Genotoxic, histologic, immunohistochemical, morphometric and hormonal effects of di-(2-ethylhexyl)-phthalate (DEHP) on reproductive systems in pre-pubertal male rats

Endocrine disruptors (EDs) with androgenic and anti-androgenic effects may alter reproductive function by binding to androgenic receptors (AR) and inducing or modulating AR-dependent responses in the male reproductive system. However, the molecular mechanism(s) underlying these events remains unclear. Thus, in the present study, we elucidated the prenatal effects of maternal testosterone propionate (TP), flutamide (Flu), and di-(2-ethylhexyl) phthalate (DEHP) on male reproductive organs of newborn rats. Pregnant Sprague-Dawley (n = 32 in total, n = 8/each group) rats were treated with these compounds at gestation days 11 to 21, and newborn males (n = 154 in total) were euthanized at post-neonatal day (PND) 63. Interestingly, maternal exposure to Flu or DEHP caused fluctuations in the neonatal levels of serum testosterone (T) and luteinizing hormone (LH). Serum T and LH were up-regulated by Flu, but these hormones were down-regulated by DEHP. The anogenital distances (AGD) of male newborns were detected at PND 1, 21, and 63. Male rats treated prenatally with DEHP (100 mg kg–1 mother’s body weight) or Flu showed an AGD shorter than that of control rats. At PND 63, the sperm concentration, viability, and mobility were reduced in the maternal DEHP and Flu-treated groups. The numbers of seminiferous tubules were reduced in the Flu- and DEHP-treated offspring when compared with vehicle- and TP-treated groups, and the tubules of the testes at PND 63 were disrupted by a high dose of Flu. In addition, we examined differential gene expression patterns in the testes by microarray analysis following ED exposure, particularly in sex determination-related genes. Significantly distinct expressions of sex determination-related genes were observed in the testes by microarray analysis following treatments with different types of EDs in this study. Although Flu and DEHP are considered to be identical with regard to their anti-androgenic effects, their effects on developing male reproductive organs were distinct, suggesting that Flu competes with endogenous T, while DEHP influences a different step in androgenesis.

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Effects of di-2-ethylhexyl phthalate on lipid composition of liver, testis and serum of male rats

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)60438-5 ◽

1983 ◽

Vol 33 ◽

pp. 245

Author(s):

Shinshi Oishi ◽

Kogo Hiraga

Keyword(s):

Lipid Composition ◽

Male Rats ◽

Ethylhexyl Phthalate

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Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer Di(2-ethylhexyl) phthalate.

Environmental Health Perspectives ◽

10.1289/ehp.01109229 ◽

2001 ◽

Vol 109 (3) ◽

pp. 229-237 ◽

Cited By ~ 216

Author(s):

R W Moore ◽

T A Rudy ◽

T M Lin ◽

K Ko ◽

R E Peterson

Keyword(s):

Sexual Development ◽

In Utero ◽

Male Rats ◽

Lactational Exposure ◽

Ethylhexyl Phthalate

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Exposures of male rats to environmental chemicals [bisphenol A and di (2-ethylhexyl) phthalate] affected expression of several proteins in the developing epididymis

Andrology ◽

10.1111/andr.12451 ◽

2017 ◽

Vol 6 (1) ◽

pp. 214-222 ◽

Cited By ~ 1

Author(s):

F. M. Abdel-Maksoud ◽

R. Knight ◽

K. Waler ◽

N. Yaghoubi-Yeganeh ◽

J. O. Olukunle ◽

...

Keyword(s):

Bisphenol A ◽

Environmental Chemicals ◽

Male Rats ◽

Ethylhexyl Phthalate

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Effects of di(2-ethylhexyl) phthalate on the gonadal pathophysiology, sperm morphology, and reproductive performance of male rats.

Environmental Health Perspectives ◽

10.1289/ehp.8665343 ◽

1986 ◽

Vol 65 ◽

pp. 343-350 ◽

Cited By ~ 4

Author(s):

D K Agarwal ◽

S Eustis ◽

J C Lamb ◽

J R Reel ◽

W M Kluwe

Keyword(s):

Reproductive Performance ◽

Sperm Morphology ◽

Male Rats ◽

Ethylhexyl Phthalate

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Endocrine interactions: adrenal steroids and precursors

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1994.266.4.e676 ◽

1994 ◽

Vol 266 (4) ◽

pp. E676-E681

Author(s):

G. T. Taylor ◽

J. Scherrer ◽

J. Weiss ◽

J. Pitha

Keyword(s):

Adult Male ◽

Male Rats ◽

Adrenal Steroids ◽

Reproductive Systems ◽

Cyclodextrin Complexes ◽

Androgen Therapy ◽

Testosterone Synthesis

Adult male rats (n = 48) were castrated and treated daily for 4 wk with adrenal steroids in the presence or absence of adjuvant testosterone. Dehydroepiandrosterone (DHEA), DHEA sulfate, and androstenedione (2 mg/kg body wt) were administered as cyclodextrin complexes to mimic the pharmacodynamics of the endogenous products. Although they are the substrates for testosterone synthesis in target tissues, supplements of adrenal steroids alone were unable to maintain integrity of sociosexual responses and androgen target tissues after castration. More surprising, groups administered adrenal precursor plus testosterone showed substantial suppression of the typical restoration of reproductive systems in castrates receiving androgen therapy. The adrenal steroids, however, were not functionally identical. Each steroid interacted with testosterone to leave its own distinctive “footprint” on androgen-sensitive systems. The conclusion is that the endogenous adrenal products are not simply passive precursors of testosterone. Adrenal steroids may serve as endocrine regulators of androgen bioavailability and bioactivity.

