One report of respiratory infections in growing goat clones (2/6) (Keefer et al. 2001) ... One report of goat doe clones conceiving and delivering normal offspring (Reggio et al. ...
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Animal Safety Amey L. Adams, PhD Center for Veterinary Medicine Food and Drug Administration November 4, 2003
Context for Consideration of Animal Health Risks • Do the risks experienced by animals involved in the cloning process differ qualitatively from those experienced by animals undergoing other assisted reproductive technologies?
Critical Biological Systems Approach: Animal Safety Surrogate Dam and Fetus Cell Fusion Through Fetal Development Development of hydrops, normal expulsion of non-viable conceptus, return to cycling, reproductive tract exams Surrogate Dams and Newborn Clones Perinatal Development and Function Birth weight, evidence of hydrops or dystocia, dam’s readiness for delivery, onset of lactation and mothering behavior, newborn organ function and IgG levels Juvenile Clones Juvenile Development and Function Growth and development, feed intake, activity level, blood clinical chemistry, heart and lung function, disease incidence Breeding Clones Adult Clones Reproductive Development And Function Post-Pubertal Maturation Onset of puberty, estrous cycling and behavior, breeding soundness, sperm motility and morphology, reproductive tract exams, hormone profiles, breeding success, delivery of healthy offspring Growth to maturity, gait, activity level, blood clinical chemistry, heart and lung function Progeny
Overview • Surrogate Dams of Clones • Neonatal Clones • Juvenile to Prepuberty Clones • Puberty through Reproductive Maturity • Maturity and Aging • Progeny of Clones
Cattle and sheep: • Studies indicate increased risk of mid- to late- gestational complications • Hydrops (edema of fetus or fetal membranes) • Dystocia (difficulty giving birth) • Other complications
Hydrops • A collective term referring to excessive build-up of fluids in fetus or fetal membranes • May be detected as early as the sixth month of pregnancy in cattle (clone producers)
Hydrops (continued) • Degree varies from mild to severe (clone producers) • Severe hydrops - death of the dam and/or fetus (Heyman et al. 2002) • Incidence highly variable among laboratories • Data indicate risk higher in clone pregnancies vs. IVF (Pace et al. 2002 (some transgenic; 30/178), clone producers (~1/300))
Dystocia • Causes: • fetal oversize compared to pelvic opening • malpresentation of the fetus • multiple fetuses presenting simultaneously • Also in conventionally bred animals bearing single, large fetus (Lucy 2001, Dwyer 2003)
Dystocia in Clone Pregnancies • Often result from fetal oversize (i.e. Large Offspring Syndrome) • May cause damage to the reproductive tract and musculo-skeletal system • Incidence varies with LOS, management decisions (clone producers)
Less Frequent Complications • Also observed in cattle and sheep surrogate dams (Hammer et al. 2001, Wells et al. 1998 & 1999, Ptak et al. 2002): • Poor or absent mammary development • Absent or atypical signs of labor (uterine inertia) • Agalactia (failure to lactate) • Impaired maternal behavior Frequency of these anomalies were not reported
Goats and Swine • No reported complications in surrogate goats • No reports of hydrops or LOS in either species • Some reports indicate lack of mammary development, agalactia, uterine inertia in swine (Carter et al. 2002 (transgenic), clone producers)(Frequency not reported)
Cattle and Sheep • Large Offspring Syndrome (LOS) • Reported in IVF, BNT, SCNT-derived cattle and sheep (Kruip and de Daas 1997, Knight et al. 2001, Chavatte-Palmer et al 2002, Ptak et al. 2002): • Fetus or newborn >20% above average weight • Respiratory complications • Internal organ defects (heart and kidney) • Musculo-skeletal defects • Poor or absent suckle reflex
LOS (continued) • Increases risk of dystocia • Dystocia - stress neonatal calf or lamb, increase risk of mortality and morbidity (Moore et al. 2002, Kato et al. 1998): • Premature separation of placenta • Inhalation of amniotic fluid - respiratory complications
LOS continued • Some complications reversible, depending on severity • Incidence variable among labs for SCNT (8 to 50%) (Miyashita et al. 2002, Kato et al. 2000) • LOS in IVF calves 7 to 31% (Hasler et al. 1995, Kruip and den Daas 1997)
