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


OBJECTIVE
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 ERalpha (estrogen receptor alpha) mRNA expression was quantified in control (C) and treated (T) maternal and fetal (110-day) hypothalami and pituitary glands using semiquantitative reverse transcription polymerase chain reaction, and colocalization of kisspeptin with LHbeta (luteinizing hormone beta) and ERalpha 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 LHbeta and ERalpha 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.
Bellingham
Michelle
M
Division of Cell Sciences, Institute of Comparative Medicine, Faculty of Veterinary Medicine, University of Glasgow, Glasgow, United Kingdom.
Fowler
Paul A
PA
Amezaga
Maria R
MR
Rhind
Stewart M
SM
Cotinot
Corinne
C
Mandon-Pepin
Beatrice
B
Sharpe
Richard M
RM
Evans
Neil P
NP
D000818:Animals; D052244:Endocrine Disruptors / Q000633:toxicity*; D004781:Environmental Exposure; D004785:Environmental Pollutants / Q000633:toxicity*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012756:Sheep; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D043562:Receptors, G-Protein-Coupled; D025521:Tumor Suppressor Proteins