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Di(2-ethylhexyl)phthalate induces reproductive toxicity via JAZF1/TR4 pathway and oxidative stress in pubertal male rats

Toxicology and Industrial Health ◽

10.1177/0748233718824911 ◽

2019 ◽

Vol 35 (3) ◽

pp. 228-238 ◽

Cited By ~ 2

Author(s):

Yu-Qin Shi ◽

Guo-Qing Fu ◽

Jing Zhao ◽

Shen-Zhou Cheng ◽

You Li ◽

...

Keyword(s):

Oxidative Stress ◽

Morphological Changes ◽

Reproductive Toxicity ◽

Male Reproduction ◽

Male Rats ◽

Terminal Deoxynucleotidyl Transferase ◽

Cyclin A1 ◽

Ethylhexyl Phthalate ◽

Dehp Exposure ◽

And Oxidative Stress

Di(2-ethylhexyl)phthalate (DEHP) is a typical endocrine-disrupting chemical and reproductive toxicant. Although previous studies have attempted to describe the mechanism by which DEHP exposure results in reproductive dysfunction, few studies focused on puberty, a critical period of reproductive development, and the increased susceptibility to injury in adolescents. To elucidate the mechanism underpinning the testicular effects of DEHP in puberty, we sought to investigate the JAZF1/TR4 pathway in the testes of pubertal rats. Specifically, we focused on the role of the JAZF1/TR4 pathway in male reproduction, including the genes JAZF1, TR4, Sperm 1, and Cyclin A1. In the present study, rats were exposed to increasing concentrations of DEHP (0, 250, 500, and 1000 mg/kg/day) by oral gavages for 30 days. Then we assayed testicular zinc and oxidative stress levels. Our results indicated that DEHP exposure could lead to oxidative stress and decrease the contents of testicular zinc. Additionally, significant morphological changes and cell apoptosis were observed in testes exposed to DEHP, as identified by hematoxylin and eosin staining and the terminal deoxynucleotidyl transferase-mediated nick and labeling assay. By measuring the expression levels of the above relevant genes by qPCR, we found the DEHP-induced increased expression of JAZF1 and decreased expression of TR4, Sperm 1, and Cyclin A1. Therefore, we have demonstrated that in vivo exposure to DEHP might induce reproductive toxicity in pubertal male rats through the JAZF1/TR4 pathway and oxidative stress.

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227 AN ALTERATION IN GENE EXPRESSION PATTERNS INDUCED BY DI-(2 ETHYLHEXYL) PHTHALATE AND FLUTAMIDE IN THE TESTIS OF IMMATURE MALE RATS

Reproduction Fertility and Development ◽

10.1071/rdv21n1ab227 ◽

2009 ◽

Vol 21 (1) ◽

pp. 211

Author(s):

K.-C. Choi ◽

T. T. B. Vo ◽

E.-M. Jung ◽

V. H. Dang ◽

E.-B. Jeung

Keyword(s):

Gene Expression ◽

Reproductive System ◽

Male Reproductive System ◽

Male Rats ◽

Calcium Signal ◽

High Dose ◽

Dependent Manner ◽

Immature Male ◽

Serum Lh ◽

Ethylhexyl Phthalate

In a previous study, we demonstrated that although endocrine disruptors (EDs) with androgenic and anti-androgenic effects may alter reproductive function, their effects on the developing male reproductive organs may be distinct. To continue this line of study, we treated immature rats to examine the adverse effects of di-(2 ethylhexyl) phthalate (DEHP) and flutamide (Flu) on the male reproductive system. Immature male SD rats were treated daily with DEHP and/or Flu at postnatal day (PND) 21 to 35 in a dose-dependent manner, and the changes evoked by these EDs were determined by differences in male reproductive tract and other organ weights, testicular histology, and serum LH and testosterone levels in combination with global microarray analysis. Interestingly, the testes, prostate, seminal vesicle weight, and anogenital distances were significantly decreased in response to the highest dose of DEHP and Flu. There were no differences in serum LH and testosterone concentration at PND 35 for immature male rats exposed to DEHP and/or Flu. However, treatment with DEHP and/or Flu caused histopathological changes in testes in which the degeneration and denseness of germ cells and/or dilatation of the tubular lumen were observed in response to the high dose [500 mg kg–1 of body weight (BW)] of DEHP and medium dose (10 mg kg–1 of BW) of Flu. Additionally, the results from cDNA microarray indicated that 1272 genes were up-regulated (more than 2-fold) and 1969 genes were down-regulated in response to DEPH and/or Flu. These genes were identified based on their roles in some physiological processes (i.e. lipid and cholesterol homeostasis, steroidogenesis, sex determination, and calcium signal transduction). The significant decreases were observed in the expressions of steroidogenic genes (i.e. Star, Cyp11a1, or Hsd3b). In addition, a common set of targeting genes, including CaBP1, Vav2, Plcd1, Lhx1, and Isoc1, were altered following EDs exposure, suggesting a potential set of biomarker genes for screening anti-androgenic and/or androgenicity of EDs. Taken together, we demonstrated that exposure to DEHP and/or Flu resulted in a temporal alteration in gene expression profile in the testes of immature male rats, and their toxicological effects on male reproductive system are distinct depending on their anti-androgenicity, suggesting new insight into molecular mechanism(s) underlying detrimental impacts of EDs with anti-androgenic activities in human and wildlife.

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