Exposure to a complex cocktail of environmental endocrine-disrupting compounds disturbs the Kisspeptin/GPR54 system in ovine hypothalamus and pituitary gland

Michelle Bellingham, Paul A Fowler, Maria R Amezaga, Stewart M Rhind, Corinne Cotinot, Beatrice Mandon-Pepin, Richard M Sharpe, Neil P Evans

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

BACKGROUND: Ubiquitous environmental chemicals, including endocrine-disrupting chemicals (EDCs), are associated with declining human reproductive health, as well as an increasing incidence of cancers of the reproductive system. Verifying such links requires animal models exposed to "real-life," environmentally relevant concentrations/mixtures of EDC, particularly in utero, when sensitivity to EDC exposure is maximal.

OBJECTIVES: We evaluated the effects of maternal exposure to a pollutant cocktail (sewage sludge) on the ovine fetal reproductive neuroendocrine axes, particularly the kisspeptin (KiSS-1)/GPR54 (G-protein-coupled receptor 54) system.

METHODS: KiSS-1, GPR54, and ER alpha (estrogen receptor alpha) mRNA expression was quantified in control (C) and treated (T) maternal and fetal (110-day) hypothalami and pituitary glands using semi quantitative reverse transcription polymerase chain reaction, and colocalization of kisspeptin with LH beta (luteinizing hormone beta) and ER alpha in C and T fetal pituitary glands quantified using dual-labeling immunohistochemistry.

RESULTS: Fetuses exposed in utero to the EDC mixture showed reduced KiSS-1 mRNA expression across three hypothalamic regions examined (rostral, mid, and caudal) and had fewer kisspetin immunopositive cells colocalized with both LH beta and ER alpha in the pituitary gland. In contrast, treatment had no effect on parameters measured in the adult ewe hypothalamus or pituitary.

CONCLUSIONS: This study demonstrates that the developing fetus is sensitive to real-world mixtures of environmental chemicals, which cause significant neuroendocrine alterations. The important role of kisspeptin/GPR54 in regulating puberty and adult reproduction means that in utero disruption of this system is likely to have long-term consequences in adulthood and represents a novel, additional pathway through which environmental chemicals perturb human reproduction.

Original languageEnglish
Pages (from-to)1556-1562
Number of pages7
JournalEnvironmental Health Perspectives
Volume117
Issue number10
Early online date5 Jun 2009
Publication statusPublished - Oct 2009

Keywords

  • environmental chemicals
  • GPR54
  • hypothalamus
  • kisspeptin
  • pituitary
  • prenatal exposure
  • sheep
  • gonadotropin-releasing-hormone
  • protein-coupled receptor
  • sewage treatment plants
  • luteinizing-hormone
  • risk-assessment
  • messenger-RNA
  • polychlorinated-biphenyls
  • gene-expression
  • KISS-1 peptide
  • preoptic area

Cite this

Exposure to a complex cocktail of environmental endocrine-disrupting compounds disturbs the Kisspeptin/GPR54 system in ovine hypothalamus and pituitary gland. / Bellingham, Michelle; Fowler, Paul A; Amezaga, Maria R; Rhind, Stewart M; Cotinot, Corinne; Mandon-Pepin, Beatrice; Sharpe, Richard M; Evans, Neil P.

In: Environmental Health Perspectives, Vol. 117, No. 10, 10.2009, p. 1556-1562.

Research output: Contribution to journalArticle

Bellingham, M, Fowler, PA, Amezaga, MR, Rhind, SM, Cotinot, C, Mandon-Pepin, B, Sharpe, RM & Evans, NP 2009, 'Exposure to a complex cocktail of environmental endocrine-disrupting compounds disturbs the Kisspeptin/GPR54 system in ovine hypothalamus and pituitary gland', Environmental Health Perspectives, vol. 117, no. 10, pp. 1556-1562.
Bellingham, Michelle ; Fowler, Paul A ; Amezaga, Maria R ; Rhind, Stewart M ; Cotinot, Corinne ; Mandon-Pepin, Beatrice ; Sharpe, Richard M ; Evans, Neil P. / Exposure to a complex cocktail of environmental endocrine-disrupting compounds disturbs the Kisspeptin/GPR54 system in ovine hypothalamus and pituitary gland. In: Environmental Health Perspectives. 2009 ; Vol. 117, No. 10. pp. 1556-1562.
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T1 - Exposure to a complex cocktail of environmental endocrine-disrupting compounds disturbs the Kisspeptin/GPR54 system in ovine hypothalamus and pituitary gland

