4-Nitrophenol induces Leydig cells hyperplasia, which may contribute to the differential modulation of the androgen receptor and estrogen receptor-α and -β expression in male rat testes

Toxicol Lett. 2013 Nov 25;223(2):228-35. doi: 10.1016/j.toxlet.2013.09.011. Epub 2013 Sep 23.

Abstract

4-Nitrophenol (PNP) is generally regarded as an environmental endocrine disruptor capable of estrogenic and anti-androgenic activities. To investigate PNP-induced reproductive effects, immature male rats were injected subcutaneously with PNP (0.1, 1, 10mg/kg body weight or vehicle) daily for 4 weeks. We assessed reproductive tract alterations, sex hormone balance in the serum and estrogen receptor (ER)-α, -β and androgen receptor (AR) expression in testes. Although no significant difference was observed in body weight or testes weights of PNP-treated rats compared with the controls, the serum concentrations of testosterone in the 10mg/kg PNP-treated group were significantly elevated. This effect was accompanied by Leydig cells hyperplasia in the testes. Conversely, there was a significant decrease in estradiol concentration and aromatase expression in the testes of the 10mg/kg PNP-treated group. Furthermore, we observed a significant increase in ERα expression in the testes of the 10mg/kg PNP-treated group compared with the control group. Conversely, ERβ expression displayed a significant reduction. Moreover, AR expression was significantly increased in the 10mg/kg PNP-treated group compared with the control group. The existence of AR, ER-α and -β in the testes suggests that estradiol and testosterone directly affect germ cells and that differential modulation of AR, ER-α and -β in the testis may be involved in the direct effects of PNP or either the indirect effects of PNP-induced disruption of the estradiol-to-testosterone balance or the Leydig cells hyperplasia. Thus, the measurement of many endpoints is necessary for good risk assessment.

Keywords: 4-Nitrophenol; 4-nitrophenol; AR; Androgen receptor; BSA; DEP; EEDs; ER; Estrogen receptor; FSH; HE; Hormonal balance; LH; Leydig cells; PBS; PNP; SD; Sprague-Dawley; androgen receptor; bovine serum albumin.; diesel exhaust particles; environmental endocrine disruptors; estrogen receptor; follicle-stimulating hormone; hematoxylin and eosin; luteinizing hormone; phosphate-buffered saline.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / metabolism
  • Animals
  • Aromatase / genetics
  • Aromatase / metabolism
  • Cell Differentiation / drug effects
  • Endocrine Disruptors / toxicity*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Estrogen Receptor beta / genetics
  • Estrogen Receptor beta / metabolism*
  • Gonadal Steroid Hormones / blood
  • Hyperplasia
  • Immunohistochemistry
  • Leydig Cells / drug effects*
  • Leydig Cells / pathology
  • Male
  • Nitrophenols / toxicity*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Testis / drug effects*
  • Testis / pathology

Substances

  • Androgen Antagonists
  • Endocrine Disruptors
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Gonadal Steroid Hormones
  • Nitrophenols
  • Receptors, Androgen
  • Aromatase
  • 4-nitrophenol