Regulation of myostatin expression is associated with growth and muscle development in commercial broiler and DMC muscle

Myostatin is a negative regulator of skeletal muscle growth. Muscle tissue is the largest tissue in the body and influences body growth. Commercial Avian broiler chickens are selected for high growth rate and muscularity. Daweishan mini chickens are a slow growing small-sized chicken breed. We investigated the relations between muscle (breast and leg) myostatin mRNA expression and body and muscle growth. Twenty chickens per breed were slaughtered at 0, 30, 60, 90, 120, and 150 days of age. Body and muscle weights were higher at all times in Avian chickens. Breast muscle myostatin expression was higher in Avian chickens than in Daweishan mini chickens at day 30. Myostatin expression peaked at day 60 in Daweishan mini chickens and expression remained higher in breast muscle. Daweishan mini chickens myostatin expression correlated positively with carcass weight, breast and leg muscle weight from day 0 to 60, and correlated negatively with body weight from day 90 to 150, while myostatin expression in Avian chickens was negatively correlated with carcass and muscle weight from day 90 to 150. The results suggest that myostatin expression is related to regulation of body growth and muscle development, with two different regulatory mechanisms that switch between days 30 and 60.     

Sexual maturation and morphological development of the reproductive tract in large white and prolific Chinese Meishan pigs

Body weight of Large White gilts was greater at birth, weaning, 5 months of age and at slaughter; however, Meishan gilts reached puberty at an earlier age (91 +/- 2 vs 192 +/- 3 days, P less than 0.01), had longer periods of oestrus (60 +/- 2 vs 49 +/- 2 h, P less than 0.01) and experienced more oestrous cycles (7 +/- 0.4 vs 4 +/- 0.4, P less than 0.01) before slaughter. The interoestrous interval was longer (P less than 0.01) for Large White gilts (19.8 +/- 0.2 vs 19.1 +/- 0.2 days). At slaughter, uterine length (P less than 0.05), uterine weight, width of uterine horns, endometrial surface area, endometrial weight and percentage of uterine weight represented by endometrium was greater (P less than 0.01) for Large White gilts. However, breed differences were not significant when slaughter weight was included in analyses as a covariate. This indicated that development of the reproductive tract was proportionate to body weight at slaughter for each breed. When body weight at slaughter was included as a covariate, effects of day of the oestrous cycle and pregnancy on uterine width, uterine weight, endometrial surface area and endometrial weight were detected (P less than 0.01) and for uterine length there was a day-by-status interaction (P less than 0.01). Total number of CL (P less than 0.05) and total ovarian weight (P less than 0.05) were also greater for Large White gilts independent of body weight at slaughter. There were more CL in left ovaries for Meishan (8.1 +/- 0.4 vs 6.6 +/- 0.4) and Large White (8.4 +/- 0.4 vs 7.9 +/- 0.5) gilts.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of major histocompatibility complex on reproduction and production traits in swine

The effects of the swine lymphocyte antigen (SLA) system on different performance traits were investigated in Swiss pig breeds. Litter size and piglet weight at birth and at weaning were considered and in gilts the average daily weight gain, backfat and muscle thickness as well as percentage valuable cuts were measured. These data were analysed with least squares procedures. Although the effect of SLA on these traits was very small, a few haplotypes seemed to have some influence. Sows of the Large White breed carrying H12 had a significant smaller and those with H24 had a bigger litter size at weaning. Some mating studies were performed to investigate the effects of SLA homozygosity. The obtained results suggest that this has a negative effect on the litter size, especially when H19 in the Large White breed and H7 in Landrace are involved.     

