Oral exposure of rats to dienestrol during gestation and lactation: Effects on the reproductive system of male offspring.

This study was aimed at determining whether dienestrol (DIES) affects reproduction in male offspring of rats following oral maternal exposure during gestation and lactation. Pregnant rats were treated from GD 6 to PND 21. Animals received 0 (control-vehicle), 0.75, 1.5, 3.12, 6.25, 12.5, 50, 75 μg/kg bw/d of DIES. A control group -without vehicle-was also included. High DIES concentrations caused abortions at 75 and 50 μg/kg bw/d, while at 12.5 μg/kg bw/d had still miscarriages. Ten male rats per group were kept alive until PND 90 to ensure sexual maturity. Body and organ weights, anogenital distance (AGD) at PNDs 21 and 90, biochemical and sperm parameters like motility, viability, morphology, spermatozoa and resistant spermatid counts, and histopathology for sexual organs and liver were determined. An increase in organ weight (liver and sexual organs) and a decrease in AGD due to vehicle were found. A reduction of sperm motility and viability, and an increase of abnormal sperm morphology were caused by DIES, which provoked a dose-dependent prostatitis. Maternal exposure to DIES induced toxicity on the reproductive system of the male offspring, which could affect the capacity of fertilization.

[1]  R. J. Heitzman.  The absorption, distribution and excretion of anabolic agents. , 1983, Journal of animal science.

[2]  C. Corcini,et al.  Influence of mineral, olive or sunflower oils on male reproductive parameters in vitro – the wild rodent Calomys laucha , 2014, Andrologia.

[3]  M. Leal,et al.  Prepubertal subchronic exposure to soy milk and glyphosate leads to endocrine disruption. , 2017, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[4]  Y. Martín.  Determination of three anabolic compounds in calf urine by liquid chromatography with photodiode-array detection. , 2000, The Analyst.

[5]  C. Monneret.  What is an endocrine disruptor? , 2017, Comptes rendus biologies.

[6]  J. Hernández-Borges,et al.  Hollow-fiber liquid-phase microextraction for the determination of natural and synthetic estrogens in milk samples. , 2013, Journal of chromatography. A.

[7]  R. Fry,et al.  Effects of prenatal exposure to endocrine disruptors and toxic metals on the fetal epigenome. , 2017, Epigenomics.

[8]  M. Metzler.  The metabolism of diethylstilbestrol. , 1981, CRC critical reviews in biochemistry.

[9]  Ping Li,et al.  Packed-fiber solid-phase extraction coupled with high performance liquid chromatography-tandem mass spectrometry for determination of diethylstilbestrol, hexestrol, and dienestrol residues in milk products. , 2014, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[10]  D. Caserta,et al.  The effect of maternal exposure to endocrine disrupting chemicals on fetal and neonatal development: A review on the major concerns. , 2016, Birth defects research. Part C, Embryo today : reviews.

[11]  Liju Tan,et al.  Preparation and characterization of magnetic molecularly imprinted polymers for selective trace extraction of dienestrol in seawater. , 2016, Journal of chromatography. A.

[12]  M. Gomendio,et al.  Sperm design and sperm function , 2006, Biology Letters.

[13]  A. Gore,et al.  Endocrine-disrupting chemicals , 2022, Current Biology.

[14]  Rosalind,et al.  Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the U.S. EPA-sponsored workshop. , 1996, Environmental health perspectives.

[15]  M. Churchwell,et al.  Comparative estrogenicity of endogenous, environmental and dietary estrogens in pregnant women I: Serum levels, variability and the basis for urinary biomonitoring of serum estrogenicity. , 2018, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[16]  Qian Xu,et al.  Trace analysis of diethylstilbestrol, dienestrol and hexestrol in environmental water by Nylon 6 nanofibers mat-based solid-phase extraction coupled with liquid chromatography-mass spectrometry. , 2011, The Analyst.

[17]  L. Giudice,et al.  Endocrine-disrupting chemicals: an Endocrine Society scientific statement. , 2009, Endocrine reviews.

