by maintenance of energy status or by enhancing DNA repair pathways that are facilitated by NAD and no longer need to secrete pro-inflammatory signals.

Table 1. Erythema in hairless guinea pigs, treated with NAD after exposure to UV-B

n Sample Average erythema
12 control 0.77
versus
NAD in n.i. liposomes 0.29
12 control 0.90
versus
n.i. liposomes 0.69
12 control 1.23
versus
PBS + NAD 0.73
12 control 1.15
versus
PBS 1.46
12 control 1.08
versus
liposomes + NAD 0.79
12 control 0.73
versus
liposomes 0.85
12 control 0.81
versus
indomethacin 0.48
12 control 0.60
Versus
indomethacin solvent 0.63
12 control 1.63
versus
control 1.50

Effect of topical application of NAD on UV-B induced erythema. Groups of Hartley albino guinea pigs were epilated 72 h before irradiation and at time t = 0 were exposed to a constant UV-B dose, corresponding to one minimal erythemal dose (MED). 30, 60 and 90 min after exposure, 0.1 ml of NAD was topically applied to a 7 cm2 surface (NAD was 20 mM). At t = 4 h, the erythema for every animal was read according to the following score (0, no erythema; 0.5, barely visible erythema; 1, erythema; 2, clear erythema; 3, marked erythema; 4, intense erythema) and averaged.

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Gametogenesis, Fertilization and Early Development

Kim L. McIntyre , ... Paul D. Waters , in Encyclopedia of Reproduction (Second Edition), 2018

Conservation of X Chromosome, Degeneration of Y Chromosome

Gene content and order on the eutherian X chromosome is remarkably conserved, as demonstrated by global conservation of the human, horse, pig, cat, cattle, and elephant chromosomes (reviewed in Livernois et al., 2012). Even on the rodent X chromosome, where rearrangements have altered gene order, the gene content remains similar to that of other eutherians (Fig. 2). Compared with the eutherians, marsupials have a somewhat smaller X chromosome: 490 protein coding genes and 213 noncoding genes in the opossum, Monodelphis domestica (Ensembl release 89). The marsupial X chromosome shares homology with the entire long arm and part (the pericentric region) of the short arm of the human X chromosome. The remainder of the eutherian X chromosome is an autosome in marsupials. This autosome was fused to the sex chromosomes in the eutherian ancestor and on the X chromosome is called the X-added region (Fig. 2).

In contrast to the significant conservation of the X chromosome, on the Y chromosome only 18 genes from the ancestral Y gene complement have been retained in at least one therian representative. On the modern human Y chromosome, only five genes are retained from the ancestral Y chromosome. A further 13 genes (2 of which have degraded to pseudogenes) are retained from the autosome added to the sex chromosomes in the eutherian ancestor (Cortez et al., 2014).

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Kisspeptin

Shinji Kanda , Yoshitaka Oka , in Handbook of Hormones, 2016

Supplemental Information

E-Figure 1B.1. Kisspeptin: precursor and mature hormone sequences of various animals.

The alignment of amino acid sequences of kisspeptin precursor polypeptides in vertebrates. Perfectly conserved residues are shaded in black, and highly conserved (>80%) are shaded in gray.

 Adapted with permission from Akazome et al., 2010 [6], © The Fisheries Society of the British Isles.

E-Table 1B.1. Accession Numbers or Location of Genes and cDNAs for Kisspeptins

kiss1/Kiss1/KISS1 kiss2/Kiss2/KISS2
Human Homo sapiens NM_002256
Mouse Mus musculus NM_178260
Rat Rattus norvegicus NM_181692
Opossum Monodelphis domestica NM_001144132
Platypus Ornithorhynchus anatinus AAPN01239752 1688–1735 AAPN01043280 1–5154
Lizard Anolis carolinensis XM_003220766
Western clawed frog. Xenopus tropicalis kiss1a EU853681 EU853683
kiss1b EU853682
Medaka Oryzias latipes AB272755 AB439562
Zebrafish Danio rerio AB245404 AB439561
Goldfish Carassius auratus FJ465137 FJ465138
Sea bass Dicentrarchus labrax FJ008914 FJ008915
Stickleback Gasterosteus aculeatus Ensembl scaffold 221 3202–3411
Green spotted puffer Tetraodon nigroviridis Scaffold SCAF14526 48391410–48392988
Torafugu Takifugu rubripes Ensembl scaffold 171 390309–392041
Elephant shark Callorhinchus milii kiss1a AAVX01162971 1–922 AAVX01172388 970–1300
kiss1b AAVX01250489 370–680
Sea lamprey Petromyzon marinus EB7222290 Ensembl contig3941 12551–18595