The Dutch-Belted rabbit: an alternative breed for developmental toxicity testing

BACKGROUND: Historical control data play a crucial role in the interpretation of observations made from developmental and reproductive toxicity studies. METHODS: In our effort to develop the Dutch‐Belted rabbit as an alternative breed of rabbit for testing of small molecule pharmaceuticals, data collected from 236 untreated pregnant Dutch Belted rabbits are summarized and compared to data collected from 350 untreated pregnant New Zealand White Rabbits. RESULTS: The data presented include mean maternal body weight and food consumption values, mean maternal hematological and serum biochemical values collected during gestation, maternal reproductive (laparotomy) parameters collected at cesarean section, and incidences of spontaneous fetal morphological alterations collected during 1999–2002. Due to their smaller size the use of this breed of rabbit would require approximately 40% less drug than studies conducted with New Zealand White rabbits. Because the Dutch‐Belted rabbit is pigmented this breed also offers the ability to test the potential effects of various xenobiotics on melanocyte development and to evaluate the potential sequela of drugs that have a propensity to bind melanin in the skin and pigmented retinal epithelium. CONCLUSIONS: Based on these data, the Dutch‐Belted rabbit is considered to be a practical alternative to use of the New Zealand White rabbit for these types of studies. Birth Defects Res B 68:439–448, 2003. © 2003 Wiley‐Liss, Inc.     

Genetic diversity among chicken breeds estimated through randomly amplified polymorphic DNA.

The randomly amplified polymorphic DNA (RAPD) markers were used to detect polymorphism among five breeds of chicken i.e. White Leghorn and Rhodes Island Red (selected for part period egg production and egg mass respectively), Red Cornish and White Plymouth Rock (selected for early body weights) and Kadaknath (native breed). Twelve of the fifty random primers screened yielded distinct polymorphic RAPD profiles. Of the total 96 fragments amplified, about 25% showed polymorphism. Using the RAPD data matrix, the within population and between population genetic similarity was estimated. The selected improved breeds showed higher within population genetic similarity in comparison to the native breed. The two meat type breeds showed a high level of genetic similarity between themselves. The White Leghorn breed showed a low genetic similarity with other breeds. The native breed showed highest similarity with Rhodes Island Red. The dendogram was constructed to show phylogenetic relationship among these breeds. As expected, the genetic distances were lowest within similar type breeds and were highest between dissimilar type breeds. The results indicated the effectiveness of RAPD in detecting polymorphism between chicken populations and their applicability in population studies and establishing genetic relationships among the chicken populations.     

Variation in body condition of breeding Savi’s Warblers Locustella luscinioides: the reproductive stress and flight adaptation hypothesis revisited

Current theory suggests that mass change in adult birds while breeding may be adaptive (to reduce wing-loading during nestling feeding) or result from physiological stress. To test which might be more important in determining mass loss in breeding Savi’s Warblers (Locustella luscinioides), we used a new approach in which the variation in four indices of body condition was described: weight, fat score, muscle score and lean weight (i.e. excluding fat and muscle). We expected weight variations to be adaptive if they involved changes in fat and lean weight, whereas physiological stress should influence the muscle score to a greater extent. As in other species, females showed a greater variation in weight, and carried more fat, than males during the breeding cycle. During incubation, females had greater weight and fat score than males. The weight remained constant and lean weight declined in both sexes, whereas females increased in muscle, which probably reflects the regression of the reproductive organs. During the nestling stage, both sexes declined significantly in all four indices of condition, showing evidence of physiological stress. However, the greater decline in weight in females than in males is consistent with the flight-adaptation hypothesis, as are the cyclic changes in lean weight associated with the various nesting attempts. The fact that both sexes declined significantly in weight, muscle and lean weight with an increasing number of nesting attempts, but not in fat, which was recovered after each nestling period, also indicates that both reproductive stress and adaptive changes occur during breeding. When the whole breeding season was considered, females showed a greater decline in muscle than males, which we interpret to be evidence for a greater reproductive stress in females. We suggest that the small breast muscle size and depleted protein reserves at the end of the breeding period might influence future survival through impaired flight ability and a compromised post-breeding moult.     

