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Papers by Jeanette Axelsson

BMC …, Jan 1, 2006

Background: Differentiation of the brain during development leads to sexually dimorphic adult rep... more Background: Differentiation of the brain during development leads to sexually dimorphic adult reproductive behavior and other neural sex dimorphisms. Genetic mechanisms independent of steroid hormones produced by the gonads have recently been suggested to partly explain these dimorphisms.

Brain research bulletin, Jan 1, 2005

A number of environmental contaminants have been shown to interfere with the endocrine system. Ma... more A number of environmental contaminants have been shown to interfere with the endocrine system. Many of these compounds bind to estrogen receptors, thereby potentially disrupting estrogen-regulated functions. In this paper, we review some background data on avian sexual differentiation and present some of the results from our studies on effects of estrogenic chemicals administered during sexual differentiation in the Japanese quail. Initially, our goal was to elucidate whether a decreased male sexual behavior in quail is a suitable endpoint for studying long-term effects of exposure to estrogenic compounds during sexual differentiation in ovo. We thereafter tested some environmental pollutants, suspected to act via mimicking estrogens, using the test system developed. Results from our studies on the synthetic estrogens ethinylestradiol and diethylstilbestrol, as well as the environmental pollutants bisphenol A, tetrabromobisphenol A, and o,p'-DDT are reviewed in this paper. We conclude that the Japanese quail is well suited as an animal model for studying various long-term effects after embryonic exposure to estrogenic compounds. Depressed sexual behavior proved to be the most sensitive of the variables studied in males and we find this endpoint appropriate for studying effects of endocrine modulating chemicals in the adult quail following embryonic exposure.

Ecotoxicology, Jan 1, 2003

This mini-review focuses on sexual differentiation of the reproductive organs and the brain in bi... more This mini-review focuses on sexual differentiation of the reproductive organs and the brain in birds and the effects of endocrine modulators on these processes. Sex determination in birds is genetically controlled, but the genetic events implicated are largely unknown. Female birds have one Z and one W sex chromosome, while males have two Z sex chromosomes. It is not clear whether it is the presence of the W chromosome in females, the double dose of the Z chromosome in males vis-aÁ-vis females, or both of these characteristics that are crucial for the determination of sex in birds. Oestradiol directs sexual differentiation in birds during critical periods of development. Consequently, exogenous compounds that interfere with the endogenous oestrogen balance can disrupt sexual differentiation of the reproductive organs and the brain. Therefore, sexual differentiation in birds provides a good model for studying the effects of endocrine modulators at various biological levels from gene expression to behaviour. Some compounds known to be present in the environment can alter endocrine function and have adverse effects when administered during development, resulting in alterations in gonads, accessory sexual organs, and behaviour. Data reviewed in this paper are mostly from laboratory studies on endocrine modulators with oestrogenic activity, whereas evidence for adverse effects of pollutants on sexual differentiation in avian wildlife is scarce.

Journal of …, Jan 1, 2006

Two estrogen receptors (ERs), denoted ERalpha and ERbeta, have been identified in humans and vari... more Two estrogen receptors (ERs), denoted ERalpha and ERbeta, have been identified in humans and various animal species, including the Japanese quail. Estrogens play a key role in sexual differentiation and in activation of sexual behavior in Japanese quail. The distribution of ERalpha in the brain of male and female adult quail has previously been studied using immunohistochemistry, whereas in situ hybridization has been employed to study the distribution of ERbeta mRNA in males only. In this article, we used in situ hybridization to study the distribution of mRNAs for both ERalpha and ERbeta in brain areas controlling sexual behavior of Japanese quail. Our results show that both ERalpha mRNA and ERbeta mRNA are localized in areas important for sexual behavior, such as the preoptic area and associated limbic areas, in both males and females. Moreover, we found differences in distribution of mRNA for the two receptors in these areas. The results of this article support previously reported data and provide novel data on localization of ER mRNAs in adult quail brain of both sexes.

Archives of toxicology, Jan 1, 2005

Embryonic exposure to estrogens and estrogenic pollutants is known to demasculinize sexual behavi... more Embryonic exposure to estrogens and estrogenic pollutants is known to demasculinize sexual behavior in adult male Japanese quail. In the present study, we administered the insecticide methoxychlor to quail eggs at a dose of 150 lg/g egg and then studied sexual behavior and other reproductive variables in adult males. In a second experiment we administered the same dose of methoxychlor together with 10 lg/g egg of the commercial polychlorinated biphenyl (PCB) mixture Clophen A50 (CA50) and also CA50 alone. Neither methoxychlor nor CA50 had any significant effects by themselves, but when they were administered together a significant reduction in male sexual behavior was observed. It seems likely that induction of biotransformation enzymes in the embryos by CA50 resulted in increased conversion of methoxychlor to the more estrogenic metabolite 2,2-bis(p-hydroxyphenyl)-1,1,1trichloroethane (HPTE).