E-Table 1B.2. Accession Numbers or Location of Genes and cDNAs for Kisspeptin Receptor Genes (gpr54/GPR54)

gpr54-1/Gpr54-1/GPR54-1 gpr54-2/Gpr54-2/GPR54-2
Human Homo sapiens AAK83235
Mouse Mus musculus AAK83236
Rat Rattus norvegicus AAD19664
Platypus Ornithorhynchus anatinus Ensembl Ultra_266:390150:395924
Bullfrog Rana catesbeiana EU681171
Western clawed frog Silurana tropicalis gpr54-1a: EU853678 EU853680
gpr54-1b: EU853679
Cobia Rachycentron canadum L. DQ790001
Croaker Micropogonias undulatus L. DQ347412
Mullet Mugil cephalus L. DQ683737
Senegalese sole Solea senegalensis EU136710
Zebrafish Danio rerio EU047918 EU 047917
Medaka Oryzias latipes Chromosome 9, 4480521–4500733 Chromosome 17, 29839761–29855706
Tilapia Oreochromis niloticus L AB162143
Torafugu Takifugu rubripes Ensembl scaffold 80: 1035934–1046929
Stickleback Gasterosteus aculeatus L. Ensembl group III: 13,328,756–13,335,295

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Safety Assessment including Current and Emerging Issues in Toxicologic Pathology

Eric D. Lombardini , ... Mark A. Melanson , in Haschek and Rousseaux's Handbook of Toxicologic Pathology (Third Edition), 2013

7.4 Ultraviolet Radiation Carcinogenesis

Epidemiologic Evidence

Evidence for the role of sunlight in non-melanoma skin cancer (NMSC) in humans (basal cell and squamous cell carcinomas) is based on a number of observations. First, people with light skin color are more susceptible to NMSC than those more heavily pigmented. Second, the frequency of NMSC in light-skinned people increases near the Equator, where solar radiation is high. Third, those who spend much of their time outdoors have a higher incidence of NMSC than those staying mostly indoors. Fourth, NMSC develops predominantly on sun-exposed parts of the body. Fifth, Xeroderma pigmentosum patients unable to repair DNA photoproducts develop NMSC in sun-exposed areas at a frequency much greater than DNA repair-proficient individuals. Finally, NMSC can be produced in mice by chronic UVB irradiation. Although sun exposure contributes to the development of melanoma in humans, its exact role is unclear. In the past few decades, there has been an alarming increase in the number of NMSC and melanomas among light-skinned populations throughout the world, leading some scientists to postulate an emerging epidemic of skin cancer.

Animal Models

Species and strains vary considerably in their susceptibility to UV-induced skin cancer. These differences are due largely to variables such as pigmentation, hair coat, and thickness of the stratum corneum. Mice appear to be the experimental animals most susceptible to UV carcinogenesis. Hairless SKH-1 mice are widely used for photobiology studies. Advantages of these mice are that they do not require shaving, are unpigmented, and have a relatively normal immune system; however, a limitation is that the mice are not inbred. Furthermore, UV exposure alone does not cause melanomas in mice or other commonly used experimental animals, although a combination of chemical carcinogen and UV is effective. For this reason, a variety of unusual animal models susceptible to UV-induced melanoma, such as the South American opossum ( Monodelphis domestica ) and swordtail or platy fish (Xiphophorus sp.), have been used to study the relationship between UV exposure and melanomas. In the former case, under experimental conditions, the opossum demonstrated high levels of ultraviolet radiation (UVB)-induced neoplasms including papillomas, keratoacanthomas, squamous cell carcinomas, basal cell tumors, fibrosarcomas, and both melanocytomas and melanomas. Swordtail platy fish hybrids have been used as a model for UVB-induced melanomas, and have been critical in the debate as to the carcinogenicity of different forms of UV irradiation (Figure 44.51). With the advent of new strains of genetically altered mice, a host of new murine models is becoming available, including mice that are highly susceptible to melanoma, heterozygous and homozygous p53 knockout mice, and murine models of xeroderma pigmentosum. Furthermore, the hairless mouse has been used to prove that UVA is in fact a complete carcinogen, through its ability to initiate and promote squamous cell carcinomas in that species.

