• Phthalate exposure induces features of aging in mouse oocytes, including reduced fertilization rate. 
  • NMN prevents disruptions in mitochondrial health induced by phthalates in mouse oocytes. 
  • Oocyte cell death and DNA damage induced by phthalate are prevented by NMN. 

The female reproductive system ages faster than any other system in the body, and the ability of oocytes (eggs) to become fertilized declines with age. Thus, accelerating the age of oocytes can promote infertility. Now, a new study from Nanjing Medical University in China suggests that phthalates may accelerate oocyte aging, which could be reversed by NMN. 

As reported in Cell Proliferation, Jiang and colleagues show that benzyl butyl phthalate (BBP) induces many common features of aging in mouse oocytes, including reduced fertilization rate. They then show that NMN prevents many of the underlying cellular features of phthalate exposure and aging, including DNA damage, mitochondrial damage, and cell death. 

“These findings revealed a mechanism of BBP-induced toxicity on female reproduction and showed that NMN provides an effective treatment for BBP actions,” state Jiang and colleagues. 

Chemical in Plastics Damages Oocytes 

BBP is a chemical known as a plasticizer, which makes plastics more flexible. BBP is currently undergoing risk evaluation by the Environmental Protection Agency (EPA) and is regarded as an environmental pollutant because of its estrogenic activity. To determine the effects of BBP on female reproduction, Jiang and colleagues fed female mice 1.5 mg/kg of BBP for 8 days and compared them to female mice not exposed to BBP. 

To test fertilization rate, the female mice were mated with male mice and their oocytes were removed for examination. While most of the oocytes from the mice not exposed to BBP developed into two-cell embryos, many of the oocytes from BBP-exposed mice went unfertilized. A lack of fertilized eggs suggests higher levels of infertility, the chances of which increase with age. 

Aneuploidy — an abnormal number of chromosomes — is the leading cause of miscarriages and developmental disabilities. Aneuploidy is considered a hallmark of oocyte aging, because it increases by 50% with advanced age. Another feature of aging oocytes that leads to aneuploidy is poor spindle — proteins that help equally divide chromosomes — organization. Jiang and colleagues found that oocytes from BBP-exposed mice had both increased spindle disorganization and aneuploidy. 

(Jiang et al., 2023 | Cell Proliferation) Phthalate Induces Oocyte Aging. Exposing mouse oocytes to benzyl butyl phthalate (BBP) induces common features of aging, including reduced fertilization rate, aberrant spindle formation, and aneuploidy when compared to normal oocytes (Control). 

Cellular aging encompasses universal features that affect not only oocytes but all cells. These features include mitochondrial dysfunction. Mitochondria, like batteries, need to remain at a specific voltage to produce cellular energy. When mitochondria become unhealthy, as with aging, this voltage dissipates. Jiang and colleagues found that the mitochondria contained within the oocytes of BBP-exposed mice had reduced voltages, indicative of poor mitochondrial health. However, this reduction in voltage was reversed by injecting the mice with 200 mg/kg/day of NMN.  

Unhealthy mitochondria produce excessive levels of reactive oxygen species (ROS). ROS react with proteins, fats, and DNA, causing damage to cells, a process called oxidative stress. Like mitochondrial dysfunction, oxidative stress is a universal hallmark of cellular aging. Jiang and colleagues found that oocytes from BBP-exposed mice had increased ROS levels, which were reduced to normal levels by NMN. 

(Jiang et al., 2023 | Cell Proliferation) NMN Restores Mitochondrial Health. Compared to normal mouse oocytes (Control), oocytes exposed to benzyl butyl phthalate (BBP) display reduced mitochondrial health (JC-1 signal) and increased reactive oxygen species (ROS), cell-damaging molecules generated by unhealthy mitochondria. However, NMN prevents this mitochondrial dysfunction and ROS overproduction.

With aging, oxidative stress causes DNA damage that accumulates and leads to further decrements that exacerbate aging. Furthermore, when the voltage of damaged mitochondria reaches a specific threshold, cell death is activated. Jiang and colleagues found that both cell death and DNA damage were increased in the oocytes of BBP-exposed mice. Moreover, NMN prevented the occurrence of both of these aging features. 

(Jiang et al., 2023 | Cell Proliferation) NMN Restores Cell Health. Compared to normal mouse oocytes (Control), oocytes exposed to benzyl butyl phthalate (BBP) display increased cell death (Apoptosis) and DNA damage. However, NMN prevents this cellular catastrophe.

Phthalates, Human Sperm and Muscle Aging, and How to Avoid Them 

Recent studies have linked phthalates to male sperm aging and sarcopenia — the age-related loss of muscle mass and strength — in humans. Studies like these add to concerns of phthalate’s effects on our health, especially reproductive health. To address this concern, a recent study has outlined lifestyle interventions for reducing exposure to phthalate, as well as phenol, another endocrine-disrupting chemical found in many consumer products. One of the interventions is to replace items known to be a source of phthalate or phenol with other products. While knowing which products contain these chemicals may require investigation, the study provides common routes of exposure:  

(Martin et al., 2022 | Environment International) Potential Sources of Endocrine-Disrupting Chemicals (EDCs) – phthalates and phenols. 

While it is difficult to assess the level of BBP exposure for each individual, some foods have been found to have high levels of BBP, such as vegetable oil with 1.69 mg/kg in one study reported from China. A European study showed that minced meat has 0.078 mg/kg of BBP. Since Jiang and colleagues used 1.5 mg/kg of BBP in this study, these levels are above or near dangerous levels of BBP exposure.