Developmental …, Jan 1, 2007

Purpose-Estrogenic endocrine disruptors acting via estrogen receptors α and β have been implicate... more Purpose-Estrogenic endocrine disruptors acting via estrogen receptors α and β have been implicated in the etiology of hypospadias. However, the expression and distribution of estrogen receptors α and β in normal and hypospadiac human foreskins is unknown. We characterized the location and expression of estrogen receptors α and β in normal and hypospadiac foreskins.

General and comparative …, Jan 1, 2009

Estrogen production by the female avian embryo induces development of a female phenotype of the r... more Estrogen production by the female avian embryo induces development of a female phenotype of the reproductive organs whereas the low estrogen concentration in the male embryo results in a male phenotype. Treatment of female embryos with exogenous estrogens disrupts Müllerian duct development resulting in malformations and impaired oviductal function. Exposure of male embryos to estrogens results in ovotestis formation and persisting Müllerian ducts in the embryos and testicular malformations, reduced semen production and partially developed oviducts in the adult bird. Furthermore, studies in Japanese quail show that the male copulatory behavior is impaired by embryonic estrogen treatment. Results from our experiments with selective agonists for ERa and ERb suggest that the effects of estrogens on the reproductive organs are mediated via activation of ERa. Abundant expression of ERa mRNA was shown in gonads and Müllerian ducts of early Japanese quail embryos. Both ERa and ERb transcripts were detected by real-time PCR in early embryo brains of Japanese quail indicating that both receptors may be involved in sex differentiation of the brain. However, in 9-day-old quail embryo brains in situ hybridization showed expression of ERb mRNA, but not of ERa mRNA, in the medial preoptic nucleus (POM) and the bed nucleus of the stria terminalis (BSTm), areas implicated in copulatory behavior of adult male quail. Furthermore, embryonic treatment with the selective ERa agonist propyl pyrazol triol (PPT) had no effect on the male copulatory behavior. These results suggest that ERb may be important for the effects of estrogens on brain differentiation.

BMC Veterinary …, Jan 1, 2011

Background: Multiple congenital ocular anomalies (MCOA) syndrome is a hereditary congenital eye d... more Background: Multiple congenital ocular anomalies (MCOA) syndrome is a hereditary congenital eye defect that was first described in Silver colored Rocky Mountain horses. The mutation causing this disease is located within a defined chromosomal interval, which also contains the gene and mutation that is associated with the Silver coat color (PMEL17, exon 11). Horses that are homozygous for the disease-causing allele have multiple defects (MCOA-phenotype), whilst the heterozygous horses predominantly have cysts of the iris, ciliary body or retina (Cyst-phenotype). It has been argued that these ocular defects are caused by a recent mutation that is restricted to horses that are related to the Rocky Mountain Horse breed. For that reason we have examined another horse breed, the Icelandic horse, which is historically quite divergent from Rocky Mountain horses. Results: We examined 24 Icelandic horses and established that the MCOA syndrome is present in this breed. Four of these horses were categorised as having the MCOA-phenotype and were genotyped as being homozygous for the PMEL17 mutation. The most common clinical signs included megaloglobus, iris stromal hypoplasia, abnormal pectinate ligaments, iridociliary cysts occasionally extending into the peripheral retina and cataracts. The cysts and pectinate ligament abnormalities were observed in the temporal quadrant of the eyes. Fourteen horses were heterozygous for the PMEL17 mutation and were characterized as having the Cyst-phenotype with cysts and occasionally curvilinear streaks in the peripheral retina. Three additional horses were genotyped as PMEL17 heterozygotes, but in these horses we were unable to detect cysts or other forms of anomalies. One eye of a severely vision-impaired 18 month-old stallion, homozygous for the PMEL17 mutation was examined by light microscopy. Redundant duplication of non-pigmented ciliary body epithelium, sometimes forming cysts bulging into the posterior chamber and localized areas of atrophy in the peripheral retina were seen. Conclusions: The MCOA syndrome is segregating with the PMEL17 mutation in the Icelandic Horse population. This needs to be taken into consideration in breeding decisions and highlights the fact that MCOA syndrome is present in a breed that are more ancient and not closely related to the Rocky Mountain Horse breed.

