Despite advancements in medicine over the past decades, there exists a significant unmet global need for new and improved contraceptive methods for men and women. The development of innovative contraceptives will be facilitated via advancements in biomedical science, biomedical engineering, and drug development technologies. This article describes the need for new methods, opportunities afforded by advancements in biomedical science, strategies being employed to advance innovative novel methods, value of drug development accelerators and the need for industry involvement to provide men and women worldwide greater reproductive autonomy.

Summary Sentence

There is an urgent need for innovation in contraception.

Cancer incidence and relative survival are expected to increase over the next few decades. With the majority of patients receiving combinatorial chemotherapy, an increasing proportion of patients experience long-term side effects from treatment—including reproductive disorders and infertility. A limited number of studies have examined mechanisms of single-agent chemotherapy-induced gonadotoxicity, with chemotherapy-induced oxidative stress being implicated in the loss of reproductive functions. Current methods of female fertility preservation are costly, invasive, only moderately successful, and seldom presented to cancer patients. The potential of antioxidants to alleviate chemotherapy has been overlooked at a time when it is becoming increasingly important to develop strategies to protect reproductive functions during chemotherapy. This review will summarize the importance of reactive oxygen species homeostasis in reproduction, chemotherapy-induced mitochondrial dysfunction in oocytes, chemotherapy-induced oxidative stress, and several promising natural adjuvants.

Summary Sentence

Chemotherapy-induced oxidative stress has long-lasting and devastating impacts on female fertility and reproduction; while there is a devastating lack of affordable and effective interventions available, antioxidants are potential adjuvants.

Graphical Abstract

The contribution of sperm to embryogenesis is gaining attention with up to 50% of infertility cases being attributed to a paternal factor. The traditional methods used in assisted reproductive technologies for selecting and assessing sperm quality are mainly based on motility and viability parameters. However, other sperm characteristics, including deoxyribonucleic acid integrity, have major consequences for successful live birth. In natural reproduction, sperm navigate the male and female reproductive tract to reach and fertilize the egg. During transport, sperm encounter many obstacles that dramatically reduce the number arriving at the fertilization site. In humans, the number of sperm is reduced from tens of millions in the ejaculate to hundreds in the Fallopian tube (oviduct). Whether this sperm population has higher fertilization potential is not fully understood, but several studies in animals indicate that many defective sperm do not advance to the site of fertilization. Moreover, the oviduct plays a key role in fertility by modulating sperm transport, viability, and maturation, providing sperm that are ready to fertilize at the appropriate time. Here we present evidence of sperm selection by the oviduct with emphasis on the mechanisms of selection and the sperm characteristics selected. Considering the sperm parameters that are essential for healthy embryonic development, we discuss the use of novel in vitro sperm selection methods that mimic physiological conditions. We propose that insight gained from understanding how the oviduct selects sperm can be translated to assisted reproductive technologies to yield high fertilization, embryonic development, and pregnancy rates.

Summary Sentence

Understanding how sperm are selected during their transport through the oviduct provides the underpinning for rational development of new technologies for treating infertility.

Trophoblast cells are critical to placental angiogenesis in the first trimester of pregnancy. Dysfunction of trophoblast leads to defective vascular remodeling and impaired angiogenesis, which is believed as the major cause of placental insufficiency and pregnancy failure. Protein O-fucosyltransferase 1 (poFUT1) is mainly responsible for O-fucosylated glycan biosynthesis on glycoproteins, and poFUT1 deficiency causes embryonic lethality in mice. However, the expression and function of poFUT1 in trophoblast-mediated human placental vessel formation remain unclear. In the current study, we showed that fewer blood vessels were observed in the villi and decidua of miscarriage patients than in normal pregnancy women. The expression of poFUT1 was decreased in the trophoblast cells of miscarriage patients compared with normal pregnancy women. Employing HTR/SVneo cells and an in vivo chorioallantoic membrane assay, we demonstrated that poFUT1 promoted the proliferation, migration ability, and angiogenesis potential of trophoblast cells. The results also indicated that poFUT1 upregulated O-fucosylation on uPA, facilitated the binding of uPA and uPAR, activated the RhoA signaling pathway, and further enhanced the angiogenic capacity of trophoblast cells. Our study provides new evidence for a relationship between poFUT1/O-fucosylation and placental angiogenesis. These findings may provide potential diagnostic biomarkers and targeted therapies for miscarriage patients.