FIGURE 44.51. Scaled skin: platy fish exposed to UVR. Cutaneous melanoma (top left) with invasion of the dorsal fin, elevation and obliteration of the scales. H&E stain. Bar   =   200   μm.

Mechanisms

Animal studies indicate that UV is a complete skin carcinogen. UV is an initiator by virtue of its mutagenic capability, a promoter due to its ability to alter gene expression and thus stimulate proliferation, and it drives tumor progression by a combination of its mutagenic and growth-promoting activities. The most effective wavelengths for UV-induced NMSC in the hairless mouse are those in the UVB range, with peak activity at 293   nm. This action spectrum implicates DNA as the primary chromophore for NMSC. UVA (340   nm) can induce NMSC in hairless mice, but it is 10   000-fold less effective than UVB. In general, changes in fluence rate or interval between doses do not alter the shape or slope of the NMSC incidence curve, but may affect the latent period.

The p53 tumor suppressor gene provides significant protection against UV-induced NMSC. UV-induced DNA damage is a potent inducer of wild-type P53 protein. P53 induces cell-cycle arrest in cells with damaged DNA, thus permitting repair of minor DNA damage and stimulating apoptosis of cells too badly damaged for effective repair. This eliminates genetically altered and potentially transformed cells from the skin. When p53 is mutationally inactivated or deleted, deleterious mutations accumulate in UV-exposed keratinocytes, leading to the development of NMSC. More than 90% of UV-induced NMSC in the human and in the hairless mouse have mutationally inactivated p53 genes. Mutations are concentrated in exons 5–8 of the p53 gene. Most are missense point mutations arising on the non-transcribed strand of DNA. Most p53 mutations in NMSC are hallmark UV mutations, C to T and CC to TT, at dipyrimidine sites, suggesting that UV is the proximate carcinogen for these tumors.

Skin Neoplasms

Chronic natural or experimental exposure to UV leads to the development of hyperplastic and neoplastic skin lesions in a variety of animal species. In many cases, hyperplastic lesions appear to serve as precursors for neoplastic lesions. Actinic keratoses in humans appear to give rise to squamous cell carcinoma. In the hairless mouse, foci of epidermal hyperplasia can evolve into sessile or pedunculated papillomas, and squamous cell carcinomas may arise in those papillomas (Figure 44.52). With continued UV exposure, squamous cell carcinomas in the hairless mouse progress to increasingly invasive and anaplastic tumors.

FIGURE 44.52. Gross appearance of skin lesions induced by chronic UV exposure in the hairless mouse. A number of pedunculated papillomas and three ulcerated squamous cell carcinomas are visible. Lesions arise and evolve independently.

 Figure reproduced from Handbook of Toxicologic Pathology, 2nd Ed. W. M Haschek, C. G. Rousseaux and M. A. Wallig, eds. (2002) Academic Press, Vol. 1, Fig. 34, p. 586, with permission.

The behavior of UV-induced squamous cell carcinomas in humans and experimental animals is similar. Although clearly malignant and locally invasive, these tumors rarely metastasize. Squamous cell carcinoma in the unpigmented skin of dogs, the pinna and nasal planum of white cats, and the vulva of cattle and goats has been linked to natural sunlight exposure. Keratoacanthomas are invaginated keratin-filled masses lined by thickened epithelium that develop in humans and in some experimental animals in response to UV. In humans, these tumors are self-limiting and undergo involution, while in experimental animals they appear to be capable of giving rise to squamous cell carcinomas. Basal cell tumors similar to those caused by sunlight in humans rarely arise in experimental animals; however, a murine model of basal cell carcinoma, the Patched knockout mouse, has been developed.