[18]  S. Fenton,et al.  Exposure to diethylstilbestrol during sensitive life stages: a legacy of heritable health effects. , 2013, Birth defects research. Part C, Embryo today : reviews.

[19]  Antonio V. Herrera-Herrera,et al.  Multiresidue analysis of oestrogenic compounds in cow, goat, sheep and human milk using core-shell polydopamine coated magnetic nanoparticles as extraction sorbent in micro-dispersive solid-phase extraction followed by ultra-high-performance liquid chromatography tandem mass spectrometry , 2018, Analytical and Bioanalytical Chemistry.

[20]  J. Haseman,et al.  Developmental exposure to diethylstilbestrol (DES) alters uterine response to estrogens in prepubescent mice: low versus high dose effects. , 2004, Reproductive toxicology.

[21]  R. Hood.  Developmental and Reproductive Toxicology : A Practical Approach , 2011 .

[22]  T. Braden,et al.  Neonatal Estrogen Exposure of Male Rats Alters Reproductive Functions at Adulthood1 , 2003, Biology of reproduction.

[23]  Stephany Rw,et al.  [Anabolic steroid residues in administration sites in slaughtering cattle. October 1983 - January 1985]. , 1985 .

[24]  Jorma Toppari,et al.  Possible developmental early effects of endocrine disrupters on child health , 2012 .

[25]  P. Foster,et al.  Early-Onset Endocrine Disruptor–Induced Prostatitis in the Rat , 2008, Environmental health perspectives.

[26]  R. Hoover,et al.  Reproductive and hormone-related outcomes in women whose mothers were exposed in utero to diethylstilbestrol (DES): A report from the US National Cancer Institute DES Third Generation Study. , 2019, Reproductive toxicology.

[27]  J. Quiles,et al.  Gene pathways associated with mitochondrial function, oxidative stress and telomere length are differentially expressed in the liver of rats fed lifelong on virgin olive, sunflower or fish oils. , 2018, The Journal of nutritional biochemistry.

[28]  J. Braun,et al.  Early-life exposure to EDCs: role in childhood obesity and neurodevelopment , 2017, Nature Reviews Endocrinology.

[29]  C. Spiliopoulou,et al.  Human exposure to endocrine disruptors and breast milk. , 2009, Endocrine, metabolic & immune disorders drug targets.

[30]  M. Poutanen,et al.  Increased endogenous estrogen synthesis leads to the sequential induction of prostatic inflammation (prostatitis) and prostatic pre-malignancy. , 2009, The American journal of pathology.

[31]  Caren L. S. Vilela,et al.  Water contamination by endocrine disruptors: Impacts, microbiological aspects and trends for environmental protection. , 2018, Environmental pollution.

[32]  C. Elliott,et al.  Development of a rapid method for the analysis of synthetic growth promoters in bovine muscle using liquid chromatography tandem mass spectrometry. , 2009, Analytica chimica acta.

[33]  J. Maher,et al.  Isocaloric manipulation of macronutrients within a high-carbohydrate/moderate-fat diet induces unique effects on hepatic lipogenesis, steatosis and liver injury. , 2016, The Journal of nutritional biochemistry.

[34]  A. Herbst,et al.  Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. , 1971, The New England journal of medicine.

[35]  H. Hiura,et al.  Epigenetic alterations in sperm associated with male infertility , 2015, Congenital anomalies.

[36]  M. Gomendio,et al.  Male Fertility in Natural Populations of Red Deer Is Determined by Sperm Velocity and the Proportion of Normal Spermatozoa1 , 2005, Biology of reproduction.

[37]  J. K. Day,et al.  Uterine responsiveness to estradiol and DNA methylation are altered by fetal exposure to diethylstilbestrol and methoxychlor in CD-1 mice: effects of low versus high doses. , 2002, Toxicology and applied pharmacology.

[38]  L. Ding,et al.  Development and characterization of a nanodendritic silver-based solid-phase extraction sorbent for selective enrichment of endocrine-disrupting chemicals in water and milk samples. , 2015, Analytica chimica acta.