Cell surface carbohydrate antigens sialyl Lewis X (sLeX) and Lewis Y (LeY) are paramount glycoconjugates and are abundantly expressed in the receptive endometrium. Furthermore, among the important biological functions of both antigens is their role in leukocytes adhesion and extravasation. Interleukin-1 beta (IL-1β) is involved in the process of human embryo implantation and placenta development. Here, we used an in vitro model to investigate whether sLeX and LeY are playing a role in the embryo implantation process mediated by IL-1β. Our results are showing that the expression of cell surface sLeX was enhanced in endometrial RL95-2 cells after exposure to IL-1β. RT-qPCR detection indicated that the transcript level of glycosyltransferase gene fucosyltransferase 3 (FUT3) was significantly elevated and that of FUT4/7 and ST3 beta-galactoside alpha-2,3-sialyltransferase 3/4 (ST3GAL3/4) were decreased by treatment with IL-1β. Modulatory role of glycosyltransferase FUT3 on sLeX biosynthesis was determined by FUT3 siRNA transfection in RL95-2 cells. Results showed that the expression level of sLeX was suppressed, but no change was observed in regard to LeY. Moreover, IL-1β promoted the HTR-8/SVneo trophoblast spheroids attachment to the RL95-2 endometrial monolayer, which was partially blocked by anti-sLeX antibody and FUT3 knockdown. Gene expression analysis of the RNA-seq transcriptome data from human secretory endometrium demonstrated a significantly higher level of FUT3 in the mid-secretory phase compared to the early secretory phase, which was correlated with the expression of IL1B. In summary, the inflammatory microenvironment at the fetomaternal interface can regulate the glycosylation pattern of endometrial cells at the time of implantation. SLeX can be significantly induced by IL-1β via increasing FUT3 expression, which facilitates the trophoblast adhesion during embryo implantation.

Summary Sentence

sLeX can be significantly induced by IL-1β via increasing FUT3 expression, which facilitates trophoblast adhesion during human embryo implantation.

Graphical Abstract

Genetically engineered mice are widely used to study the impact of altered gene expression in vivo. Within the reproductive tract, the Amhr2-IRES-Cre(Bhr) mouse model is used to ablate genes in ovarian granulosa and uterine stromal cells. There are reports of Amhr2-IRES-Cre(Bhr) inducing recombination in non-target tissues. We hypothesized the inefficiency or off-target Cre action in Amhr2-IRES-Cre(Bhr) mice is due to lack of recombination in every cell that expresses Amhr2. To investigate, we created a new targeted knock-in mouse model, Amhr2-iCre(Fjd), by inserting a codon-optimized improved Cre (iCre) into exon 1 of the Amhr2 gene. Amhr2-iCre(Fjd)/+ males were mated with females that contain a lox-stop-lox cassette in the Sun1 gene so when DNA recombination occurs, SUN1-sfGFP fusion protein is expressed in a peri-nuclear pattern. In adult Amhr2-iCre(Fjd)/+ Sun1^LsL/+ mice, Amhr2-iCre(Fjd)-mediated genetic recombination was apparent in uterine epithelial, stromal, and myometrial cells, while Amhr2-IRES-Cre(Bhr)/+ Sun1^LsL/+ females demonstrated inter-mouse variability of Amhr2-IRES-Cre(Bhr) activity in uterine cells. Fluorescence was observed in Amhr2-iCre(Fjd)-positive mice at post-natal Day 1, indicating global genetic recombination, while fluorescence of individual Amhr2-IRES-Cre(Bhr)-positive pups varied. To determine the developmental stage that genetic recombination first occurs, Sun1^LsL/LsL females were super-ovulated and mated with Amhr2-IRES-Cre(Bhr)/+ or Amhr2^(iCre/+^)Fjd males, then putative zygotes were collected and cultured. In the four-cell embryo, Amhr2-iCre(Fjd) and Amhr2-IRES-Cre(Bhr) activities were apparent in 100% and 25–100% of cells, respectively. In conclusion, Amhr2-IRES-Cre(Bhr) or Amhr2-iCre(Fjd) driven by the Amhr2 promoter is active in the early embryo and can lead to global genetic modification, rendering this transgenic mouse model ineffective.

