Animal Models in Toxicologic Research: Nonhuman Primate

2.1

The Cynomolgus Macaque ( Macaca fascicularis )

The cynomolgus macaque (syn: crab-eating macaque; long-tailed macaque) is the NHP species most commonly used in regulatory toxicology studies today ( ). Cynomolgus macaques belong to the family Cercopithecidae, genera Macaca alongside the rhesus macaque, also commonly used in biomedical research. Following the ban on exportation of rhesus macaques from India in 1978, the biomedical research community sought an NHP species that was easy to source, house, and breed in support of the growing demand for NHPs in biomedical research that continued from the previous decades ( ). The cynomolgus macaque was selected over the rhesus macaque for its smaller size, resulting in lower compound requirements in toxicity studies, its less aggressive temperament, and nonseasonal breeding characteristics ( ).

Cynomolgus macaques have red-brown to gray fur with lighter underparts and tail that is considerably longer than their body length; however, there is considerable variation in both the coat color and tail length depending on the origin of particular animals ( ; ). Males and females are sexually dimorphic, with males being larger than females and having much larger maxillary canine teeth. The skin of the face and perineum is typically pink, except in females during estrous when there is swelling and red coloration of the perineal skin, known as “sex skin.” All macaques have prominent ischial callosities: thick keratinized regions of skin overlying the ischial tuberosities. Additional biological characteristics of the cynomolgus macaque are summarized on Table 21.1 .

The natural habitat of cynomolgus macaques is expansive and covers much of the islands and mainland of South East Asia ( ). Two major natural subgroups of cynomolgus macaque have been described: insular (originating in the Philippines and Indonesia) and Indochinese/“Asian” (originating in Vietnam, Cambodia, Thailand, Laos, and the Malaysian Peninsula) ( ). Mauritian animals represent a third subgroup that expanded from a small number of founder animals introduced to the island from mainland Asia ( ).

2.2

The Rhesus Macaque ( Macaca mulatta )

Rhesus macaques are commonly used NHPs in biomedical research and, based on research awards, the most commonly utilized macaque for general research purposes ( ). They have been critical in our understanding of many fields of human development and disease.

Rhesus macaques have a thick brown to auburn pelage and, compared to the cynomolgus macaque, are considerably larger with relatively shorter tails ( ). Skin is red to pink on both the face and perineal region, which are predominantly hairless. Females exhibit similar reddening and swelling of the perineal region during the menstrual cycle as cynomolgus macaques. Like other macaque species, rhesus monkeys have ischial callosities and males are larger than females with prominent maxillary canines. Additional biological characteristics of the rhesus macaque are summarized in Table 21.1 .

Rhesus macaques have the largest natural habitat of any primate, other than humans, which covers most of Asia ( ).

2.3

The Common Marmoset ( Callithrix jacchus )

Common marmosets are arboreal New World monkeys of the family Callitrichidae that are native to Brazil ( ). Their use in biomedical research was the subject of a recently published textbook “The Common Marmoset in Captivity and Biomedical Research” to which the reader is referred for more in-depth data ( ).

The fur of the common marmoset is a mixture of brown, gray, and yellow over the body. They have conspicuous white ear tufts, a blaze of white fur on the forehead, and long banded tails. Unlike Old World monkeys (e.g., macaques), common marmosets have wide, flat noses with laterally placed nostrils, do not have opposable thumbs or ischial callosities, and have claws rather than nails except on the first digit of the hindlimb. They do not exhibit apparent sexual dimorphism ( ). Additional biological characteristics of the common marmoset are summarized in Table 21.1 .

2.4

The Baboon ( Papio sp.)

Several species of baboon are commonly utilized in general research associated with reproductive biology, evolutionary biology, and ecology ( ; ; ; ). Up to the mid-1960s, use of baboons as laboratory subjects was relatively low in the United States, with most successful colonies existing in the Soviet Union ( ). Largely due to National Institute of Health (NIH) support, captive breeding programs in the United States began to grow in the 1970s. Today the baboon has gained in popularity and reached a high level of utility. The genus Papio originates from the plains and savannas of sub-Saharan Africa and the Arabian Peninsula. Although hybridization between species under natural conditions can blur the distinction between them, there are currently five species commonly recognized including the Guinea baboon ( Papio papio), the Olive baboon ( Papio anubis), the Yellow baboon ( Papio cynocephalus), the Chacma baboon ( Papio ursinus), and the Hamadryas baboon (Papio hamadryas). A sixth species, the Kinda baboon ( Papio kindae), is recognized and noted to hybridize with Chacma baboons in Zambia ( ). Each of these species has distinguishing features, primarily hair coat color and body size, but also shares features of the genus including a long sloping hairless muzzle and medium-short tails. There are sexual dimorphisms among baboons including differences in body size (e.g., males are larger than females), dentition (e.g., males having larger canine teeth), and ischial callosities (e.g., males having fused ischial callosities below the anus and females having separate ischial callosities) ( ; ; ).

