Toxicity of Methoxyacetic Acid in Cultured Human Luteal Cells

Abstract

Ethylene glycol monomethyl ether (EGME) and its proximate metabolite, 2-methoxyacetic acid (MAA), increase ovarian luteal cell progesterone production in the female rat in vivo and in cultured rat luteal cells in vitro, respectively. In order to better assess the potential hazard of EGME and MAA to women, these studies were conducted to determine whether the same concentrations of MAA increase progesterone in human luteinized granulosa cells as in rat luteal cells. Human cells were collected from healthy anonymous oocyte donors, washed, plated 25,000 viable cells per well, and treated with 10 IU hCG and 0-5 mM MAA for 6-48 hr. Progesterone in media was significantly elevated after 24 hr incubation at 3=1 mM MAA. MAA had no effect on ATP levels at 6 or 24 hr. Thus, MAA increased progesterone production in cultured human luteal cells at the same concentration as MAA increased progesterone in rat luteal cells. The implication is that EGME has the potential to alter ovarian luteal function in women. These data should be useful for determining the real health hazards and potential risks of EGME exposure, e i»7 society of To Ethylene glycol monomethyl ether (EGME) is a commonly used solvent that has been identified as a reproductive toxicant in humans and in animal models of human disease (reviewed in National Institute for Occupational Safety and Health, 1983, 1991). Recently published epidemiological studies have associated ethylene glycol-based solvent exposure in women with increased risks of spontaneous abortion, menstrual cycle dysfunction, and subfertility (Pastides et al., 1988;Gold et al., 1995;Correa et al, 1996). Specifically, solvent-exposed women had a 4.6-fold increase in risk of infertility (95% confidence interval 1.6-13.3) and a 2.8-fold increase in risk of spontaneous abortion (95% confidence interval 1.4-5.6) (Correa et al., 1996). A dose-response relationship between estimated ethylene glycol exposure and each of these outcomes has also been found.Concurrent with the publication of these studies, we determined that the luteal cell is a target for EGME and its proximate toxic metabolite, 2-methoxyacetic acid (MAA), in the female rat (Davis et al., 1997). Specifically, in vivo dosing with EGME (300 mg/kg) elevated serum progesterone and suppressed cyclicity, inhibited ovulation, and increased corpora lutea size by inhibiting luteolysis. In vitro, 1-10 mM MAA elevated progesterone after 24 hr of treatment, but had no effect on cAMP at 1, 3, 24, or 48 hr or ATP levels at 24 hr. Based on these data, we concluded that EGME and MAA increase ovarian luteal cell progesterone production independent of LH-stimulated cAMP.The question remains as to how the reproductive toxicity of EGME and MAA in the rat relates to the potential reproductive toxicity of EGME and MAA in women. To begin to bridge the knowledge gap, this study was designed to determine whether MAA affects progesterone production in cultured human luteinized granulosa cells at concentrations similar to those in the rat and provide data to allow d...

Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition

“…Our initial studies led us to ethylene glycol monomethyl ether (EGME), a pervasive industrial solvent found in varnishes, paints, dyes, and fuel additives. Exposure to this compound and its primary metabolite MAA induce severe reproductive toxicity in both humans and rodents (11,12). Based on reports that toxic doses of EGME give rise to 5 mM MAA plasma levels in rodents and that similar concentrations of MAA are observed in the urine of humans after occupational EGME exposure (13,14), we treated cells with 5 mM MAA to achieve comparable MAA levels for our studies.…”

Prolonged menstrual cycles in female workers exposed to ethylene glycol ethers in the semiconductor manufacturing industry

“…8 9 This metabolite altered the ovarian luteal function, and increased ovarian luteal cell progesterone production in female rats 10 and in cultured human cells. 11 Previous epidemiological studies suggested that long cycles may indicate delayed ovulation, 27 and short cycles may reflect a short follicular phase 28 or anovulation. 29 Exposure to EGEs was associated with prolonged time to pregnancy in female fab workers.…”

“…7 Animal studies and human culture cells have suggested that the major metabolite of ethylene glycol monomethyl ether, 2-methoxyacetic acid, is most significantly associated with the increase of these risks. [8][9][10][11] Few studies 12 13 have discussed the relation between occupational exposure to contaminants and a change in menstrual cycles. A prospective semiconductor industry study 12 found that the mean and standard deviation of the cycle length were significantly greater among female workers engaged in thin film and ion implantation jobs than among non-fabrication (non-fab) workers.…”

Effects of sulpiride and ethylene glycol monomethyl ether on endometrial carcinogenicity in Donryu rats

“…In female rats, EGME induces PRL secretion (Taketa et al, ). EGME and its active metabolite, 2‐methoxy acetic acid, are also known to induce the hypersecretion of P4 from luteal cells (Almekinder et al, ; Davis et al, ).…”