Fertility of Transgenic Female Mice Expressing Bovine Growth Hormone or Human Growth Hormone Variant Genes1

Abstract

Although growth hormone (GH) exerts various direct and indirect stimulatory effects on gonadal development and function, excessive levels of GH in acromegalic patients and in transgenic animals are often associated with reproductive disorders. We have examined reproductive performance of transgenic female mice expressing the following hybrid genes: mouse metallothionein-1 (MT)/human placental GH variant (hGH.V), MT/bovine GH(bGH), and phosphoenolpyruvate carboxykinase (PEPCK)/bGH. This allowed us to evaluate the effects of chronic GH excess in three animal models and to obtain some information on the significance of the lactogenic activity of the foreign GH (hGH.V vs. bGH) and on the developmental stage of transgene expression (MT vs. PEPCK). Transgenic animals from each line had elevated plasma insulin-like growth factor-I levels and greatly increased adult body weight. Plasma bGH levels were significantly higher in PEPCK/bGH than in MT/bGH transgenic mice. Approximately 20% of transgenic MT/hGH.V and MT/bGH females and over 60% of transgenic PEPCK/bGH females were infertile. Transgenic females that did reproduce ovulated either a normal or increased number of eggs but exhibited a variety of reproductive disorders including increased interval between pairing with a male and conception, increased interval between litters, reduced number of litters, reduced fetal growth, increased pre- and postnatal mortality, and alterations in sex ratio. Among adult offspring of these females, the proportion of transgenic animals was significantly less than the expected 50%. While some characteristics (e.g., fetal crown-rump length and weight on Day 14 of pregnancy) were affected to a comparable extent in transgenic females from all three lines, MT/hGH.V and PEPCK/bGH females were, in general, more severely affected than the MT/bGH animals. Sterility of PEPCK/bGH females appeared to be due to luteal failure since treatment with progesterone led to pregnancy. Greatly increased intervals between successive litters appeared to be due to failure to mate during postpartum estrus and to sterile matings during this period. Reduced fetal size and weight may have been due to chronic glucocorticoid excess because comparable changes could be induced in normal females by injections of dexamethasone during pregnancy, and plasma corticosterone levels were previously shown to be elevated in transgenic mice from each of these lines. Comparison of these results with data obtained from matings of normal female mice to transgenic males from the same lines suggests that reduced fetal growth is due primarily to maternal genotype, while reduced "transmission" of the hybrid genes is not, and presumably reflects increased mortality of transgenic progeny at various stages of development.(ABSTRACT TRUNCATED AT 400 WORDS)

Mitochondrial oxidant generation and oxidative damage in Ames dwarf and GH transgenic mice

“…In sharp contrast, mice overexpressing G H live significantly shortened lives, exhibit increased indices of free radical processes (66), decreased antioxidative defenses (14,67), signs of accelerated aging including reduced replicative potential of cells in vitro (75), and signs of premature central nervous system aging including reduced catecholamine turnover, increased astrogliosis, and impaired learning and memory (19,76,77). In addition, these animals typically reach sexual maturation earlier and cessation of reproduction sooner than wild type siblings (21,78). According to Kajiura and Rollo (79), the increased rate of physiological decline in mice overexpressing GH maybe due to a disproportional allocation of energy towards growth versus repair mechanisms, reproduction and behavioral activities.…”

Hormonal regulation of longevity in mammals

“…These mice have high circulating GH levels and live half as long (12 months) as wild type siblings (Steger et al, 1993). Female GH transgenic mice exhibit early puberty and increased ovulation rates; however, fertility is reduced and the reproductive life span is severely shortened when compared to wild-type mice (degree of suppression appears to depend on level of circulating GH; Naar et al, 1991;Bartke et al, 1994;Cecim et al, 1995). Male mice with elevated GH levels are fertile, but exhibit alterations in sexual behavior, reproductive pituitary hormone secretion, and a reduced reproductive life span (Chandrashekar et al, 1988;Meliska et al, 1997).…”

Transgenic strategies in reproductive endocrinology

“…Coincident with the increased growth, infertility or subfertility (i.e., less successful matings, gestational failure, etc.) have frequently been observed (Hammer et al, 1984;Morello et al, 1986;Bartke et al, 1988;Purse1 et al, 1989;Bchini et al, 1991;Naar et al, 1991). The nature of the cause(s) of the subiinfertility is not well understood.…”

“…The nature of the cause(s) of the subiinfertility is not well understood. Naar et al (1991) reported varying degrees of impairment of female reproductive functions in mice transgenic for three different GH fusion genes. The highest degree of infertility (65%) was observed in mice expressing a phosphoenolpyruvate carboxykinase-bovine GH (PEPCK-bGH) gene in which plasma levels of bGH were >ZOO ng/ml.…”