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Biomedical subjects

M Barkley

Publications and source records attributed to M Barkley.

13 recordsLinked to original sources
PubMed2001

Genetic variation in physiological sensitivity to estrogen in mice.

Genetic variation in susceptibility to endocrine disruption by estrogenic agents was examined in juvenile male mice. Mice were implanted with increasing doses of estradiol (E2) at 3 weeks of age and reproductive responses were determined 3 weeks later. Greater than 16-fold differences in susceptibility to the disruption of reproductive development by E2 were detected between strains of mice. CD-1 was much more resistant to the inhibition of testes weight, vesicular gland weight and spermatogenesis by increasing doses of E2. Spermatid maturation was eliminated by low doses of E2 in unselected strains such as C17/Jls and C57BL/6J. In contrast, widely used, large litter size selected CD-1 mice showed little or no inhibition in spermatogenesis even in response to 16-fold higher doses of E2. Testicular sulfotransferase activity (EST) per gram body weight was 3.5-fold higher in untreated CD-1 than in B6 strain males. This suggests that genetic differences in testicular EST activity may play a critical role in the detoxification of estrogens. These and other findings emphasize the need to identify and study genetic variation in sensitivity to estrogen in laboratory animal models used to assess the risk of xenobiotic estrogen exposure.

Animals↗
PubMed2001

Reassessment of models used to test xenobiotics for oestrogenic potency is overdue.

Product safety bioassays need to include data from animals with susceptible genotypes or the potential for environmental compounds to disrupt reproductive development in hormonally sensitive populations may be greatly underestimated. The continued use of resistant animal models is likely to result in allowable releases of toxic levels of oestrogenic agents that could differentially disrupt reproductive development and function of sensitive genotypes, leading to reproductive failure and loss or extinction of susceptible individuals, populations and species. Rather than ignoring the role of genetic differences in susceptibility to oestrogenic agent-induced carcinogenicity and endocrine disruption, government agencies should support efforts to identify the genetic mechanisms involved in these responses, and to screen for and develop strains of mice and rats which are sensitive to the induction of genotoxicity/carcinogenicity as well as the inhibition of reproductive development and function by oestrogenic agents. Such sensitive strains would be even more optimal for testing chemicals for endocrine disruptor activity.

Animals↗
PubMed1999

Genetic variation in susceptibility to endocrine disruption by estrogen in mice.

Large (more than 16-fold) differences in susceptibility to disruption of juvenile male reproductive development by 17beta-estradiol (E2) were detected between strains of mice. Effects of strain, E2 dose, and the interaction of strain and E2 dose on testes weight and spermatogenesis were all highly significant (P < 0.0001). Spermatid maturation was eliminated by low doses of E2 in strains such as C57BL/6J and C17/Jls. In contrast, mice of the widely used CD-1 line, which has been selected for large litter size, showed little or no inhibition of spermatid maturation even in response to 16 times as much E2. Product safety bioassays conducted with animals selected for fecundity may greatly underestimate disruption of male reproductive development by estradiol and environmental estrogenic compounds.

Animals↗
PubMed1999

Genetic control of hormone-induced ovulation rate in mice.

The nature of genetic differences in ovarian responsiveness to gonadotropins was examined in mouse strains and subspecies. Hormone-induced ovulation rate (HIOR) differed 5-fold between Mus musculus strains A/J (10.3 +/- 1.6 eggs in cumulus) and C57BL/6J (B6) (47.3 +/- 2.5 eggs in cumulus), and 6-fold among Mus spretus lines and crosses. Subspecies differed up to 10-fold in HIOR (Mus spretus/Ros: 4.8 +/- 1.0 eggs in cumulus versus B6). An additional experiment examined the genetics of HIOR in crosses. The number of eggs ovulated in response to equine chorionic gonadotropin (CG)/human CG averaged 8.4 +/- 0.9 in A/J, 40.7 +/- 1.7 in B6, 33.9 +/- 1.6 in B6AF1, and 20.2 +/- 0.3 in (B6xA)xA backcrosses. The 5-fold genetic differences in hormone-induced ovulation rate between Mus musculus strains A/J and B6 segregated in backcrosses as though they were controlled by the action of approximately 3 loci with major effects. This study demonstrates genetic variation in HIOR both within and between mouse subspecies, and provides confirmation that genetic differences are a major source of variation in the regulation of ovarian responsiveness to gonadotropins.