Determination of tamoxifen and metabolites in serum by capillary electrophoresis using a nonaqueous buffer system

Tamoxifen (TAM), an antiestrogen, is widely used to treat hormone-dependent breast cancer in post-menopausal women. TAM may be used as a chemopreventive agent in women of child-bearing age; however, few data exist describing potential TAM-induced fetal toxicity. In support of the National Toxicology Program's characterization of reproductive and developmental effects of TAM, this work describes an analytical technique utilizing capillary electrophoresis (CE) for the detection of circulating levels of TAM, N-desmethyltamoxifen (DMT), and 4-hydroxytamoxifen (4-HT) in maternal rodent serum. Greater than 90% of ³H-labeled TAM was extractable from serum using 98:2 hexane–isoamyl alcohol. Optimum separation of TAM, DMT, and 4-HT was obtained on a 57 cm×50 μm capillary using a nonaqueous buffer system of 1:1 methanol–acetonitrile containing 50 mM ammonium acetate and 1% acetic acid. 4-Dimethylaminopyridine was used as internal standard. Temperature and voltage were optimized at 40°C and 15 kV, respectively. The limit of detection of TAM by UV detection at 214 nm was approximately 800 amol. TAM and DMT were confirmed in serum of female rats 4 h following a single oral dose of 120 mg/kg. Transplacental exposure of TAM to fetal tissue will be evaluated using this technique.     

Genetic polymorphisms of proteins in different breeds and different populations of chickens

Six polymorphic protein systems in 15 chicken breeds have been investigated. In the Silkie breed another variant of G3 proteins (G₃ A^F Silkie) has been observed characterized by higher electrophoretic mobility than G₃ A. The frequencies of individual alleles in various lines and different generations have been determined in two breeds (White Leghorn and White Cornish).     

Structure of skeletal muscles in leghorn type chicken from conservative and parent flocks

Intensive selection conducted within closed populations has led to the creation of specialized chicken strains that differ significantly in meat yield and reproduction performance. The effect of the selection conducted on the birds is differentiation identified not only on the molecular but also on the cellular level, among other things in the skeletal muscles. The aim of this study was to compare the structure of chosen homological skeletal muscles from Leghorn chickens (LSL), originating from parent flock, intensively selected for reproductive traits and from conservative flock (G99), unselected for many generations. The structure of musculus pectoralis superficialis and musculus biceps femoris (the thickness of the muscle fibres and the share of the fibre types in the bundle) in 8 and 20 week old chickens was compared. A significant impact of the origin on all examined slaughter parameters was recorded. Body weight before slaughter, carcass weight and the weight of breast and leg muscles in 8 weeks old LSL chicken made up from 60% to about 85% of the respective values in the G99 Leghorn. Lack of red fibres in the breast muscles of all the individuals from the parental flock (LSL) was noted, whereas in 12 individuals (among 24) from the conservative flock (G99), red fibres were observed in this muscle from 2.75% up to 7.09%. White fibres in 8 week old chicks were always thicker, both in pectoralis superficialis and biceps femoris muscle in birds with higher body weight as well as higher weight of breast and legs muscles, i.e. in chicks from conservative flock (G99), P<0.01. However, in 20 week old birds, the diameters of the white fibres were similar in both groups. Also the diameters of the red fibres in musculus biceps femoris in 8 week old chickens were higher in cockerels and pullets from conservative flock (G99).     

Understanding the low breeding success in Greater Rheas populations through an energy budget model

We propose an individual-based energy budget model of the Greater Rhea (Rhea americana) with the purpose of analyzing the population's recruitment. One remarkable characteristic of this species is that female rheas lay eggs communally and males incubate the eggs and care for the chicks without the assistance of females.The model is based on a system of equations daily updating the weight of each bird as a function of its ingestion rate and the energetic cost of its activity pattern. Ingestion rate is calculated from field experiments. Daily energetic costs are estimated from activity patterns observed in the field, taking into account gender and factors that influence behavior (e.g., photoperiod, season). Concatenating daily model outputs, the weight dynamics of an individual can be calculated over any given period of time.The possible factors that affect the successful breeding of the Greater Rhea and therefore population growth are analyzed using the model. Different reproductive strategies for each gender are analyzed and the minimal body weight, and thus energy reserves, that an individual needs to achieve for ensuring reproductive success is determined. Model outputs show that the reproductive success of males depends strongly on their body weight while females exhibit low nutritional requirements for producing eggs. An analysis of model outputs allows inferring that males in wild populations might not be able to breed in consecutive years but could successfully breed every other year. They also allow estimating the incidence that food availability has on population growth. Management strategies that are easy to implement in extensive and semi-extensive farms may allow obtaining male individuals capable of breeding every year.     