Summary Sentence

A new mouse model was created by inserting iCre recombinase in the Amhr2 locus, to improve a previous genetic strain of mice. However, Amhr2-iCre causes DNA recombination in the preimplantation embryo, leading to total body genetic modification.

Graphical Abstract

Genetic recombination in the Amhr2-IRES-Cre(Bhr)/+ mouse has mosaic characteristics leading to variation in the genetic recombination in the whole mouse or apparent “leakiness” of Cre activity. The use of iCre to make an Amhr2-iCre(Fjd) mouse causes a more robust and consistent genetic recombination in all cells in the early embryo, leading to a global modification.

Adenomyosis is a benign disease, but it exhibits a metastatic property similar to tumors. Its pathogenesis is still unclear. One theory is that adenomyosis is the result of epithelial-mesenchymal transition (EMT) in displaced embryonic Muller cells. Macrophages accumulate in the eutopic endometrium of adenomyosis and play an important role in EMT and the pathogenesis of adenomyosis. Extracellular vesicles (EVs) are considered an important mechanism of intercellular communication, but few studies have shown the role of EVs between endometrial epithelial cells and macrophages. In this study, we collected the eutopic endometrium of adenomyosis, and acquired the primary endometrial cells, then isolated EVs from the culture supernatants. We identified the characteristics of EVs by transmission electron microscopy, nanoparticle tracking, and western blot, and then detected the mRNA expression levels of CD163, IL-10, iNOS, and TNF-α in macrophages by qRT-PCR after co-cultured with EVs; the expression levels of E-cadherin, CK7, N-cadherin, and Vimentin by Western blot, and the migration abilities of epithelial cells by Transwell assay. The results showed that macrophages were highly expressed in the mRNA levels of CD163, IL10, and TNF-α after treated by EVs from adenomyosis patients; endometrial epithelial cells expressed lower protein levels of E-cadherin and CK7, higher levels of N-cadherin and Vimentin after co-cultured with the above polarized macrophages; and the migration abilities of epithelial cells were enhanced. In conclusion, EVs derived from adenomyosis can induce macrophages to polarize toward M2b, and the polarized macrophages could, in turn, induce EMT process in endometrial epithelial cells.

Summary Sentence

Adenomyosis-derived extracellular vesicles promote epithelial-mesenchymal transition in endometrial epithelial cells by inducing macrophage to polarize toward M2b.

Graphical Abstract

Polycystic ovary syndrome (PCOS) is one of the most common female reproductive and metabolic disorders. The ketogenic diet (KD) is a diet high in fat and low in carbohydrate. The beneficial effects of KD intervention have been demonstrated in obese women with PCOS. The underlying mechanisms, however, remain unknown. The aim of the present study was to investigate the effects of a KD on both reproductive and metabolic phenotypes of dehydroepiandrosterone (DHEA)-induced PCOS mice. Female C57BL/6 mice were divided into three groups, designated Control, DHEA, and DHEA+KD groups. Mice of both Control and DHEA groups were fed the control diet, whereas DHEA+KD mice were fed a KD with 89%(kcal) fat for 1 or 3 weeks after PCOS mouse model was completed. At the end of the experiment, both reproductive and metabolic characteristics were assessed. Our data show that KD treatment significantly increased blood ketone levels, reduced body weight and random and fasting blood glucose levels in DHEA+KD mice compared with DHEA mice. Glucose tolerance, however, was impaired in DHEA+KD mice. Ovarian functions were improved in some DHEAmice after KD feeding, especially in mice treated with KD for 3 weeks. In addition, inflammation and cell apoptosis were inhibited in the ovaries of DHEA+KD mice. Results from in vitro experiments showed that the main ketone body β-hydroxybutyrate reduced inflammation and cell apoptosis in DHEA-treated KGN cells. These findings support the therapeutic effects of KD and reveal a possible mechanism by which KD improves ovarian functions in PCOS mice.