Female baboons reach puberty at approximately 3–4 years of age, cycle continuously throughout the year, and are able to reproduce in any season. Changes in turgor and color of the female perineal skin (sexual swelling of the sex skin) signal changes in hormonal levels, onset of the periovulatory period, and reproductive receptivity to the male ( ; ). The female baboon has an approximately 33-day estrus cycle. The rise in urinary oxytocin content during the periovulatory period may initiate or maintain intersexual relationships with the consort males during peak receptivity ( ). Gestation is approximately 6 months for baboons and the infant is usually born at night. Female baboons generally approach menopause in their late 20s or early 30s, as defined by 6 months without vaginal bleeding or evidence of cycling ( , https://amboselibaboons.nd.edu ).

Male baboons reach puberty at approximately 5–6 years of age, but successful breeders are usually over 6 years of age when they are able to maintain control of the harem ( ). In general, baboons may reach an age of over 40 years in captivity. For additional information on the baboon, access The Animal Diversity Web ( https://animaldiversity.org ).

2.5

The Squirrel Monkey ( Saimiri sp . )

The squirrel monkey was a standard and popular lab animal species prior to the 1970s, as they were small and relatively easy to keep in colonies, but their reproduction in captivity remained poor, so that additional animals needed to be obtained from wild stocks ( ). As South and Central American countries began to limit or ban the exportation of these monkeys in the 1970s, it became more urgent to develop successful captive breeding colonies in order to support the ongoing research for which they were commonly utilized. Colonies were established in the United States and Caribbean, but as the resource had become more limited, other monkeys, namely the macaques, were substituted to meet the needs of the NIH and other research establishments. Today, most of the squirrel monkeys are provided to research facilities from breeding colonies, with low numbers imported each year ( ).

The breeding season for squirrel monkeys is approximately 3 months long, with females cycling approximately every 9–10 days (9–10 and 10–12 days reported in various sources) accompanied by high circulating steroid hormones and behavioral changes (increased genital investigation and sexual invitation) ( ; ; ; ). For additional information on the Squirrel monkey, access The Animal Diversity Web ( https://animaldiversity.org ).

2.6

The Tamarins ( Saguinus sp . )

The tamarins are members of the subfamily Callitrichinae, along with marmosets, and are a diverse group of NHPs found throughout the Amazon, Guianas, Colombia, and Central America. There are multiple species within the genus Saguinus ; perhaps the best-known tamarin in biomedical research is the cotton-top tamarin ( Saguinus oedipus ), as it is the most commonly utilized member of its genus. They are small monkeys, averaging 260–380 g and are famous for having white shaggy fur on their head. Cotton-top tamarins breed twice yearly, and generally produce nonidentical twins. They are sexually mature at 18 months for females and 24 months for males. For more information, access The Animal Diversity Web ( https://animaldiversity.org ).

2.7

The Vervet and Green Monkeys ( Chlorocebus aethiops ssp. sabaeus and pygerythrus )

The Vervet and Green monkeys belong to the genus Chlorocebus; however, the terms green monkey, vervet monkey, or grivet are often applied interchangeably to the members of the subspecies and both have been extensively used in biomedical research. These monkeys originate from Ethiopia, including most of West Africa from Senegal to Ghana and in the Northeast to the Red Sea. Both monkeys have green-tinted golden fur by which they acquired the name green monkey. They differ in facial coloration, with Chlorocebus aethiops sabaeus having a dark blue hairless face and Chlorocebus aethiops pygerythrus having a sooty-black face. For additional information on the green monkey, access The Animal Diversity Web ( https://animaldiversity.org ).

2.8

The Capuchin Monkey ( Cebus sp.)

Carl Linnaeus denoted the capuchin monkey as Cebus with two species, apella and capucinus, based on differences in appearance, and in years that followed, the monkeys were separated into additional species ( ). However, the phylogenetics of the capuchin monkey has come under scrutiny in recent years, with dissent over the single genus “ Cebus. ” Some primatologists prefer to split capuchin monkeys into two species, the commonly used “ Cebus ” and the recently proposed “ Sapajus ” ( ). Regardless, most databases currently refer to six species under the genus of “ Cebus ” ( ; ; ; ; ; ; ITIS partners) . These neotropical monkeys inhabit the forests of Central and South America. They are polygynous and without a true breeding season. Females have a 150–160-day gestation period and generally give birth to one infant per year, with twins rarely reported. Females and males are considered mature at 4 and 7 years of age, respectively ( ). For additional information on the Capuchin monkey, access The Animal Diversity Web ( https://animaldiversity.org ).