The only human sarcoma clearly associated with sunlight is the atypical fibroxanthoma of the elderly. However, chronic UV exposure in haired mice and in Monodelphis domestica can induce dermal fibrosarcomas and hemangiosarcomas, and sunlight exposure has been proposed as a cause of hemangiosarcoma in the sparsely haired skin of dogs. Some UV-induced spindle-cell tumors of the dermis in mice may represent anaplastic squamous cell carcinomas, and carcinosarcomas or "collision tumors" have been described. A number of models for human melanoma have been or are being developed, but none is entirely satisfactory.

Chronic UV exposure induces benign and malignant melanomas and the precursor lesion of melanocytic hyperplasia in Monodelphis domestica. Genetically altered mice that develop a high incidence of melanoma have also been created; however, these mice tend to succumb very rapidly to metastatic disease, making them difficult to work with. Furthermore, in both mice and Monodelphis, melanomas arise in the dermis and show little or no junctional activity, unlike the situation in humans. Melanomas associated with natural sunlight exposure in animals include perineal melanomas of gray horses, and melanomas of the ears in Angora goats.

Ocular Neoplasia

In humans, squamous cell carcinoma of the conjunctiva is rare. It occurs with increased frequency in the tropics and in xeroderma pigmentosum patients, establishing a link with solar UV. Early papillary lesions are often found in association with chronic inflammation and stromal collagen degeneration. Squamous cell carcinoma of the eye is a serious economic problem in some breeds of cattle. The disease in cattle is clearly related to cumulative solar exposure, with pigmentation, genetic background, and viral infection also playing a role in the disease. The neoplasms develop from plaques and papillomas to carcinoma in situ and, ultimately, invasive squamous cell carcinoma.

Squamous cell carcinoma of the conjunctiva has been associated with sunlight exposure in dogs. In mice chronically exposed to UV, ocular squamous cell carcinomas develop less frequently than corneal fibrosarcomas and hemangioendotheliomas. Precursor lesions include epithelial hyperplasia, neovascularization, and fibroplasia. Virtually all Monodelphis domestica chronically exposed to UV develop corneal fibroplasia and neovascularization that evolve into mesenchymal tumors of the cornea. It has also been observed that intraocular melanoma in humans has a higher incidence in those with blue eyes and in those living in the southern versus northern United States, suggesting a possible link to UV exposure.

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The comparative genomics of tammar wallaby and Cape fur seal lactation models to examine function of milk proteins

Julie A. Sharp , ... Kevin R. Nicholas , in Milk Proteins, 2008

Fractionation of milk and analysis of bioactive proteins

The fractionation of milk from tammar wallabies at the major phases of lactation provides an opportunity to identify fractions with bioactivity and to follow changes in activity in specific fractions across the duration of lactation. Temporal changes in activity would probably suggest an association with particular developmental process(es) in the developing young, although a potential autocrine effect on mammary gland function could also be considered. The microarray used to identify differentially expressed genes, described previously, was limited to approximately 5000 genes and it is likely that the number of differentially expressed genes coding for secreted bioactive components will increase when a microarray with whole genome coverage becomes available.

The genome of another marsupial, Monodelphis domestica , has been sequenced to eight-fold coverage and the genome of the tammar wallaby has been sequenced to two-fold coverage; this information will probably lead to a marsupial whole transcriptome microarray. The disadvantage of analyzing fractionated whey is that often the sample assayed comprises a mixture of proteins, requiring additional work to identify the specific protein(s) associated with the bioactivity. However, this approach potentially allows identification of proteins and peptides that are not currently represented on the tammar wallaby EST microarray and which may have either undergone post-translational processes or resulted from alternative splicing of genes.

Whey samples collected from tammar wallabies in Phases 2B and 3 were fractionated by reverse phase high performance liquid chromatography (HPLC) as shown in Figure 2.7. Proteins and peptides bound to the column were eluted with a linear acetonitrile gradient and the 60 fractions were analyzed in cell-based assays for potential to stimulate growth and differentiation of cells (ERK activity), pro- and anti-apoptotic assays, and assays for stimulation and inhibition of immune response. Analysis of ERK showed activity in specific fractions (Figure 2.7) in whey from tammar wallabies at Phase 2B. However, activity was evident not only in the same fractions in whey from tammar wallabies in Phase 3 of lactation, but also in an additional set of whey fractions. A specific role for this factor/s is not yet apparent, but it has considerable potential because it is correlated with a dramatic increase in milk production and growth of the young as they emerge from the pouch and begin to eat herbage and consume milk.