Summary Sentence

Our findings support the role of KD intervention in weight loss, reducing blood glucose, and improving ovarian functions in PCOS mice and reveal a possible mechanism by which KD improved ovarian functions by inhibiting inflammation and cell apoptosis in ovarian granulosa cells in PCOS.

Growth differentiation factor 9 (GDF9) is a secreted protein belonging to the transforming growth factor beta superfamily and has been well characterized for its role during folliculogenesis in the ovary. Although previous studies in mice and sheep have shown that mutations in GDF9 disrupt follicular progression, the exact role of GDF9 in pigs has yet to be elucidated. The objective of this study was to understand the role of GDF9 in ovarian function by rapidly generating GDF9 knockout (GDF9–/–) pigs by using the CRISPR/Cas9 system. Three single-guide RNAs designed to disrupt porcine GDF9 were injected with Cas9 mRNA into zygotes, and blastocyst-stage embryos were transferred into surrogates. One pregnancy was sacrificed on day 100 of gestation to investigate the role of GDF9 during oogenesis. Four female fetuses were recovered with one predicted to be GDF9–/– and the others with in-frame mutations. All four had fully formed oocytes within primordial follicles, confirming that knockout of GDF9 does not disrupt oogenesis. Four GDF9 mutant gilts were generated and were grown past puberty. One gilt was predicted to completely lack functional GDF9 (GDF9–/^–), and the gilt never demonstrated standing estrus and had a severely underdeveloped reproductive tract with large ovarian cysts. Further examination revealed that the follicles from the GDF9–/^– gilt did not progress past preantral stages, and the uterine vasculature was less extensive than the control pigs. By using the CRISPR/Cas9 system, we demonstrated that GDF9 is a critical growth factor for proper ovarian development and function in pigs.

Summary Sentence

Inactivation of growth differentiation factor 9 revealed its critical role for proper ovarian development and function in pigs.

Reproductive longevity is associated with health outcomes. Early menopause, loss of ovarian function, and male infertility are linked to shorter lifespan and increased adverse health outcomes. Here we examined the extragonadal effects of whole animal loss of spermatogenesis and oogenesis specific basic helix–loop–helix 1 (Sohlh1) gene in mice, a well-described mouse model of female and male infertility. Sohlh1 encodes a transcription factor that is primarily expressed in the male and female germline and regulates germline differentiation. The Sohlh1 knockout mouse model, just like human individuals with SOHLH1 loss of function, presents with hypergonadotropic hypogonadism and loss of ovarian function in females and impaired spermatogenesis in males, with a seemingly gonad restricted phenotype in both sexes. However, extragonadal phenotyping revealed that Sohlh1 deficiency leads to abnormal immune profiles in the blood and ovarian tissues of female animals, sex-specific alterations of metabolites, and behavior and cognition changes. Altogether, these results show that Sohlh1 deficiency impacts overall health in both male and female mice.

Summary Sentence

Sohlh1 deficiency affects systemic health beyond gonadal dysfunction in mice, inducing changes in immune cell populations, metabolism, and cognition.

Ovulation is an integral part of women's menstrual cycle and fertility. Understanding the mechanisms of ovulation has broad implications for the treatment of anovulatory diseases and the development of novel contraceptives. Now, few studies have developed effective models that both faithfully recapitulate the hallmarks of ovulation and possess scalability. We established a three-dimensional encapsulated in vitro follicle growth (eIVFG) system that recapitulates folliculogenesis and produces follicles that undergo ovulation in a controlled manner. Here, we determined whether ex vivo ovulation preserves molecular signatures of ovulation and demonstrated its use in discovering novel ovulatory pathways and nonhormonal contraceptive candidates through a high-throughput ovulation screening. Mature murine follicles from eIVFG were induced to ovulate ex vivo using human chorionic gonadotropin and collected at 0, 1, 4, and 8 hours post-induction. Phenotypic analyses confirmed key ovulatory events, including cumulus expansion, oocyte maturation, follicle rupture, and luteinization. Single-follicle RNA-sequencing analysis revealed the preservation of ovulatory genes and dynamic transcriptomic profiles and signaling. Soft clustering identified distinct gene expression patterns and new pathways that may critically regulate ovulation. We further used this ex vivo ovulation system to screen 21 compounds targeting established and newly identified ovulatory pathways. We discovered that proprotein convertases activate gelatinases to sustain follicle rupture and do not regulate luteinization and progesterone secretion. Together, our ex vivo ovulation system preserves molecular signatures of ovulation, presenting a new powerful tool for studying ovulation and anovulatory diseases as well as for establishing a high-throughput ovulation screening to identify novel nonhormonal contraceptives for women.