Animals↗
PubMed1999

Mapping genes that control hormone-induced ovulation rate in mice.

The present study mapped quantitative trait loci (QTL) that control 6-fold genetic differences in hormone-induced ovulation rate (HIOR) between C57BL/6J (B6) (HIOR = 54) and A/J strain mice (HIOR = 9). (The gene name is Ovulation Rate Induced [ORI] QTL and the gene symbol is Oriq.) QTL linkage analysis was conducted on 167 (B6xA)xA backcross mice at 165 loci. Suggestive B6 ORI QTL that control the number of eggs in cumulus mapped, as follows, near: Cyp19 and D9Mit4 on chromosome (Chr) 9 (Oriq1); D2Mit433 on Chr2 (Oriq2); D6Mit316 on Chr6 (Oriq3); DXMit22 on ChrX (Oriq4) and were associated with a 2.7, 2.7, 2.6, and 4.2 egg increases in HIOR, respectively. Oriq3 was significant (LOD = 3.45) based on composite interval mapping. QTL linkage analysis of the number of eggs matured by endogenous gonadotropins and ovulated by eCG mapped a significant Oriq5 to Chr 10 and suggestive Oriq to Chr 6, 7, and X. These data provide the first molecular genetic markers for reproductive QTL that control major differences in ovarian responsiveness to gonadotropins. These and closely linked syntenic molecular markers will enable a more accurate prediction of ovarian responsiveness to gonadotropins and provide selection criteria for improving reproductive performance in diverse mammalian species.

Animals↗
PubMed1995

Genetic variation in plasma androgens and ovarian aromatase activity during mouse pregnancy.

Genetic variation in fetal survival, maternal plasma androgen levels, and ovarian aromatase activity was examined mid (Day 9) and late gestation (Day 16) in strains of mice that differ in reproductive performance (A/J, C57BL/6J, C8/JIs, C17/JIs, and S15/JIs). At both gestational stages, females selected for large litter size (S15/JIs) carried more fetuses than any of the other strains examined. Particularly at midpregnancy, S15/JIs females also maintained higher plasma levels of androstenedione and testosterone relative to both control strains, C8/JIs and C17/JIs. Consistent with previously reported changes in peripheral estrogen levels during mouse pregnancy, aromatase activity was higher on Day 16 than on Day 9. This study demonstrates genetic variation in fetal survival that is correlated with increased maternal androgen levels. A stage-specific gestational increase in aromatase activity occurs in several strains of mice and is associated with elevated plasma estrogen during the second half of pregnancy.

Androgens↗
PubMed1993

Pheromonal regulation of the mouse estrous cycle by a heterogenotypic male.

The role of male pheromones in estrous cyclicity was studied in mice selected for different reproductive traits. When females are exposed to males of their own strain, estrous cycles are highly regular in females selected for increased embryo survival (line E). In contrast, cycle regularity is reduced by exposure of line E females to males from a strain characterized by irregular estrous cycles (line CN-). To investigate the inhibition of estrous cyclicity and the role of androgen in this phenomenon, line E females were housed in the olfactory presence of E males and later rehoused with one of the following: intact or castrated males of line E (homogenotypic condition) or line CN-heterogenotypic condition) or castrated CN- males provided with testosterone replacement. A final exposure to homogenotypic (line E) males was provided. Estrous cyclicity was decreased when line E females were rehoused with intact or castrated CN- males. Metestrus was prolonged by intact CN- males, whereas diestrus was prolonged in the presence of castrated CN- males. Androgen treatment did not enable castrated CN- males to prolong metestrus. These results demonstrate that: 1) heterogenotypic pheromones inhibit estrous cyclicity in line E; and 2) the inhibitory influence of line CN- males on line E estrous cyclicity is mediated by factors in addition to or other than testosterone.