Subgroup-A Rous sarcoma virus-induced growth stimulation of chick embryos infected via the chorioallantoic membrane.

Chicks that hatch from eggs containing group specific antigen (gs antigen) of lymphoid leukosis virus (LLV) subgroups, grow poorly. In our laboratory for more precise identification of LLV-of subgroup A (LLV-A) resistant and susceptible genotypes by progeny testing, the chorioallantoic membrane (CAM) assay in complemented by liver tumour (LT) assay, wherein Rous sarcoma virus (RSV) of subgroup A (homologous to LLV-A) was used. The present study was conducted in a light breed (White Leghorn) and also in a heavy breed (Rhode Island Red) to ascertain the effect of infection on embryonic growth by RSV subgroup A. Mean relative body weight (rbw) of infected LT negative chicks of either breed exceeded the control highly significantly (P < 0.01) by 2%. However, neither the dose of virus inoculated per embryo, nor egg size influenced the relative body weight of day old chicks (P > 0.05). No difference in relative body weight of LT positive and control chicks was observed.     

Interaction of sesame seed and tamoxifen on tumor growth and bone health in athymic mice

Some premenopausal breast cancer patients use phytoestrogen-rich soy and flaxseed to alleviate side effects induced by drugs such as tamoxifen (TAM). Lignan-rich flaxseed protects against breast cancer and increases the effectiveness of TAM. This study determined the interactive effects of lignan-rich sesame seed (SS) and TAM on estrogen-responsive MCF-7 breast tumor growth and bone health in ovariectomized athymic mice under premenopausal-simulated conditions. Ovariectomized mice with an estrogen implant and established MCF-7 tumors were treated for 8 weeks as follows: (i) positive control fed basal diet (BD), (ii) SS group fed BD supplemented with 10% ground SS, (iii) TAM group with TAM implant fed BD, (iv) SS + TAM group with TAM implant fed BD supplemented with 10% SS, and (v) negative control fed BD with no estrogen implant. Palpable tumor data, adjusted for body weight, showed that SS does not inhibit MCF-7 tumor growth and tends to negate the tumor inhibitory effect of TAM by increasing cell proliferation and reducing apoptosis. SS alone and combined with TAM enhanced femur biomechanical strength but caused no differences in bone mineral content or bone mineral density in either the femur or lumbar vertebrae. SS is not protective and interacts adversely with TAM in MCF-7 breast tumors but induces beneficial effects on bone both alone and when combined with TAM.     

Nutrition‐ and sex‐dependent utilization of body resources in relation to reproduction in a scorpionfly

Reproduction often comes at a cost of a reduction in body functions. In order to enhance their reproductive output, some insect species degenerate their thoracic muscles, typically resulting in reduced flight ability. From a life‐history trade‐off perspective, we expect the importance of body resource utilization to be amplified both with increased reproductive expenditure and with increased resource limitation. In this study, we measured age‐related changes in thorax weight, as a measure of flight muscle size, during a major part of the adult lifespan in males and females of the scorpionfly Panorpa vulgaris. The aim of the study was twofold: first to investigate whether scorpionflies have the potential to degenerate their flight muscles; second, and more importantly, to determine whether the magnitude of flight muscle degeneration is a plastic response in relation to resource availability, and if it differs between the sexes. The results clearly demonstrate that food availability does influence investment in flight muscle development. The build‐up of the thoracic muscles was strongly influenced by nutrient availability. Furthermore, the age‐related decrease in thorax weight was significantly different for males and females. Only females showed a strong age‐dependent decrease in thorax weight, indicative of muscle degeneration, yet no difference between food treatments was detected. For males, there was no significant directional change in thorax weight. Nevertheless, with increasing age, the difference in thorax weight between food treatments increased significantly. © 2010 The Linnean Society of London, Biological Journal of the Linnean Society, 2011, 102 , 199–207.     