AU - Bellingham, Michelle

AU - Fowler, Paul A

AU - Amezaga, Maria R

AU - Rhind, Stewart M

AU - Cotinot, Corinne

AU - Mandon-Pepin, Beatrice

AU - Sharpe, Richard M

AU - Evans, Neil P

PY - 2009/10

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N2 - BACKGROUND: Ubiquitous environmental chemicals, including endocrine-disrupting chemicals (EDCs), are associated with declining human reproductive health, as well as an increasing incidence of cancers of the reproductive system. Verifying such links requires animal models exposed to "real-life," environmentally relevant concentrations/mixtures of EDC, particularly in utero, when sensitivity to EDC exposure is maximal.OBJECTIVES: We evaluated the effects of maternal exposure to a pollutant cocktail (sewage sludge) on the ovine fetal reproductive neuroendocrine axes, particularly the kisspeptin (KiSS-1)/GPR54 (G-protein-coupled receptor 54) system.METHODS: KiSS-1, GPR54, and ER alpha (estrogen receptor alpha) mRNA expression was quantified in control (C) and treated (T) maternal and fetal (110-day) hypothalami and pituitary glands using semi quantitative reverse transcription polymerase chain reaction, and colocalization of kisspeptin with LH beta (luteinizing hormone beta) and ER alpha in C and T fetal pituitary glands quantified using dual-labeling immunohistochemistry.RESULTS: Fetuses exposed in utero to the EDC mixture showed reduced KiSS-1 mRNA expression across three hypothalamic regions examined (rostral, mid, and caudal) and had fewer kisspetin immunopositive cells colocalized with both LH beta and ER alpha in the pituitary gland. In contrast, treatment had no effect on parameters measured in the adult ewe hypothalamus or pituitary.CONCLUSIONS: This study demonstrates that the developing fetus is sensitive to real-world mixtures of environmental chemicals, which cause significant neuroendocrine alterations. The important role of kisspeptin/GPR54 in regulating puberty and adult reproduction means that in utero disruption of this system is likely to have long-term consequences in adulthood and represents a novel, additional pathway through which environmental chemicals perturb human reproduction.

AB - BACKGROUND: Ubiquitous environmental chemicals, including endocrine-disrupting chemicals (EDCs), are associated with declining human reproductive health, as well as an increasing incidence of cancers of the reproductive system. Verifying such links requires animal models exposed to "real-life," environmentally relevant concentrations/mixtures of EDC, particularly in utero, when sensitivity to EDC exposure is maximal.OBJECTIVES: We evaluated the effects of maternal exposure to a pollutant cocktail (sewage sludge) on the ovine fetal reproductive neuroendocrine axes, particularly the kisspeptin (KiSS-1)/GPR54 (G-protein-coupled receptor 54) system.METHODS: KiSS-1, GPR54, and ER alpha (estrogen receptor alpha) mRNA expression was quantified in control (C) and treated (T) maternal and fetal (110-day) hypothalami and pituitary glands using semi quantitative reverse transcription polymerase chain reaction, and colocalization of kisspeptin with LH beta (luteinizing hormone beta) and ER alpha in C and T fetal pituitary glands quantified using dual-labeling immunohistochemistry.RESULTS: Fetuses exposed in utero to the EDC mixture showed reduced KiSS-1 mRNA expression across three hypothalamic regions examined (rostral, mid, and caudal) and had fewer kisspetin immunopositive cells colocalized with both LH beta and ER alpha in the pituitary gland. In contrast, treatment had no effect on parameters measured in the adult ewe hypothalamus or pituitary.CONCLUSIONS: This study demonstrates that the developing fetus is sensitive to real-world mixtures of environmental chemicals, which cause significant neuroendocrine alterations. The important role of kisspeptin/GPR54 in regulating puberty and adult reproduction means that in utero disruption of this system is likely to have long-term consequences in adulthood and represents a novel, additional pathway through which environmental chemicals perturb human reproduction.

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KW - sheep

KW - gonadotropin-releasing-hormone

KW - protein-coupled receptor

KW - sewage treatment plants

KW - luteinizing-hormone

KW - risk-assessment

KW - messenger-RNA

KW - polychlorinated-biphenyls

KW - gene-expression

KW - KISS-1 peptide

KW - preoptic area

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JO - Environmental Health Perspectives

JF - Environmental Health Perspectives

SN - 0091-6765

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