Neonatal Survival • Critical survival period first 48 hours (Cyagra) • Neonatal death rate ~ 20% in clone cattle (Pace et al. 2002 (some transgenic), Cyagra) • Death rate in early IVF cattle studies 14 to 16% (Hasler et al. 1995, Kruip and den Daas 1997)
Neonatal Goats and Swine • Two reports of neonatal mortality in goat clones (Keefer et al. 2001 (1/6), Keefer et al. 2002 (2/9)) • Few reports of complications in neonatal swine clones • Low birth-weight (Polejaeva et al. 2000, Walker et al. 2002) (actual frequency not reported) • One report of physical deformity (anal atresia) in non-transgenic clone pig (1/28) (Walker et al. 2002)
Juvenile Clones • Most reports indicate normal growth and development following the neonatal period • Behavioral studies in cattle and swine note no abnormalities (Savage et al. 2003, Archer et al. 2003) • Results of blood tests indicate cattle and swine in this age group are mostly within the range of conventionally bred animals of the same age (Cyagra, Archer et al. 2003; Chavatte-Palmer et al. 2002, Kato et al. 2000)
Juvenile Cattle • A few individual animals reported to have health problems which may stem from LOS (Cyagra, n=134) • Non-resolving musculo-skeletal (2) • Failure to thrive (1) • Umbilical surgeries (29) • GI tract problems (2) • Heart abnormalities (1) Some of these animals had more than one anomaly
Juvenile Goats and Swine • One report of respiratory infections in growing goat clones (2/6)(Keefer et al. 2001) • One report of hyperkeratosis in a swine clone (1/9)(Archer et al. 2003)
Other Complications • Cryptorchidism (3/134) (Cyagra)(all from one cell line) • Dwarfism (1/134) (Cyagra) • Hyperkeratosis (Archer et al. 2003) (1/9) Cryptorichidism and dwarfism may be related to genetics of nuclear donor Hyperkeratosis (dermatitis vegetans) rarely a recessive gene
Pubertal Cattle • No health problems noted; blood chemistries normal (Cyagra) • Most reports indicate heifers reach puberty, conceive and deliver healthy calves (Lanza et al. 2001 (transgenic), Pace et al. 2002 (some transgenic), Enright et al. 2002) • One report of clone heifers achieving puberty slightly later than controls, but within the normal range for their breed (actual frequency not reported) (Enright et al. 2002) • No detailed information on bulls (Forsburg et al. 2002, Kato et al. 2000, Kubota et al. 2000)
Other Species • One report each on fertility of ram and buck clones, indicating normal age at puberty, fertility, and sperm quality (Wells et al. 1998, Gauthier et al. 2001) • One report of goat doe clones conceiving and delivering normal offspring (Reggio et al. 2001) • No reports on reproduction in swine clones
Maturity and Aging • Insufficient time to evaluate aging in farm animal species • Aging study in mice observed shorter lifespans, increased health problems (Ogonuki et al. 2002) • Studies of telomeres conflicting; not good predictor of lifespan (Betts et al. 2001, Lanza et al. 2000, Tian et al. 2000, Miyashita et al. 2002, Kubota et al. 2000)
Offspring of Clones • Several cursory reports state offspring are “normal and healthy” • No details available in farm animal species • Reports from mice indicate offspring do not inherit clone-associated abnormalities of parents (Shimazowa et al. 2002, Tamashiro et al. 2002)
Cattle and Sheep: • Critical period: late gestation - first post-natal days (surrogate dams and clones) • Risk of perinatal morbidity and mortality higher in clone pregnancies compared to other ARTs • Most clones that survive perinatal period appear healthy and similar to conventional counterparts • No abnormalities reported in offspring
Swine • A few reports of complications in surrogate sows • One report of deformity in a clone pig • Anal atresia also noted in conventionally bred swine • No reports on reproductive maturity of clones or health of offspring
Goats • No complications noted for surrogate does carrying goat clones • Very few health problems noted in goat clones • Two deaths during labor, three deaths due to respiratory infection • Appear to mature normally and produce healthy offspring
Overall Conclusions • No qualitative differences from other ARTs or natural breeding • Frequency of anomalies increased even relative to IVF • Adverse outcomes observed more frequently in cattle and sheep than swine and goats
VMAC Question Question 1: Based on what we have presented, has the risk assessment adequately identified the hazards and characterized the risks relating to animal health?