Figure 2.7. Fractionation and analysis of tammar wallaby whey. Whey from milk collected in Phase 2B and Phase 3 of lactation was fractionated by reverse phase HPLC. Proteins and peptides bound to the column were eluted with a linear acetonitrile gradient and the 60 fractions were analyzed for potential to stimulate ERK (growth and differentiation of cells) in a cell-based assay.

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Mammalian Hormone-Behavior Systems

R.E. Johnston , J. delBarco-Trillo , in Hormones, Brain and Behavior (Second Edition), 2009

1.11.4.4.1 Hormonal responses to odors

Lesions of the VNO are especially likely to influence hormonal responses caused by exposure of subjects to opposite-sex conspecifics or odors from such animals (see Table 1 ). In female mammals a few examples of these effects include: induction of estrus by males or male odors in gray short-tailed opossum, Monodelphis domestica (Jackson and Harder, 1996) and acceleration of puberty onset by odors of the opposite sex in mice (Kaneko et al., 1980; Koyama, 2004; Lomas and Keverne, 1982; Vandenbergh, 1983a), Djungarian hamsters (Gudermuth et al., 1992), and several species of voles (Richmond and Stehn, 1976). Additional effects include delay of reproductive development by odors of conspecifics (Rissman et al., 1984; Vandenbergh, 1983a), and modulation of estrous cycles in female rats by exposure to male and female odors (Beltramino and Taleisnik, 1983; McClintock, 1983). Table 1 provides an extensive list of specific effects.

Table 1. Effect of lesions of the vomeronasal system (VNO) or main olfactory system (MOS) on hormonal and behavioral responses to odors of other individuals

