2024 review examines impact of BPA and BPA alternatives on egg quality

Researchers reviewed over 100 studies that investigated BPA and egg quality, finding that 85% reported negative effects, relating to lower follicle counts, fewer eggs retrieved, and poor egg morphology.

Estrogen receptors interact with estrogen hormones to ensure proper reproductive processes, and endocrine disruptors like bisphenol A (BPA) can disrupt how these receptors function.

To read more about endocrine disruptors, check out my post Endocrine disruptors and their impact on fertility.

This post is a summary of an article by Peters et al. (2024), who reviewed over 100 articles on how BPA or BPA alternatives can affect egg health. Here’s a breakdown of the number of studies they reviewed, covering either BPA or BPA alternatives. Keep in mind these BPx acronyms that will be used in this post, which represent BPA alternatives.

• Bisphenol A (BPA, 86)
• Bisphenol S (BPS, 18)
• Bisphenol F (BPF, 5)
• Bisphenol AF (BPAF, 6)
• Bisphenol B (BPB, 2)
• Bisphenol A diglycidyl ether (BADGE, 1)

For measuring egg quality, the researchers considered five criteria: Follicle counts, Number of eggs collected, Meiotic progression (to examine how well eggs can complete meiosis to become mature), Egg morphology (to examine how the egg looks under the microscope) and Egg spindle integrity (to examine the integrity of the meiotic spindle in the egg, which is the cellular machinery involved in separating chromosomes during meiosis).

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What is BPA and how might it affect egg health?

BPA disrupts the HPG axis, impacting reproductive health by altering GnRH levels and the release of FSH, LH and sex hormones (Silva et al. (2023)).

BPA is a chemical found in plastics and is found everywhere in daily life. BPA is used in making synthetic polymers like epoxy resins and polycarbonate, found in reusable bottles, kitchen utensils, varnishes, and coatings for canned food and beverages. The main dietary sources of BPA exposure are canned food, meat products, and fish (Silva et al. (2023)).

BPA release from plastics into food is accelerated by stressors like heat, microwave radiation, UV radiation, and repeated use, leading to over 90% of human BPA exposure occurring orally (Yang et al. 2011, Bertoli et al. 2015, Vandenberg et al. 2007).

As reviewed by Peters et al. (2024), in 2008, the FDA set the “no observed adverse effect level” (NOAEL) for BPA at 5 mg/kg/day based on industry-funded rodent studies, with a tolerable daily intake (TDI) of 0.05 mg/kg/day in several countries, including the USA, Australia, New Zealand, Japan, South Korea, and the EU.

Does BPA-free mean there’s no BPA in a product?

Manufacturers have used BPA for over 70 years, but in response to consumer health concerns, ‘BPA-free’ products have emerged, with some using alternatives like Bisphenol S (BPS), Bisphenol F (BPF), Bisphenol AF (BPAF), Bisphenol B (BPB), and Fluorene-9-Bisphenol (BHPF).

Emerging research shows that these substitutes may not be safe, with some evidence demonstrating that BPA alternatives can cause similar harmful health effects as BPA (Rochester and Bolden 2015, Pelch et al. 2019). Kojima et al. 2019 showed that BPAF and BPB can bind more strongly to the estrogen receptor than BPA itself.

There are few regulations for BPA substitutes, with some limits on packaging and children’s products.

Direct effects of BPA and BPA alternatives on egg quality

As mentioned, this review by Peters et al. (2024) included over 100 studies examining the effect of BPA and BPA alternatives on egg health.

There were 27 studies that examined the direct effect of BPA on egg health and 18 that examined BPA alternatives. By “direct effects,” I mean that extracted eggs, follicles or ovaries were directly exposed to BPA and studied (ie. these were in vitro experiments). Most of these studies were done using animal tissues, but some were done using human tissues.

Follicle counts. Four studies focused on BPA’s impact on follicle numbers, finding it led to reduced primordial follicles in neonatal mice and rats.