Sex and Breed-Dependent Organ Development and Metabolic Responses in Foetuses from Lean and Obese/Leptin Resistant Swine

The present study aimed to determine the effects of breed and sex on growth patterns and metabolic features of advanced-pregnancy foetuses exposed to the same environmental conditions. Thus, at Day 62 of pregnancy, swine foetuses from an obese breed with leptin resistance (Iberian breed) were compared to lean crossbred foetuses (25% Large White ×25% Landrace ×50% Pietrain). There were differential developmental patterns in foetuses with leptin resistance, mainly a higher relative weight of the brain resembling “brain-sparing effect”. Prioritization of brain growth may be protective for the adequate growth and postnatal survival of the Iberian individuals, an ancient breed reared in extensive semi-feral conditions for centuries. There were also clear sex-related differences in foetal development and metabolism in the Iberian breed. Female Iberian foetuses were similar in size and weight to male littermates but had a significantly higher relative liver to body weight ratio resembling “liver-sparing effect” and a trend for a higher relative intestine to body ratio. Moreover, the availability of triglycerides, cholesterol and IL-6 in female Iberian foetuses was similar to that of lean crossbred foetuses. Overall, these features may favour a better postnatal survival and development of females, the sex more critical for the species survival. These findings set the basis for future translational studies aimed at increasing the knowledge on the interaction between genetic and environmental factors in the early programming of the adult phenotype.     

Hormonal correlates of dominance in meerkats (Suricata suricatta)

In cooperatively breeding meerkats (Suricata suricatta), individuals typically live in extended family groups in which the dominant male and female are the primary reproductives, while their offspring delay dispersal, seldom breed, and contribute to the care of subsequent litters. Here we investigate hormonal differences between dominants and subordinates by comparing plasma levels of luteinizing hormone (LH), estradiol and cortisol in females, and testosterone and cortisol in males, while controlling for potential confounding factors. In both sexes, hormone levels are correlated with age. In females, levels of sex hormone also vary with body weight and access to unrelated breeding partners in the same group: subordinates in groups containing unrelated males have higher levels of LH and estradiol than those in groups containing related males only. When these effects are controlled, there are no rank-related differences in circulating levels of LH among females or testosterone among males. However, dominant females show higher levels of circulating estradiol than subordinates. Dominant males and females also have significantly higher cortisol levels than subordinates. Hence, we found no evidence that the lower levels of plasma estradiol in subordinate females were associated with high levels of glucocorticoids. These results indicate that future studies need to control for the potentially confounding effects of age, body weight, and access to unrelated breeding partners before concluding that there are fundamental physiological differences between dominant and subordinate group members.     

Effects of p-nonylphenol and resveratrol on body and organ weight and in vivo fertility of outbred CD-1 mice

The aim of this study was to analyse the multigenerational effects of para-nonylphenol (NP) and resveratrol (RES) on the body weight, organ weight and reproductive fitness of outbred CD-1 mice. The data indicate that in male mice, NP had an effect on the weight of selected reproductive organs and the kidneys in the parental (P) generation males. Effects on selected reproductive organs, the liver and kidneys in the F1-generation males were also seen. In females, effects of NP on body weight and kidney weight were seen in the P generation, but no effects on any measured parameter were seen in the F1 generation. RES had no effect on body weight but did have some effect on selected male and female reproductive organs in the P generation. RES altered the spleen and liver weights of P-generation males and the kidney weight of F1-generation males. Acrosomal integrity (using a monoclonal antibody against intra-acrosomal sperm proteins) was assessed for both generations of NP- and RES-treated mice. A significant reduction in acrosomal integrity was seen in both generations of NP-treated, but not in RES-treated, mice. Fewer offspring were observed in the second litter of the F2 generation of mice treated with NP; no similar effect was seen in RES-treated mice. The litter sex ratio was not different from controls. Unlike RES, NP had a negative effect on spermatogenesis and sperm quality with a resultant impact on in vivo fertility.     

