Table 1.
Causes of efferent ductule dysfunction, with potential for the induction of testicular atrophy
| CAUSE | DESCRIPTION | POTENTIAL TARGETa | REFERENCES |
|---|---|---|---|
| CHEMICAL | |||
| ICI 182,780 | Fulvestrant | Inhibition of fluid resorption; blocks ESR1 and ESR2; similar to Esr1KO | 6,76,78,88-90 |
| GR40370X | 5-hydroxytryptamine receptor agonist; Serotonin-like, monoamine neurotransmitter | Inhibition of fluid resorption; vasoconstriction of venous plexus | 156 |
| PDE4 inhibitor | Phosphodiesterase-4 inhibitor | Inhibition of fluid resorption followed by occlusion; sperm granulomas | 147 |
| Uranyl nitrate hexahydrate | Dietary long-term exposure; proximal convoluted tubules of kidney sensitive | Inhibition of fluid resorption; progressive dilation of seminiferous tubules | 157 |
| LTI-1 | Leukotriene A(4) hydrolase inhibitor | Occlusion; dysregulation in fluid reabsorption; sperm granuloma | 2 |
| 6-chloro-6-deoxysugars | α-chlorohydrin-like chemicals | Occlusion; dysregulation of fluid resorption; sperm granuloma in efferent ductules; initial segment epididymis necrosis; inhibit glyceraldehyde-3-phosphate dehydrogenase | 148,158-165 |
| Isoproterenol | Beta-adrenergic agonist | Potential increase in rate of resorption; upregulates endothelin receptor-A; Et-1 increases Slc9a3 and inflammation | 166-168 |
| Benomylb | Methyl [1-[(butylamino)carbonyl]-1H-benzimidazol-2-yl]carbamate | Occlusion; microtubule disruption; germ cell sloughing; sperm granuloma | 4,130,131,135,136,169,170 |
| 2-Methylimidazole | Polymerization cross-linking and catalytic curing agent for epoxy resins | Occlusion; efferent duct sperm granuloma near caput epididymis | 171 |
| EDS | Ethane-1,2-dimethyl-sulfonate | Occlusion; alkylating agent, cellular toxicity; sperm granuloma | 158,172 |
| Cadmium | Chemical element, Cd | Occlusion; vascular endothelium; sperm granuloma | 173, 174 |
| 1,3-dinitrobenzene | m-Dinitrobenzene | Occlusion; impaired oxygen transport; sperm granuloma | 175, 176 |
| Dibutyl phthalate (DBP) | Di-n-butyl phthalate | Occlusion; prenatal exposure; epididymal malformation | 177 |
| Linuron | N - (3,4-dichlorophenyl)-N’-methoxy-N’-methylurea | Occlusion; herbicide; prenatal exposure; epididymal malformation | 178 |
| DES | Diethylstilbestrol | Neonatal exposure; decreases androgen receptor; sperm granuloma; dilation of lumen | 179-185 |
| Estradiol | β-estradiol 17-cypionate; 17β-estradiol; estradiol benzoate; ethinyl estradiol | Neonatal exposure; sperm granuloma; dilation lumen | 181, 182,186-188 |
| GENE MANIPULATIONd | |||
| Esr1 KO | Estrogen receptor-α | Inhibition of fluid resorption; decreases in SLC9A3, CA2, AQP-1, AQP-9, CAR14, SLC4A4; increases in CFTR, SLC9A1, SLC26A3 | 6,19,35,47,74, 75,77-80,97 |
| AF2ERKI MT | ESR1 AF-2 mutation | Inhibition of fluid resorption; blocks ESR1 AF-2 domain; similar to Esr1 KO | 97 |
| Slc9a3 KO | Sodium/hydrogen exchanger-3 | Inhibition of fluid resorption | 77 |
| Car2 MT | Carbonic anhydrase II | Inhibition of fluid resorption | 77 |
| Gpr64 KO | G protein-coupled receptor 64 (He6) | Inhibition of fluid resorption | 126 |
| He6 KO | GPR64; orphan member of the LNB-7TM (B(2)) subfamily of G-protein-coupled receptors | Inhibition of fluid resorption; proximal efferent ductules; partial sperm stasis | 126 |
| Lgr4 KO or MT | G protein-coupled receptor | Inhibition of fluid resorption; decreased expression of ESR1 and SLC9A3; also occlusion | 123, 124 |
| Prkar1a+/− | Protein kinase A (PKA) type Iα regulatory subunit (RIα) | Inhibition of fluid resorption; inhibition of Slc9a3 by over phosphorylation | 127 |
| Fst OE | Follistatin; inhibitor of activin | Inhibition of fluid resorption or ductule contraction; sperm stasis; decreased expression of ESR1 | 125 |
| Lfng KO | O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase | cNotch signaling; blocked connection with efferent ducts | 189 |
| Notch1 OE | Notch homolog 1, translocation-associated | cTransmembrane, oncogene, efferent ductule overgrowth | 190 |
| Pkd1 KO | Polycystic kidney disease 1 homolog | Abnormal epididymal development; dilation of efferent ductules | 191 |
| TE rat MT | Outbred Wistar strain | Autoimmune disorder; sperm granuloma | 192 |
| Dax1 KO | Nr0b1; transcription | cOcclusion; overgrowth of Sertoli cell and efferent duct epithelium | 193 |
| ProxE-AR or CEAR KO | Androgen receptor knockout in initial segment or caput epididymis | Occlusion; differentiation failure in caput epididymis; sperm granuloma | 194, 195 |
| Dicer1KO | Endoribonuclease; RNA interference | Occlusion; abnormal growth and blockage | 196 |
| HUMAN DISEASE | |||
| Von Hippel-Lindau disease | Papillary cystadenoma of the epididymis; also cystic kidney | Dysregulation of HIF1α; upregulation of vascular endothelial growth factor (VEGF) | 197-201 |
| Young's syndrome | Chronic sinopulmonary infections; azoospermia | Abnormal secretion or resorption; occlusion of caput and middle epididymis | 202-205 |
| Varicocele | Dilation of veins near rete testis and efferent ductules | Occlusion; compression of excurrent ducts and edema; blockage | 206 |
| Spontaneous granuloma | Caput epididymis efferent ductules | Occlusion; sperm granuloma; fibrosis; recanalization | 207-209 |
| Renal failure | Renal dialysis; renal malformations; renal cysts | Dilation of rete testis and epididymis; can lead to occlusion; intraductal calcium oxalate deposits | 210-216 |
| PHYSICAL | |||
| Ligation of ductules | Surgical blockage | Fluid accumulation; greater testicular effects when occluded closer to the rete testis | 1,129,133,150,151,217-225 |
| Arterial occlusion | Superior epididymal artery | Occlusion; localized ischaemia, sperm granuloma | 151,226,227 |
aPotential target for mechanisms in efferent ductules and rete testis, not necessarily testis or other organs.
bIncluding its metabolite carbendazim.
cOcclusion involves overgrowth of epithelium in rete testis and efferent ductules, but may also involve disruption of fluid reabsorption.
dGene knockout (KO); overexpression (OE); mutation (MT).