Action of Endocrine Disrupters on Leydig Cells
Diethylhexylphthalate (DEHP) is a suspected endocrine-disrupting chemical that is a common constituent of flexible plastics; Council research is investigating the effect of DEHP on the function of Leydig cells, the cells responsible for making testosterone.
Phthalates are used as plasticizers in certain infant toys and medical products and as ingredients in consumer products such as soap, shampoo, perfume, and cosmetics. As a group, phthalates act as antiandrogens, suppressing fetal testosterone biosynthesis and causing demasculinization in rodents.
A second toxicant, bisphenol A (BPA), is widely used in the manufacture of polycarbonates for food packaging and as a constituent of dental sealants. This compound is known to bind the estrogen receptor and is thus classified as a xenoestrogen.
The effects of diethylhexylphthalate (DEHP) and BPA on the function of Leydig cells, the cells responsible for making testosterone, were studied to determine whether:
- DEHP and BPA effects are dependent on the stage of development at exposure;
- DEHP- and BPA-related effects exerted early in development persist into adulthood; and
- Exposure to DEHP induces Leydig cell hyperplasia.
Phthalates are of epidemiological significance given their ubiquitous presence in the environment. Indeed, unusually high levels of these agents were measured in the urine of young girls exhibiting premature breast development in Puerto Rico and in other human reference populations. Data indicate that DEHP effects are influenced by the stage of development at exposure, inducing changes in androgen biosynthetic enzyme activity and serum luteinizing hormone levels. Furthermore, chronic postnatal DEHP exposures:
- Increased gonadotropin stimulation that ultimately decreased Leydig cell steroidogenic function; and
- Caused aberrations in the cell division cycle that supported increased mitotic activity and Leydig cell hyperplasia (an abnormal increase in the number of cells).
The study of BPA shows that this agent may affect reproductive activity at very low levels of exposure by suppressing pituitary and/or Leydig cell function. The affinity of BPA for the estrogen receptor may also be greater than previously thought.
Phthalate levels and low birth weight: A nested case-control study of Chinese newborns (abstract) (PDF)
Zhang,Yunhui; Lin,Ling; Cao,Yang; Chen,Bingheng; Zheng,Lixing; Ge,Renshan
Journal of Pediatrics 155(4): 500-504
Publication date: 2009
Phthalate ester toxicity in Leydig cells: Developmental timing and dosage considerations (abstract) (HTML)
Ge,Renshan; Chen,Guo-Rong; Tanrikut,Cigdem; Hardy,Matthew P.
Reproductive Toxicology 23(3): 366-373
Publication date: 2007
Inhibition of testicular steroidogenesis by the xenoestrogen bisphenol A is associated with reduced pituitary luteinizing hormone secretion and decreased steroidogenic enzyme gene expression in rat Leydig cells (abstract) (PDF)
Akingbemi,Benson T.; Sottas,Chantal M.; Koulova,Anna I.; Klinefelter,Gary R.; Hardy,Matthew P.
Endocrinology 145(2): 592-603
Publication date: 2004
Phthalate-induced Leydig cell hyperplasia is associated with multiple endocrine disturbances (abstract) (PDF)
Akingbemi,Benson T.; Ge,Renshan; Klinefelter,Gary R.; Zirkin,Barry R.; Hardy,Matthew P.
Proceedings of the National Academy of Sciences of the United States of America 101(3): 775-780
Publication date: 2004
Estrogen receptor-α gene deficiency enhances androgen biosynthesis in the mouse Leydig cell (abstract) (HTML)
Akingbemi,Benson T.; Ge,Renshan; Rosenfeld,Cheryl S.; Newton,Leslie G.; Hardy,Dianne O.; Catterall,James F.; Lubahn,Dennis B.; Korach,Kenneth S.; Hardy,Matthew P.
Endocrinology 144(1): 84-93
Publication date: 2003
Modulation of rat Leydig cell steroidogenic function by di(2-ethylhexyl) phthalate (abstract) (PDF)
Akingbemi,Benson T.; Youker,Robert T.; Sottas,Chantal M.; Ge,Renshan; Katz,Emily; Klinefelter,Gary R.; Zirkin,Barry R.; Hardy,Matthew P.
Biology of Reproduction 65(4): 1252-1259
Publication date: 2001
Oestrogenic and antiandrogenic chemicals in the environment: Effects on male reproductive health [review] (abstract) (HTML)
Akingbemi,Benson T.; Hardy,Matthew P.
Annals of Medicine 33(6): 391-403
Publication date: 2001
A metabolite of methoxychlor, 2,2-bis(p-hydroxyphenyl)-1,1, 1-trichloroethane, reduces testosterone biosynthesis in rat Leydig cells through suppression of steady-state messenger ribonucleic acid levels of the cholesterol side-chain cleavage enzyme (abstract) (HTML)
Akingbemi,Benson T.; Ge,Renshan; Klinefelter,Gary R.; Gunsalus,Glen L.; Hardy,Matthew P.
Biology of Reproduction 62(3): 571-578
Publication date: 2000
Location: United States
Reproductive health biomedical research
Duration: 4/1999 - ongoing
Barry Zirkin (Johns Hopkins University)
Gary R. Klinefelter (US Environmental Protection Agency)
US National Institutes of Health