[39]  Jie Zhou,et al.  Investigation of diethylstilbestrol residue level in human urine samples by a specific monoclonal antibody , 2017, Environmental Science and Pollution Research.

[40]  A. Adeyoju,et al.  Diethylstilboestrol for the treatment of prostate cancer: past, present and future , 2014, Scandinavian journal of urology.

[41]  Vikas Kumar,et al.  Effects on the reproductive system of young male rats of subcutaneous exposure to n-butylparaben. , 2017, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[42]  Tolga Ünüvar,et al.  Fetal and Neonatal Endocrine Disruptors , 2012, Journal of clinical research in pediatric endocrinology.

[43]  Elizabeth Hatch,et al.  Diethylstilbestrol Revisited: A Review of the Long-Term Health Effects , 1995, Annals of Internal Medicine.

[44]  R. Cavalcante,et al.  Endocrine disruption in Sphoeroides testudineus tissues and sediments highlights contamination in a northeastern Brazilian estuary , 2016, Environmental Monitoring and Assessment.

[45]  Antonio V. Herrera-Herrera,et al.  Determination of estrogenic compounds in milk and yogurt samples by hollow-fibre liquid-phase microextraction-gas chromatography-triple quadrupole mass spectrometry , 2016, Analytical and Bioanalytical Chemistry.

[46]  W. Burnett,et al.  Vaginal cancer after maternal treatment with synthetic estrogens. , 1971, The New England journal of medicine.

[47]  L. Radko,et al.  Application of the yeast-based reporter gene bioassay for the assessment of estrogenic activity in cow's milk from Poland. , 2015, Environmental toxicology and pharmacology.

[48]  Antonio V. Herrera-Herrera,et al.  Multiresidue determination of estrogens in different dairy products by ultra-high-performance liquid chromatography triple quadrupole mass spectrometry. , 2017, Journal of chromatography. A.

[49]  S. Krieg,et al.  ENVIRONMENTAL EXPOSURES : PREGNANCY , PLACENTA , AND MISCARRIAGE Environmental exposure to endocrine-disrupting chemicals and miscarriage , 2016 .

[50]  R. Newbold.  Prenatal exposure to diethylstilbestrol (DES). , 2008, Fertility and sterility.

[51]  Asad Ullah,et al.  Impact of low-dose chronic exposure to bisphenol A and its analogue bisphenol B, bisphenol F and bisphenol S on hypothalamo-pituitary-testicular activities in adult rats: A focus on the possible hormonal mode of action. , 2018, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[52]  C. Sergi,et al.  Current perspective of diethylstilbestrol (DES) exposure in mothers and offspring. , 2017, Reproductive Toxicology.

[53]  K. Yamasaki,et al.  Effects of olive, corn, sesame or peanut oil on the body weights and reproductive organ weights of immature male and female rats. , 2001, Experimental animals.

[54]  H. Chao,et al.  High estrogen concentrations in receiving river discharge from a concentrated livestock feedlot. , 2010, The Science of the total environment.

[55]  Lorenzo Pissinatti,et al.  Cell junctions in the prostate: an overview about the effects of Endocrine Disrupting Chemicals (EDCS) in different experimental models. , 2018, Reproductive toxicology.

[56]  M. Ohkawa,et al.  Neonatally administered diethylstilbestrol retards the development of the blood-testis barrier in the rat. , 2001, Journal of andrology.

[57]  Taotao Ma,et al.  Chemiluminescence screening assay for diethylstilbestrol in meat. , 2008, Food chemistry.

[58]  Michael F. Sweeney,et al.  Environmental endocrine disruptors: Effects on the human male reproductive system , 2015, Reviews in Endocrine and Metabolic Disorders.

[59]  Eva Rahman Kabir,et al.  A review on endocrine disruptors and their possible impacts on human health. , 2015, Environmental toxicology and pharmacology.

[60]  G. Prins,et al.  The Role of Estrogens in Normal and Abnormal Development of the Prostate Gland , 2006, Annals of the New York Academy of Sciences.