Mechanism of Antifertility in Male Rats Treated With 3-Monochloro-1,2-Propanediol (3-McPd)

Abstract

3-Monochloro-1,2-propanediol (3-MCPD) is a food contaminant that is often found in foods containing acid-hydrolyzed (AH) protein, like seasonings and savory food products. The purpose of the present study was to investigate the effects of 3-MCPD on male fertility, sperm, and hormonal levels and its antifertility mechanism. In vivo male fertility testing was performed to observe the adverse effects of 3-MCPD on the functioning of the male reproductive system and pregnancy outcome. 3-MCPD (0.01-5 mg/kg) was administered daily by gavage to Sprague-Dawley (SD) male rats for 4 wk. At the end of the pretreatment period, male rats were mated overnight with untreated females. Males successfully inducing pregnancy were sacrificed to assess sperm parameters, reproductive organ histopathology, and spermatogenesis. The resulting pregnant females were sacrificed on 20 of gestation to evaluate pregnancy outcome. The paternal administration of 3-MCPD (5 mg/kg) was found to result in adverse effects on male fertility and pregnancy outcome without inducing remarkable histopathological changes in testes and epididymides. Additionally, 3-MCPD (5 mg/kg) significantly reduced sperm motility, copulation, fertility indices, and the number of live fetuses showed steep dose-response curves. 3-MCPD did not affect spermatogenesis or induce hormonal changes in the blood and testes of male rats. An in vitro hormone assay using primary isolated Leydig cells showed no significant changes in related hormone levels after 3-MCPD treatment. To evaluate the effects of 3-MCPD on apoptotic induction and H+-ATPase levels in the testis and epididymis, 10 or 100 mg/kg of 3-MCPD was administered by gavage to male rats and testes and epididymides were examined at 3, 6, 12, and 24 h later. Apoptosis was not detected in the testes of animals treated with 100 mg/kg 3-MCPD. However, the level of H+-ATPase in the cauda epididymis was reduced by 3-MCPD treatment. These results indicate that 3-MCPD induced a spermatotoxic effect, which was mediated by reduced H+-ATPase expression in the cauda epididymis, and suggest that an altered pH level in the cauda epididymis might lead to a disruption of sperm maturation and the acquisition of motility.

Proteomic analysis of 3-MCPD and 3-MCPD dipalmitate toxicity in rat testis

“…Interference with glycolysis due to an inhibition of GAPDH activity by b-chlorolactaldehyde, a metabolite of 3-MCPD and 3-MCPD esters, has been reported by different groups (JECFA, 2002;Jones and Porter, 1995;Mohri et al, 1975). Earlier studies postulated that 3-MCPD treatment reduces sperm motility, thus massively hampering fertilization (Kwack et al, 2004;Miki et al, 2004). Apart from its function in energy metabolism, GAPDH is also capable of altering cytoskeletal structure and interacts with tubulin and actin in microtubule bundling and actin polymerization (Sirover, 2011).…”

“…At higher doses of 3-MCPD of >10e20 mg/kg body weight per day, alterations in sperm morphology and epididymal lesions are additionally observed in rats (Jones, 1983). Moreover, spermatotoxic effects of 3-MCPD are suggested to be mediated by reduced H1-ATPase expression and effects on protein kinase A signaling, leading to a disruption of sperm maturation and reduced sperm motility (Kwack et al, 2004;Zhang et al, 2012). Nevertheless, further studies are necessary to elucidate the molecular consequences of 3-MCPD testicular toxicity and its esters.…”

Risks for human health related to the presence of 3‐ and 2‐monochloropropanediol (MCPD), and their fatty acid esters, and glycidyl fatty acid esters in food

“…3-MCPD is considered to cause toxicity in several tissues and spermatozoa through inhibition of GAPDH and therefore glycolysis with energy depletion as result (Ford and Waites, 1982;Kwack et al, 2004;Skamarauskas et al, 2007). This mechanism may be involved also in neurons because cytotoxicity of 3-MCPD in primary mouse neocortical cells was associated with a drop in cellular ATP, and both decrease in ATP and cell death were ameliorated by addition of pyruvate to the culture medium (Sheline and Choi, 1998).…”

The selective neurotoxicity produced by 3-chloropropanediol in the rat is not a result of energy deprivation

“…It has been clearly shown that the toxicity of 3-CPD to spermatozoa (Jones and Porter, 1995;Kwack et al, 2004) is attributable to catalytic inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a polyfunctional protein (Sirover, 1997) that plays a key role in glycolysis. In addition, it has been shown in neuronal cultures that 3-CPD causes cell death and an increase in the concentration of dihydroxyacetone phosphate (which is in isomeric equilibrium with glyceraldehyde-3-phosphate, G3P), and that neuronal death could be antagonised by addition of pyruvate, the product of GAPDH (Sheline and Choi, 1998).…”