Animals↗
PubMed1991

Female genotype influences the behavioral performance of mice selected for reproductive traits.

The behavioral performance of mice that differ in regularity of the estrous cycle and litter size was studied after female exposure to a male of the same or a different strain. Emotional reactivity was measured using the pole, straightaway and open field tests. Factor interpretations of emotionality included motor discharge, autonomic imbalance and acrophobia. Mice characterized by regular estrous cycles and large litters (line E) were more explorative and emotionally reactive with respect to motor discharge and autonomic imbalance. In contrast, mice with less regular estrous cycles and small litter size (line CN-) were more acrophobic. These strain differences in behavioral performance were influenced by the genotype of the female rather than the cohabitating male.

Animals↗
PubMed1991

The influence of fetal number on maternal concentrations of progesterone and testosterone in the mouse.

Mice selected for large litters were used to study the relationship between fetal number and maternal progesterone and testosterone concentration. Experimental adjustment of conceptus number demonstrated that the presence of one fetus was sufficient to elevate maternal progesterone concentration above that found in females from which all conceptuses were removed. When one of more fetuses occupied the uterus, maternal progesterone concentration did not increase with increasing conceptus number. In contrast, maternal testosterone concentration was positively correlated with the number of fetal-placental units.

Animals↗
PubMed1990

Evidence for maternal regulation of progesterone production at midpregnancy in the mouse.

Mice with major differences in embryo survival and progesterone secretion were used to study the relative roles of maternal and embryonic genotype in the control of progesterone production at midpregnancy. Reciprocal transfer of embryos from strains with high (Line S1) or low (Line G) embryo survival resulted in progesterone concentrations consistent with maternal genotype in females carrying the same number of fetuses. This suggests that maternal rather than fetal gene expression determines the setpoint for progesterone production during the period of transition from maternal to fetal-placental control of ovarian steroidogenesis.

Animals↗
PubMed1987

Inhibition of prostaglandin biosynthesis by etodolac. I. Selective activities in arthritis.

Etodolac is the first anti-inflammatory drug belonging to the tetrahydropyranoindole class. In contrast to several other common anti-inflammatory drugs, etodolac exhibited an unusually high potency as an inhibitor of established adjuvant arthritis relative to its activity against carrageenan paw edema in the rat. This phenomenon led us to investigate whether the ability of NSAIDs to inhibit prostaglandin biosynthesis differed between cultures of macrophages, which are present in inflammatory exudates, and cultures of synoviocytes and chondrocytes, which contribute to inflammation of the articulating joint. Although other anti-inflammatory drugs were found to be equally active in all three cell types, etodolac was found to be much more effective on the cells of the joint than on the macrophage. This differential activity may be responsible for the striking efficacy of etodolac as an anti-arthritic drug.

Acetates↗
PubMed1980

Urotensin II: a somatostatin-like peptide in the caudal neurosecretory system of fishes.

Urotensin II, a peptide hormone from the caudal neurosecretory system of the teleost, Gillichthys mirabilis, was isolated by using classical chromatographic techniques and high-performance liquid chromatography (HPLC). Direct microtechniques for sequence determination were used to establish its structure. Urotensin II from Gillichthys is a 1363-dalton dodecapeptide with the amino acid sequence Ala-Gly-Thr-Ala-Asp-Cys-Phe-Trp-Lys-Tyr-Cys-Val. This sequence is homologous with somatostatin in positions 1 and 2 and 7-9. The sequence has been verified by the production of a bioactive synthetic urotensin II. The possible chemical and physiological significance of its homology to somatostatin is discussed.

Amino Acid Sequence↗