Does the chicken genotype ‘Géline de Touraine’ have specific carcass and meat characteristics?

The aim of this study was to determine the specific characteristics of carcass and meat from an old French chicken breed, the ‘Géline de Touraine’ (GT), characterised by a very slow-growing rate and usually slaughtered at 120 days of age. For this purpose, we compared the GT with an experimental crossbreed (EC) exhibiting the same growth rate, and with a ‘Label rouge’ (LR) genotype usually slaughtered at 84 days of age. A total of 250 males and 250 females per genotype were reared by separating sexes and genotypes. The growth performances were recorded. At 84 days of age, 80 birds per sex and per genotype were slaughtered. The frequency of clawing and pecking injuries on the carcass was noted. We also measured the skin colour and the thickness of wing membrane. The relative percentages of carcass, breast, thigh + drumstick, abdominal fat, testis or ovary to body weight were determined. On breast and thigh muscles the ultimate pH (pHu) and colour were measured. The juice loss after 3 days’ storage at +4°C and after cooking at 85°C, and the shear force value of Warner–Bratzler were only measured on breast muscles. At 120 days of age, we repeated the same measurements but only on EC and GT genotypes in order to compare birds at the same age or at the respective slaughter age for each production. Whatever the slaughter age, the body weight of males was always higher than that of the females but the carcass yield was similar for both sexes. The females had higher breast yield and carcass fatness but lower thigh + drumstick yield than the males. The yellowness of skin and meat was higher for the females than for the males while the contrary was observed for the redness of the meat. The breast meat of the females also had higher cooking loss than that of the males. GT and EC birds exhibited a higher occurrence of carcass defects and a higher pHu in meat than LR birds. The GT chickens were characterised by a lower breast yield, a higher fattiness and an earlier sexual maturity than the other genotypes, which could confer typical sensorial attributes to their meat. Finally, the EC chickens exhibited a skin and a meat more coloured than the other genotypes, particularly for yellowness, a character which could be under genetic control.     

Costly reproductive competition between females in a monogamous cooperatively breeding bird

In many cooperatively breeding societies, only a few socially dominant individuals in a group breed, reproductive skew is high, and reproductive conflict is common. Surprisingly, the effects of this conflict on dominant reproductive success in vertebrate societies have rarely been investigated, especially in high-skew societies. We examine how subordinate female competition for breeding opportunities affects the reproductive success of dominant females in a monogamous cooperatively breeding bird, the Southern pied babbler (Turdoides bicolor). In this species, successful subordinate reproduction is very rare, despite the fact that groups commonly contain sexually mature female subordinates that could mate with unrelated group males. However, we show that subordinate females compete with dominant females to breed, and do so far more often than expected, based on the infrequency of their success. Attempts by subordinates to obtain a share of breeding impose significant costs on dominant females: chicks fledge from fewer nests, more nests are abandoned before incubation begins, and more eggs are lost. Dominant females appear to attempt to reduce these costs by aggressively suppressing potentially competitive subordinate females. This empirical evidence provides rare insight into the nature of the conflicts between females and the resultant costs to reproductive success in cooperatively breeding societies.     

Sex‐specific reproductive investment of summer spawners of Illex argentinus in the southwest Atlantic

Energy investment in reproduction and somatic growth was investigated for summer spawners of the Argentinean shortfin squid Illex argentinus in the southwest Atlantic Ocean. Sampled squids were examined for morphometry and intensity of feeding behavior associated with reproductive maturation. Residuals generated from length‐weight relationships were analyzed to determine patterns of energy allocation between somatic and reproductive growth. Both females and males showed similar rates of increase for eviscerated body mass and digestive gland mass relative to mantle length, but the rate of increase for total reproductive organ weight relative to mantle length in females was three times that of males. For females, condition of somatic tissues deteriorated until the mature stage, but somatic condition improved after the onset of maturity. In males, there was no correlation between somatic condition and phases of reproductive maturity. Reproductive investment decreased as sexual maturation progressed for both females and males, with the lowest investment occurring at the functionally mature stage. Residual analysis indicated that female reproductive development was at the expense of body muscle growth during the immature and maturing stages, but energy invested in reproduction after onset of maturity was probably met by food intake. However, in males both reproductive maturation and somatic growth proceeded concurrently so that energy allocated to reproduction was related to food intake throughout the process of maturation. For both males and females, there was little evidence of trade‐offs between the digestive gland and reproductive growth, as no significant correlation was found between dorsal mantle length‐digestive gland weight residuals. The role of the digestive gland as an energy reserve for gonadal growth should be reconsidered. Additionally, feeding intensity by both males and females decreased after the onset of sexual maturity, but feeding never stopped completely, even during spawning.     