Expected effect of VNO/MOS lesion Lesion Result Species Sex/experience References
Hormonal effects
Blocks LH surge in response to female odors VNO + Mouse Male Coquelin et al. (1984)
Blocks androgen surge in response to female odors VNO + Hamster Male, both sexually experienced and naïve Pfeiffer and Johnston (1994)
MOS ― Hamster Male Pfeiffer and Johnson (1994)
VNO + Mouse Male Wysocki et al. (1983)
Blocks LH surge in response to male odors VNO/MOS + Rat Female Beltramino and Taleisnik (1983)
VNO ― Sheep Female Cohen-Tannoudji et al. (1989)
Developmental effects
Eliminates pregnancy block by unfamiliar male VNO + Mouse Female Bellringer et al. (1980), Lloyd-Thomas and Keverne (1982)
MOS ― Mouse Female Lloyd-Thomas and Keverne (1982)
Eliminates the acceleration of puberty by male odors VNO + Mouse Female Kaneko et al. (1980), Lomas and Keverne (1982)
Eliminates estrous suppression by dominant female VNO and/or MOS ― Marmoset monkey Female Barrett et al. (1993)
Eliminates the induction of estrus in suppressed females VNO + Mouse Female Reynolds and Keverne (1979)
Eliminates the induction of estrus VNO + Prairie vole Female Wysocki et al. (1991)
VNO ― Meadow vole Female Meek et al. (1994)
VNO + Gray short-tailed opossum Female Jackson and Harder (1996)
Behavioral effects
Increases latency to investigate vaginal secretion VNO + Hamster Male, sexually experienced Pfeiffer and Johnston (1994)
MOS + Hamster Male, both sexually experienced and naïve Pfeiffer and Johnston (1994)
Reduces attraction to female odors VNO ― Hamster Male O'Connell and Meredith (1984)
MOS + Hamster Male O'Connell and Meredith (1984)
VNO + Mouse Male Pankevich et al. (2006)
Eliminates preference for novel female VNO ― Hamster Sexually satiated male Johnston and Rasmussen (1984)
MOS + Hamster Sexually satiated male Johnston and Rasmussen (1984)
Eliminates preference for estrous female urine over male urine VNO + Mouse Male Keller et al. (2006b), Pankevich et al. (2006)
Blocks discrimination of estrous vs. nonestrous urine VNO ― Sheep Male Blissitt et al. (1990)
VNO ― Hamster Female Petrulis et al. (1999)
Blocks discrimination of intact vs. castrated male urine (both volatile and nonvolatile) MOS + Mouse Female Keller et al. (2006a)
(only nonvolatile) VNO + Mouse Female Keller et al. (2006b)
(only volatile) VNO ― Mouse Female Keller et al. (2006b),
Blocks discrimination of conspecific vs. heterospecific odors VNO ― Hamster Male Murphy (1980)
MOS + Hamster Male Murphy (1980)
Blocks discrimination of individual odors VNO + Hamster Male Johnston and Peng (2000)
VNO ― Hamster Female Johnston and Peng (2000), Petrulis et al. (1999)
Blocks the learned discrimination of MHC differences in congenic mice VNO ― Mouse Female Wysocki et al. (2004)
Reduces sexual behavior VNO + Hamster Male O'Connell and Meredith (1984), Powers and Winans (1975)
MOS ― Hamster Male O'Connell and Meredith (1984)
VNO + Mouse Male Clancy et al. (1984)
VNO + Prairie vole Male Wekesa and Lepri (1994)
VNO + Rat Female Saito and Moltz (1986)
MOS + Mouse Female Keller et al. (2006a)
VNO ― Pig Female Dorries et al. (1997)
Reduces percentage of females mating VNO ― Meadow vole Female Meek et al. (1994)
VNO + Hamster Female Mackay-Sim and Rose (1986)
VNO + Mouse Female Keller et al. (2006b),
Reduces male–male aggression VNO/MOS + Hamster Male Murphy (1976)
VNO + Mouse Male Clancy et al. (1984),
VNO + Lesser mouse lemur Male Aujard (1997)
Reduces maternal aggression toward males VNO + Mouse Female Bean and Wysocki (1989)
Blocks maternal behaviors VNO+MOS + Hamster Female Marques (1979)
VNO/MOS ― Rat Female Jirik-Babb et al. (1984)
VNO + Rat Female Brouette-Lahlou et al. (1999)
Blocks pup recognition VNO + Sheep Female Booth and Katz (2000)
Reduces nest building VNO ― Mouse Female Bean and Wysocki (1989)
VNO+MOS + Hamster Female Marques (1979)
Reduces pup retrieval VNO ― Mouse Female Bean and Wysocki (1989)
VNO/MOS ― Rat Female Jirik-Babb et al. (1984)
Reduces nipple search and attachment VNO ― Rabbit Pups Hudson and Distel (1986)
MOS + Rabbit Pups Hudson and Distel (1986)
Affects scent marking MOS + Hamster Male Johnston and Mueller (1990)
VNO ― Hamster Male Johnston and Mueller (1990)
VNO ― Hamster Female Johnston (1992)
MOS + Hamster Female Johnston (1992)
VNO + Hamster Female Petrulis et al. (1999)
VNO ― Mouse Male Clancy et al. (1984)
VNO ― Lesser mouse lemur Male Aujard (1997)

In male mammals the VNO is also important in modulation of hormones; for example, lesions of the VNO or the AOB eliminate the following effects: (1) an increase in LH and testosterone in male mice after exposure to female mice or their odors (Coquelin and Bronson, 1980; Coquelin et al., 1984) and (2) increases in testosterone in male hamsters in response to female hamster vaginal secretions (Macrides et al., 1974; Pfeiffer and Johnston, 1992, 1994). It is clear from the summary of results shown in Table 1 that there are some general differences in the function of the main and accessory olfactory systems but, also, that there is often an overlap in functions. One trend that emerges from this summary is that the VNO and accessory olfactory system appear to be more often involved in hormonal responses to odors than the MOS. Nonetheless, the VNO is not always responsible for hormonal responses to odors. One notable exception to this generalization is the ram effect in ewes, in which exposure of ewes to odors from rams hastens the onset of fertility and sexual receptivity by increases in secretion of LH into the circulation (Cohen-Tannoudji et al., 1994, 1989). Lesions of the VNO have no effect on LH secretion in ewes in response to ram odors, whereas inactivation of areas involved in main olfactory inputs do block the increase in LH secretion (Gelez et al., 2004c). It is also interesting that sexual experience with rams is important for the endocrine and behavioral responses of ewes to the odors of rams (Gelez et al., 2004a,b).

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