Maternal Smoke Exposure Impairs the Long-Term Fertility of Female Offspring in a Murine Model1

Abstract

The theory of fetal origins of adult disease was first proposed in 1989, and in the decades since, a wide range of other diseases from obesity to asthma have been found to originate in early development. Because mammalian oocyte development begins in fetal life it has been suggested that environmental and lifestyle factors of the mother could directly impact the fertility of subsequent generations. Cigarette smoke is a known ovotoxicant in active smokers, yet disturbingly 13% of Australian and 12% of US women continue to smoke throughout pregnancy. The focus of our investigation was to characterize the adverse effects of smoking on ovary and oocyte quality in female offspring exposed in utero. Pregnant mice were nasally exposed to cigarette smoke for 12 wk throughout pregnancy/lactation, and ovary and oocyte quality of the F1 (maternal smoke exposed) generation was examined. Neonatal ovaries displayed abnormal somatic cell proliferation and increased apoptosis, leading to a reduction in follicle numbers. Further investigation found that altered somatic cell proliferation and reduced follicle number continued into adulthood; however, apoptosis did not. This reduction in follicles resulted in decreased oocyte numbers, with these oocytes found to have elevated levels of oxidative stress, altered metaphase II spindle, and reduced sperm-egg interaction. These ovarian and oocyte changes ultimately lead to subfertility, with maternal smoke-exposed animals having smaller litters and also taking longer to conceive. In conclusion, our results demonstrate that in utero and lactational exposure to cigarette smoke can have long-lasting effects on the fertility of the next generation of females.

Is in utero exposure to maternal socioeconomic disadvantage related to offspring ovarian reserve in adulthood?

“…In animal models, experimental studies showed that exposure to maternal smoking, similar to study findings regarding maternal nutritional status, was related to negative reproductive health outcomes in the adult offspring, including indicators of sub-fertility, lower ovarian reserve, and increased oxidative stress [68][69][70]. Consistent with these findings, in a prior study of women, maternal smoking during pregnancy was associated with earlier menopausal timing in the offspring [41].…”

Environmental pollutants, a possible etiology for premature ovarian insufficiency: a narrative review of animal and human data

“…1). This has been shown for numerous substances: BPA [47], phthalates (DEHP [39, 41], DBP [38]), PAH [41, 96], cigarette smoke [65, 76, 77, 79, 82], pesticides [51–54], dioxins [100], genistein [91], PCB [104]. Secondly, a decreased pool of primordial follicles (situation 5 in Fig.…”

“…Effect of polymorphism of glutamate cysteine ligasePrenatal exposure to BaP induced POI. Deletion of glutamate cysteine ligase increased the sensitivity of these ovarian effectsCamlin et al, 2016 [82]Nasal exposure of pregnant mice to cigarette smoke for 12 weeks. Analysis of F1 ovary and oocyte qualityAbnormal proliferation of neonatal somatic cells,⇗ apoptosis, ⇘ follicles at birth and at the adult age.⇗ oxidative stress Human Data Progetto Menopausa Italia Study Group, 2003 [74]Cross-sectional study between 1997 and 1999.Inclusion of patients between ages 45 to 75 making a 1st consultation in a specialized center for menopause in ItalyNo significant association between the risk of POI and smokingChang et al, 2007 [72]Study of risk factors in 137 menopausal patients < 40 years, 281 between 40 and 4 years, and 1318 between 45 and 60 yearsSmoking ⇗ the idiopathic risk of POI: OR = 1.82 [1.03–3.23]Kinney et al, 2007 [110]Effect of cigarette smoking on antral follicle count and FSH in 188 patients aged 22 to 49 yearsChronic cigarette smoking is associated with higher rates of FSH β = 0.21, 95% CI = 0.04, 0.39, but there is no significant difference on the AFCStrohsnitter et al, 2008 [84]Epidemiological study on 4025 women.…”

“…After in utero exposure, the Camlin et al animal study [82] revealed a decrease in the number of follicles at birth and in adulthood by increasing pro-apoptotic phenomena. A cohort study on 1399 adolescents highlighted that paternal cigarette smoking is associated with decreased rates of AMH [83].…”

The use of C57Bl/6 × CBA F1 hybrid cross as a model for human age‐related oocyte aneuploidy

“…A significant reduction in the number of retrievable good-quality GV oocytes was noted at 12 months (P < 0.0001), and this further decreased at 17 months (P < 0.0001).Collected GV oocytes were allowed to mature in vitro at 378C and 5% CO 2 for 16 hr until metaphase II (MII), in Minimum Essential Medium supplemented with fetal calf serum. The ploidy status of MII eggs was investigated using immunofluorescence confocal microscopy, as previously described by Camlin et al (2016). The spindles of MII eggs were collapsed with monastrol to spread chromosomes prior to fixation.…”