Exposure to environmentally relevant concentrations of ambient fine particulate matter (PM2.5) depletes the ovarian follicle reserve and causes sex-dependent cardiovascular changes in apolipoprotein E null mice

Abstract

Background Fine particulate matter (PM2.5) exposure accelerates atherosclerosis and contains known ovotoxic chemicals. However, effects of exposure to PM2.5 on the finite ovarian follicle pool have hardly been investigated, nor have interactions between ovarian and cardiovascular effects. We hypothesized that subchronic inhalation exposure to human-relevant concentrations of PM2.5 results in destruction of ovarian follicles via apoptosis induction, as well as accelerated recruitment of primordial follicles into the growing pool. Further, we hypothesized that destruction of ovarian follicles enhances the adverse cardiovascular effects of PM2.5 in females. Results Hyperlipidemic apolipoprotein E (Apoe) null ovary-intact or ovariectomized female mice and testis-intact male mice were exposed to concentrated ambient PM2.5 or filtered air for 12 weeks, 5 days/week for 4 h/day using a versatile aerosol concentration enrichment system. Primordial, primary, and secondary ovarian follicle numbers were decreased by 45%, 40%, and 17%, respectively, in PM2.5-exposed ovary-intact mice compared to controls (P < 0.05). The percentage of primary follicles with granulosa cells positive for the mitosis marker Ki67 was increased in the ovaries from PM2.5-exposed females versus controls (P < 0.05), consistent with increased recruitment of primordial follicles into the growing pool. Exposure to PM2.5 increased the percentages of primary and secondary follicles with DNA damage, assessed by γH2AX immunostaining (P < 0.05). Exposure to PM2.5 increased the percentages of apoptotic antral follicles, determined by TUNEL and activated caspase 3 immunostaining (P < 0.05). Removal of the ovaries and PM2.5-exposure exacerbated the atherosclerotic effects of hyperlipidemia in females (P < 0.05). While there were statistically significant changes in blood pressure and heart rate variability in PM2.5-compared to Air-exposed gonad-intact males and females and ovariectomized females, the changes were not consistent between exposure years and assessment methods. Conclusions These results demonstrate that subchronic PM2.5 exposure depletes the ovarian reserve by increasing recruitment of primordial follicles into the growing pool and increasing apoptosis of growing follicles. Further, PM2.5 exposure and removal of the ovaries each increase atherosclerosis progression in Apoe-/- females. Premature loss of ovarian function is associated with increased risk of osteoporosis, cardiovascular disease and Alzheimer’s disease in women. Our results thus support possible links between PM2.5 exposure and other adverse health outcomes in women.

Identifying the Relationship between PM2.5 and Hyperlipidemia Using Mendelian Randomization, RNA-seq Data and Model Mice Subjected to Air Pollution

“…The number of monocytes and Th17 cells was increased, and that of M0 macrophages and follicular CD4+ T cells was decreased in the female mice. This suggests that the difference in immune cell infiltration influenced by PM 2.5 is closely related to sex [57]. The increased monocyte and decreased M0 macrophage numbers in the female mice indicated that monocytes were recruited after exposure to PM 2.5 , and the phenotypic transformation of macrophages happened in the PM 2.5 -exposed female mice.…”

Ambient particulate matter air pollution exposure and ovarian cancer incidence in the USA: An ecological study

“…28,29 More recent studies have found associations with brain cancers, 30 kidney and bladder cancers, 31 hepatocellular carcinoma, 32 breast cancer, 33 and overall cancer risk and mortality. [34][35][36] Animal studies have found PM 2.5 to cause ovarian dysfunction and damage via oxidative stress and inflammation through the nuclear factor kappa B (NF-κB)/interleukin 6 (IL-6) signalling pathway in mice, 37 trigger ovarian cell DNA double-strand breaks, as measured by immunofluorescent biomarkers in zebrafish, 38 deplete ovarian follicular reserve and decrease anti-Müllerian hormone concentrations in mice, 39,40 and induce a dose-response relationship between PM 2.5 levels and ovarian degeneration in mosquitoes. 41 To date, evidence for an association between air pollution and ovarian cancer risk has been limited.…”

Melatonin ameliorates PM2.5‐induced spermatogenesis disorder by preserving H3K9 methylation and SIRT3

“…Setarehbadi et al found that the distribution of ApoE genotypes was significantly different between fertile and infertile males 26 . The latest research found that inhalational exposure to PM2.5 could deplete the ovarian follicle reserve in female ApoE −/− mice 27 . However, there was few reports about the effects of PM2.5 on spermatogenesis in hyperlipidemia mice.…”

“…26 The latest research found that inhalational exposure to PM2.5 could deplete the ovarian follicle reserve in female ApoE À/À mice. 27 However, there was few reports about the effects of PM2.5 on spermatogenesis in hyperlipidemia mice. In the present study, ApoE À/À mouse, a mature animal model of hyperlipidemia, was used to investigate whether melatonin ameliorated PM2.5-generated spermatogenesis disorder in testes.…”