Metabolism of the environmental toxicant benzo(a)pyrene by subcellular fractions of human ovary

Abstract

<jats:p> Knowledge of the ability of the female reproductive system to metabolize environmental chemicals is critical not only from the standpoint of toxicity but also from infertility risk assessment. Benzo( a)pyrene (BaP) is a toxicant that is released into the environment from automobile exhausts, cigarette smoke, burning of refuse, industrial emissions, and hazardous waste sites. In exposed animals, BaP becomes activated to reactive metabolites that interfere with target organ function and as a consequence cause toxicity. Studies on animal models conducted in our laboratories and those of others have shown that BaP possess endocrine disrupting properties. Thus, this chemical has the potential to cause infertility and cancers in the female genital tract. An understanding of BaP metabolism in the female reproductive system will be of importance in the diagnosis and management of female fertility as well as cancers in the reproductive tissues. Therefore, the objective of our study was to examine the metabolism of BaP by human ovarian subcellular fractions. Human ovary samples (eight individuals) were obtained from postoperative tissue removed from subjects with uterine tumors. Subcellular fractions (nuclear, cytosolic, mitochondrial, and microsomal) were prepared by differential centrifugation. BaP (1 μM and 3 μM) was individually incubated with individual subcellular fractions for 15 min and the products were analyzed by high-performance liquid chromatography. Among the different fractions tested, microsomal BaP metabolism was higher than the rest of the fractions. The BaP metabolites identified were as follows: BaP-9,10-diol, BaP-4,5-diol, BaP-7,8-diol, 9(OH) BaP, 3(OH) BaP, BaP-1,6-dione, BaP-3,6-dione, and BaP-6,12-dione. Of interest was the presence of DNA-reactive metabolites such as BaP-3,6-dione, BaP-6,12-dione, and BaP 7,8-diol, which have been implicated in the causation of infertility and cancer. Our results indicate that women who are exposed to BaP via cigarette smoke, occupational settings, and diet are more likely at a larger risk of this toxicant-induced infertility and cancer than others. </jats:p>

Endocrine-Disrupting Air Pollutants and Their Effects on the Hypothalamus-Pituitary-Gonadal Axis

“…Benzo(a)pyrene (BaP) is a well-known PAH that can generate reactive oxygen species and create BP diol-epoxide-DNA adducts (BPDE) [66]. BaP exposure can come from automobile exhaust and cigarette smoke [67]. Human exposures to BaP range from 8.4 to 17 µg/person/day through the diet (Ramesh et al, 2011).…”

“…Human subcellular ovary samples (n = 8) were incubated with two doses of BaP, 1 µM or 3 µM, in order to measure BaP ovarian toxicity [67]. Ovary samples were obtained from women who underwent operations to remove uterine tumors [67].…”

“…Human subcellular ovary samples (n = 8) were incubated with two doses of BaP, 1 µM or 3 µM, in order to measure BaP ovarian toxicity [67]. Ovary samples were obtained from women who underwent operations to remove uterine tumors [67]. The tissue incubated with 3 µM created significantly more BaP metabolites than the tissue incubated with 1 µM [67].…”

BaP exposure causes oocyte meiotic arrest and fertilization failure to weaken female fertility

“…BaP exposure could alter the steroid balance in females (29)(30)(31), especially the expression of ovarian estrogen receptor (30). It has also been shown that BaP is associated with premature ovarian failure, through the rapid depletion of the primordial follicle pool (32)(33)(34)(35), and causes decreased rates of conception in women who seek in vitro fertilization (36,37). In addition, BaP metabolites impair follicle growth and cause increased primordial follicle activation (38) and follicle atresia in vitro through the induction of apoptosis (39)(40)(41)(42).…”

Benzo(a)pyrene inhibits migration and invasion of extravillous trophoblast HTR‐8/SVneo cells via activation of the ERK and JNK pathway

“…The metabolites are activated to electrophilic intermediates capable of covalent binding to cellular macromolecules such as DNA, RNA or proteins, which subsequently causes deleterious effects in susceptible tissues. (Ling et al, 2004;Rekhadevi et al, 2014).…”