Pre- and postnatal development studies of lasofoxifene, a selective estrogen receptor modulator (SERM), in Sprague-Dawley rats

BACKGROUND: Lasofoxifene is a nonsteroidal selective estrogen receptor modulator (SERM) developed for the treatment of postmenopausal osteoporosis. The purpose of these studies was to evaluate the effects of lasofoxifene on the postnatal development, behavior, and reproductive performance of offspring of female rats given lasofoxifene during organogenesis and lactation. METHODS: Two range-finding studies were conducted to determine the effects of lasofoxifene at doses from 0.01-10 mg/kg on parturition and lactation in pregnant rats and on the early postnatal development of the offspring, and to optimize the dosing regimen. Maternal milk and plasma were sampled for concentrations of lasofoxifene on Lactation Days 4, 7, and 14. In the pre- and postnatal development study, lasofoxifene was administered to pregnant and lactating rats by oral gavage at dose levels of 0.01, 0.03, and 0.1 mg/kg on Gestation Days 6-17 and Lactation Days 1-20. Maternal body weight and food consumption were measured throughout pregnancy, and body weight was measured throughout lactation. Parturition was monitored closely. The F1 offspring were measured for viability, body weight, anogenital distance, the appearance of postnatal developmental indices and reflex behaviors, sensory function, in an age-appropriate functional observational battery, motor activity, auditory startle, passive avoidance, and the Cincinnati Water Maze. The F1 generation was assessed for reproductive function, and the F2 offspring were measured for body weight and viability throughout the lactation period. RESULTS: In the range-finding studies, indications of maternal toxicity included decreased body weight and food consumption, increased length of gestation, prolonged parturition, dystocia, and increased offspring mortality at birth. Concentrations of lasofoxifene in maternal plasma were similar to those in milk, increased with increasing dose, and remained consistent over a 10-day period. In the pre- and postnatal development study, maternal body weights and food consumption were decreased in all treated groups during gestation. Length of gestation was increased, parturition was prolonged, and dystocia was noted in the dams in the 0.1 mg/kg group. There was increased pup mortality in the F1 litters in the 0.1 mg/kg group and all treated groups had decreased offspring body weights beginning at 1 week of age, continuing into the postweaning period and, for the F1 males, into adulthood. Female F1 offspring in the 0.03 and 0.1 mg/kg groups had increased body weights as adults. There were delays in the age of appearance of preputial separation in the males in the 0.1 mg/kg group and vaginal opening in the females in all treated groups. Body temperature was decreased by <0.5 degrees C after weaning for male and female offspring in the 0.1 mg/kg group. The sensory, behavioral, and functional measures, including the tests of learning and memory, were unaffected by treatment. Mating success was lower for the F1 animals in the 0.1 mg/kg group, but there were no effects on the reproductive parameters. Mating, reproduction, and maternal behavior of the F1 animals in the 0.01 and 0.03 mg/kg groups and the survival and body weights of the F2 offspring in all treated groups through Postnatal Day 21 were unaffected by treatment. CONCLUSION: The maternal findings in this study were related to the pharmacologic activity of lasofoxifene. Inhibition of growth of the F1 offspring after perinatal exposure to lasofoxifene was observed, but there were no significant effects on the sensory, behavioral, or functional measures, including learning and memory. There were no effects on the F2 generation. The findings are consistent with those reported for at least one other SERM. The findings of this study do not suggest increased risk for the primary indication of use in postmenopausal women.