Summary Sentence

Ex vivo ovulation enables novel contraception discovery for women.

Graphical Abstract

Glucocorticoids modulate the feto-maternal interface during the induction of parturition. In the dog, the prepartum rise of cortisol in the maternal circulation appears to be erratic, and information about its contribution to the prepartum luteolytic cascade is scarce. However, the local placental upregulation of glucocorticoid receptor (GR/NR3C1) at term led to the hypothesis that species-specific regulatory mechanisms might apply to the involvement of cortisol in canine parturition. Therefore, here, we assessed the canine uterine/utero-placental spatio-temporal expression of hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1; reduces cortisone to cortisol), and -2 (HSD11B2; oxidizes cortisol to the inactive cortisone). Both enzymes were detectable throughout pregnancy. Their transcriptional levels were elevated following implantation, with a strong increase in HSD11B2 post-implantation (days 18–25 of pregnancy), and in HSD11B1 at mid-gestation (days 35–40) (P < 0.05). Interestingly, when compared pairwise, HSD11B2 transcripts were higher during post-implantation, whereas HSD11B1 dominated during mid-gestation and luteolysis (P < 0.05). A custom-made species-specific antibody generated against HSD11B2 confirmed its decreased expression at prepartum luteolysis. Moreover, in mid-pregnant dogs treated with aglepristone, HSD11B1 was significantly higher than -2 (P < 0.05). HSD11B2 (protein and transcript) was localized mostly in the syncytiotrophoblast, whereas HSD11B1 mRNA was mainly localized in cytotrophoblast cells. Finally, in a functional approach using placental microsomes, a reduced conversion capacity to deactivate cortisol into cortisone was observed during prepartum luteolysis, fitting well with the diminished HSD11B2 levels. In particular, the latter findings support the presence of local increased cortisol availability at term in the dog, contrasting with an enhanced inactivation of cortisol during early pregnancy.

Summary Sentence

The canine placenta appears to have increased trophoblast-mediated inactivation of cortisol during mid-pregnancy, whereas parturition appears to be marked by increased local cortisol availability.

Graphical Abstract

Preeclampsia (PE) is a relatively common but severe pregnancy disorder (with very limited effective treatments) characterized by hypertension (HTN) and usually proteinuria (PRO) or other organ damage. Genome-wide association studies (GWAS) of PE, HTN, and PRO have mostly identified risk loci single nucleotide polymorphisms (SNPs) located in noncoding genomic regions, likely impacting the regulation of distal gene expression. The latest GWAS associated (P < 1 × 10^-6) SNPs to PE (n = 25), HTN (n = 1926), and PRO (n = 170). Our algorithmic analysis (CoDeS3D) used chromatin connection data (Hi-C) derived from 70 cell lines followed by analysis of two expression quantitative trail loci (eQTL) cohorts: GTEx (838 donors, 54 tissues, totaling 15 253 samples) and DICE (91 donors, 13 blood tissue types). We identified spatially constrained eQTLs which implicate gene targets in PE (n = 16), HTN (n = 3561), and PRO (n = 335). By overlapping these target genes and their molecular pathways (protein–protein interaction networks), we identified shared functional impacts between PE and HTN, which are significantly enriched for regulatory interactions which target genes intolerant to loss-of-function mutations. While the disease-associated SNP loci mostly do not overlap, the regulatory signals (target genes and pathways) overlap, informing on PE risk mechanisms. This demonstrates a model in which genetic predisposition to HTN and PRO lays a molecular groundwork toward risk for PE pathogenesis. This overlap at the gene regulatory network level identifies possible shared therapeutic targets for future study.

