All Your Eggs in One Basket: Mechanisms of Xenobiotic Induced Female Reproductive Senescence

Sobinoff, Alexander P.; Bernstein, Ilana R.; McLaughlin, Eileen A.

doi:10.5772/33022

Cited by 1 publication

(2 citation statements)

References 121 publications

(150 reference statements)

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“…The median age of US women at menopause is 50.2 years [ 6 ], but this can be accelerated by exposure to xenobiotics [ 1 , 7 , 8 ]. Loss of follicles is also accompanied by a decline in the level of ovarian hormones, predisposing individuals to increased risk of morbidity [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…Dimethylbenz(a)anthracene (DMBA) is a model ovotoxic polycyclic aromatic hydrocarbon (PAH) which increases atresia in ovarian follicles of all stages [9][10][11]. The presence of PAHs is detectable in cigarette smoke [12], diesel exhaust, charred meat, overheated cooking oil, petroleum coke or asphalt manufacturing, waste incineration, wildfires [13][14][15], and they are air pollutants [16].…”

Section: Introductionmentioning

confidence: 99%

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Obesity partially potentiates dimethylbenz[a]anthracene-exposed ovotoxicity by altering the DNA damage repair response in mice

Rishi

Timme

White

et al. 2023

Biology of Reproduction

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Obesity adversely affects reproduction, impairing oocyte quality, fecundity, conception, and implantation. The ovotoxicant, dimethylbenz[a]anthracene, is biotransformed into a genotoxic metabolite to which the ovary responds by activating the ataxia telangiectasia mutated DNA repair pathway. Basal ovarian DNA damage coupled with a blunted response to genotoxicant exposure occurs in obese females, leading to the hypothesis that obesity potentiates ovotoxicity through ineffective DNA damage repair. Female KK.Cg-a/a (lean) and KK.Cg-Ay/J (obese) mice received corn oil or dimethylbenz[a]anthracene (1 mg/kg) at 9 weeks of age for 7 days via intraperitoneal injection (n = 10/treatment). Obesity increased liver weight (P < 0.001) and reduced (P < 0.05) primary, preantral, and corpora lutea number. In lean mice, dimethylbenz[a]anthracene exposure tended (P < 0.1) to increase proestrus duration and reduced (P = 0.07) primordial follicle number. Dimethylbenz[a]anthracene exposure decreased (P < 0.05) uterine weight and increased (P < 0.05) primary follicle number in obese mice. Total ovarian abundance of BRCA1, γH2AX, H3K4me, H4K5ac, H4K12ac, and H4K16ac (P > 0.05) was unchanged by obesity or dimethylbenz[a]anthracene exposure. Immunofluorescence staining demonstrated decreased (P < 0.05) abundance of γH2AX foci in antral follicles of obese mice. In primary follicle oocytes, BRCA1 protein was reduced (P < 0.05) by dimethylbenz[a]anthracene exposure in lean mice. Obesity also decreased (P < 0.05) BRCA1 protein in primary follicle oocytes. These findings support both a follicle stage-specific ovarian response to dimethylbenz[a]anthracene exposure and an impact of obesity on this ovarian response.

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