BMC …, Jan 1, 2006

Background: Differentiation of the brain during development leads to sexually dimorphic adult rep... more Background: Differentiation of the brain during development leads to sexually dimorphic adult reproductive behavior and other neural sex dimorphisms. Genetic mechanisms independent of steroid hormones produced by the gonads have recently been suggested to partly explain these dimorphisms.

Brain research bulletin, Jan 1, 2005

A number of environmental contaminants have been shown to interfere with the endocrine system. Ma... more A number of environmental contaminants have been shown to interfere with the endocrine system. Many of these compounds bind to estrogen receptors, thereby potentially disrupting estrogen-regulated functions. In this paper, we review some background data on avian sexual differentiation and present some of the results from our studies on effects of estrogenic chemicals administered during sexual differentiation in the Japanese quail. Initially, our goal was to elucidate whether a decreased male sexual behavior in quail is a suitable endpoint for studying long-term effects of exposure to estrogenic compounds during sexual differentiation in ovo. We thereafter tested some environmental pollutants, suspected to act via mimicking estrogens, using the test system developed. Results from our studies on the synthetic estrogens ethinylestradiol and diethylstilbestrol, as well as the environmental pollutants bisphenol A, tetrabromobisphenol A, and o,p'-DDT are reviewed in this paper. We conclude that the Japanese quail is well suited as an animal model for studying various long-term effects after embryonic exposure to estrogenic compounds. Depressed sexual behavior proved to be the most sensitive of the variables studied in males and we find this endpoint appropriate for studying effects of endocrine modulating chemicals in the adult quail following embryonic exposure.

Ecotoxicology, Jan 1, 2003

This mini-review focuses on sexual differentiation of the reproductive organs and the brain in bi... more This mini-review focuses on sexual differentiation of the reproductive organs and the brain in birds and the effects of endocrine modulators on these processes. Sex determination in birds is genetically controlled, but the genetic events implicated are largely unknown. Female birds have one Z and one W sex chromosome, while males have two Z sex chromosomes. It is not clear whether it is the presence of the W chromosome in females, the double dose of the Z chromosome in males vis-aÁ-vis females, or both of these characteristics that are crucial for the determination of sex in birds. Oestradiol directs sexual differentiation in birds during critical periods of development. Consequently, exogenous compounds that interfere with the endogenous oestrogen balance can disrupt sexual differentiation of the reproductive organs and the brain. Therefore, sexual differentiation in birds provides a good model for studying the effects of endocrine modulators at various biological levels from gene expression to behaviour. Some compounds known to be present in the environment can alter endocrine function and have adverse effects when administered during development, resulting in alterations in gonads, accessory sexual organs, and behaviour. Data reviewed in this paper are mostly from laboratory studies on endocrine modulators with oestrogenic activity, whereas evidence for adverse effects of pollutants on sexual differentiation in avian wildlife is scarce.

Journal of …, Jan 1, 2006

Two estrogen receptors (ERs), denoted ERalpha and ERbeta, have been identified in humans and vari... more Two estrogen receptors (ERs), denoted ERalpha and ERbeta, have been identified in humans and various animal species, including the Japanese quail. Estrogens play a key role in sexual differentiation and in activation of sexual behavior in Japanese quail. The distribution of ERalpha in the brain of male and female adult quail has previously been studied using immunohistochemistry, whereas in situ hybridization has been employed to study the distribution of ERbeta mRNA in males only. In this article, we used in situ hybridization to study the distribution of mRNAs for both ERalpha and ERbeta in brain areas controlling sexual behavior of Japanese quail. Our results show that both ERalpha mRNA and ERbeta mRNA are localized in areas important for sexual behavior, such as the preoptic area and associated limbic areas, in both males and females. Moreover, we found differences in distribution of mRNA for the two receptors in these areas. The results of this article support previously reported data and provide novel data on localization of ER mRNAs in adult quail brain of both sexes.

Archives of toxicology, Jan 1, 2005

Embryonic exposure to estrogens and estrogenic pollutants is known to demasculinize sexual behavi... more Embryonic exposure to estrogens and estrogenic pollutants is known to demasculinize sexual behavior in adult male Japanese quail. In the present study, we administered the insecticide methoxychlor to quail eggs at a dose of 150 lg/g egg and then studied sexual behavior and other reproductive variables in adult males. In a second experiment we administered the same dose of methoxychlor together with 10 lg/g egg of the commercial polychlorinated biphenyl (PCB) mixture Clophen A50 (CA50) and also CA50 alone. Neither methoxychlor nor CA50 had any significant effects by themselves, but when they were administered together a significant reduction in male sexual behavior was observed. It seems likely that induction of biotransformation enzymes in the embryos by CA50 resulted in increased conversion of methoxychlor to the more estrogenic metabolite 2,2-bis(p-hydroxyphenyl)-1,1,1trichloroethane (HPTE).