Summary Sentence

Our model suggests that the better studied genetic predisposition to hypertension shares a molecular basis with preeclampsia risk, suggesting shared pathways for treatment.

Graphical Abstract

Capacitation is an important event in the completion of fertilization by mammalian sperm. Cholesterol efflux is a trigger of capacitation. In general, cholesterol acceptors of albumin and β-cyclodextrins are used to induce capacitation during in vitro fertilization. Previously, we reported that methyl-β-cyclodextrin (MBCD), which is composed of seven glucoses, had a higher ability to induce capacitation than bovine serum albumin (BSA) in frozen–thawed mouse sperm. Comparison of albumin and cyclodextrins is helpful for understanding the mechanism of capacitation. In this study, we examined the effects of albumin, MBCD, and a different type of cyclodextrin, dimethyl-α-cyclodextrin (DMACD), which is composed of six glucoses, on several events of sperm capacitation. We showed that DMACD induced sperm capacitation and promoted fertilization ability. The time required to increase the fertilization rate differed among BSA, MBCD, and DMACD. BSA and MBCD enhanced cholesterol and phospholipid efflux, whereas DMACD enhanced only phospholipid efflux. BSA, MBCD, and DMACD increased sperm membrane fluidity, rearrangement of the lipid raft, and the acrosome reaction. These findings suggest that phospholipid efflux is a novel trigger of capacitation. Increasing the choice of sperm capacitation inducers may be useful for improving in vitro fertilization (IVF) techniques not only in mice, but also in various species in which it has been difficult to produce embryos by IVF.

Summary Sentence

Dimethyl-α-cyclodextrin induces capacitation by changing the membrane environment, including membrane fluidity, lipid raft relocalization and the acrosome reaction.

Graphical Abstract

Figure Abstract Overview of experimental design. Sperm were treated with BSA, MBCD (cholesterol acceptors), and DMACD (phospholipid acceptor). After incubation with BSA, MBCD, or DMACD, sperm functions were evaluated (lipids efflux, capacitation markers, fertilization ability, and developmental ability). In the analysis of lipids efflux, cholesterol and phospholipids released from sperm membrane were quantified. In the analysis of capacitation markers, membrane fluidity, localization of lipid raft, and acrosome reaction were evaluated. In the analysis of fertilization ability, fertilization rate was evaluated by in vitro fertilization. In the analysis of developmental ability, developmental rates of two-cell embryos to blastocysts or pups were examined by in vitro culture and embryo transfer.

Characterization of spermatogonial stem cells (SSCs) has been hampered by their low frequency and lack of features that distinguish them from committed spermatogonia. Few conserved SSC markers have been discovered. To identify a new SSC marker, we evaluated SIRPA expression in mouse and rat SSCs. SIRPA was expressed in a small population of undifferentiated spermatogonia. SIRPA, and its ligand CD47 were expressed in cultured SSCs. Expression of both SIRPA and CD47 was upregulated by supplementation of GDNF and FGF2, which promoted SSC self-renewal. Sirpa depletion by short hairpin RNA impaired the proliferation of cultured SSCs, and these cells showed decreased MAP2K1 activation and PTPN11 phosphorylation. Immunoprecipitation experiments showed that SIRPA associates with PTPN11. Ptpn11 depletion impaired SSC activity in a manner similar to Sirpa depletion. SIRPA was expressed in undifferentiated spermatogonia in rat and monkey testes. Xenogenic transplantation experiments demonstrated that SIRPA is expressed in rat SSCs. These results suggest that SIRPA is a conserved SSC marker that promotes SSC self-renewal division by activating the MAP2K1 pathway via PTPN11.

Summary Sentence

SIRPA is expressed on mouse and rat SSCs.

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, γ H2AX, 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 γ H2AX 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.

Summary Sentence

Different responses to DMBA exposure occur in lean and obese mice, indicating that obesity impairs DNA repair in the ovary.