Developmental …, Jan 1, 2007

Purpose-Estrogenic endocrine disruptors acting via estrogen receptors α and β have been implicate... more Purpose-Estrogenic endocrine disruptors acting via estrogen receptors α and β have been implicated in the etiology of hypospadias. However, the expression and distribution of estrogen receptors α and β in normal and hypospadiac human foreskins is unknown. We characterized the location and expression of estrogen receptors α and β in normal and hypospadiac foreskins.

General and comparative …, Jan 1, 2009

Estrogen production by the female avian embryo induces development of a female phenotype of the r... more Estrogen production by the female avian embryo induces development of a female phenotype of the reproductive organs whereas the low estrogen concentration in the male embryo results in a male phenotype. Treatment of female embryos with exogenous estrogens disrupts Müllerian duct development resulting in malformations and impaired oviductal function. Exposure of male embryos to estrogens results in ovotestis formation and persisting Müllerian ducts in the embryos and testicular malformations, reduced semen production and partially developed oviducts in the adult bird. Furthermore, studies in Japanese quail show that the male copulatory behavior is impaired by embryonic estrogen treatment. Results from our experiments with selective agonists for ERa and ERb suggest that the effects of estrogens on the reproductive organs are mediated via activation of ERa. Abundant expression of ERa mRNA was shown in gonads and Müllerian ducts of early Japanese quail embryos. Both ERa and ERb transcripts were detected by real-time PCR in early embryo brains of Japanese quail indicating that both receptors may be involved in sex differentiation of the brain. However, in 9-day-old quail embryo brains in situ hybridization showed expression of ERb mRNA, but not of ERa mRNA, in the medial preoptic nucleus (POM) and the bed nucleus of the stria terminalis (BSTm), areas implicated in copulatory behavior of adult male quail. Furthermore, embryonic treatment with the selective ERa agonist propyl pyrazol triol (PPT) had no effect on the male copulatory behavior. These results suggest that ERb may be important for the effects of estrogens on brain differentiation.

BMC Veterinary …, Jan 1, 2011

Background: Multiple congenital ocular anomalies (MCOA) syndrome is a hereditary congenital eye d... more Background: Multiple congenital ocular anomalies (MCOA) syndrome is a hereditary congenital eye defect that was first described in Silver colored Rocky Mountain horses. The mutation causing this disease is located within a defined chromosomal interval, which also contains the gene and mutation that is associated with the Silver coat color (PMEL17, exon 11). Horses that are homozygous for the disease-causing allele have multiple defects (MCOA-phenotype), whilst the heterozygous horses predominantly have cysts of the iris, ciliary body or retina (Cyst-phenotype). It has been argued that these ocular defects are caused by a recent mutation that is restricted to horses that are related to the Rocky Mountain Horse breed. For that reason we have examined another horse breed, the Icelandic horse, which is historically quite divergent from Rocky Mountain horses. Results: We examined 24 Icelandic horses and established that the MCOA syndrome is present in this breed. Four of these horses were categorised as having the MCOA-phenotype and were genotyped as being homozygous for the PMEL17 mutation. The most common clinical signs included megaloglobus, iris stromal hypoplasia, abnormal pectinate ligaments, iridociliary cysts occasionally extending into the peripheral retina and cataracts. The cysts and pectinate ligament abnormalities were observed in the temporal quadrant of the eyes. Fourteen horses were heterozygous for the PMEL17 mutation and were characterized as having the Cyst-phenotype with cysts and occasionally curvilinear streaks in the peripheral retina. Three additional horses were genotyped as PMEL17 heterozygotes, but in these horses we were unable to detect cysts or other forms of anomalies. One eye of a severely vision-impaired 18 month-old stallion, homozygous for the PMEL17 mutation was examined by light microscopy. Redundant duplication of non-pigmented ciliary body epithelium, sometimes forming cysts bulging into the posterior chamber and localized areas of atrophy in the peripheral retina were seen. Conclusions: The MCOA syndrome is segregating with the PMEL17 mutation in the Icelandic Horse population. This needs to be taken into consideration in breeding decisions and highlights the fact that MCOA syndrome is present in a breed that are more ancient and not closely related to the Rocky Mountain Horse breed.