Meiotic progression. Based on 20 studies on BPA and 12 on BPA alternatives, 90% of BPA studies and 83.3% of BPA alternatives studies reported issues like reduced polar body extrusion rates and premature arrest, suggesting potential risks to oocyte development.

Egg morphology. Eleven studies on BPA and seven on its alternatives assessed oocyte and follicle morphology. All BPA studies reported adverse effects, including reduced cumulus cell expansion and darkened granulosa cells. Similarly, five of the seven studies on BPA alternatives found issues, such as granular cytoplasm and reduced COC expansion.

Egg spindle integrity. Twelve BPA studies and 11 BPA alternatives studies examined spindle integrity. All found adverse effects, such as chromosome misalignment and altered spindle structure. They found that these negative impacts occurred even at very low exposure levels, indicating that both BPA and its alternatives can disrupt oocyte spindle integrity.

Effects of BPA and BPA alternatives on egg quality in animals

Next, the researchers reviewed 47 studies where animals were treated with BPA (35 studies) or BPA alternatives (13 studies), most of which were in mice. While the previous section covered in vitro research, this section covers in vivo research.

Follicle Counts. Changes in follicle numbers were the most common outcome in these studies. Of 24 BPA studies, 91.7% reported adverse effects, with 13 finding decreases in the number of primordial follicles, suggesting that BPA reduced ovarian reserve. Some of these effects persisted in second and third generations of offspring (ie. the grandchildren and great grandchildren were affected). Among 11 BPA alternatives studies, 81.1% found negative effects, including decreased primordial follicles from BPAF and increased atretic follicles from BPS, BHPF, and BPB.

Number of eggs collected. Only 1 out of 6 BPA studies reported a reduced number of retrieved eggs after exposure to BPA, with 1 of 5 studies on BPA alternatives finding a decrease with increasing BPS dosage.

Meiotic progression. Two out of 4 BPA studies reported reduced germinal vesicle breakdown and polar body extrusion rates at low doses (ie. BPA caused problems with meiosis). However, three other studies on BPS and BPF found no changes in meiotic progression at lower doses.

Egg morphology. All four in vivo studies on BPA exposure showed negative egg or follicle morphology, including cystic dilation of follicles, increased oocyte diameter, presence of cytoplasmic granules, and decreased zona thickness. One study on BPS exposure reported unclear oocyte structure, compromised zona, and shrinking/degeneration of immature follicles.

Egg spindle integrity. The oocyte spindle was compromised in 6 out of 7 BPA studies and all 5 BPA alternatives studies. Exposure to BPA at levels below the “no observed adverse effect level” led to spindle abnormalities, chromosome misalignment, and aneuploidy. Low-dose exposure to BPS and BPF also disrupted spindle alignment in mice. Three studies observed chromosomal abnormalities in offspring exposed to BPS, BPAF, or BADGE, indicating potential long-term reproductive effects.

Effects of BPA and BPA alternatives on egg quality in humans

Finally, the researchers compared the results of clinical studies that were done in humans. There were 21 studies that assessed BPA levels in infertility patients, with 52.4% reporting an adverse effect. One study also evaluated BPS, BPF, and BPAF alongside BPA. These studies measured BPA levels in urine, blood, or follicular fluid and correlated them with egg yield and antral follicle count. The majority of the studies took place in the US, with others conducted in Korea, Greece, China, Iran, Iraq, Poland, France, and Turkey.

The detected levels of BPA in patient samples varied widely across studies, even within the same country. Median urinary BPA concentrations spanned 0.66 to 2.35 μg/l, while maximum detected BPA levels ranged from 10.45 to 79.19 μg/l.

None of these studies reported on spindle integrity, meiotic progression, or oocyte morphology.

Follicle Count: Eight studies assessed antral follicle count, with three of them finding a negative association between BPA concentration and follicle numbers. Other studies failed to establish a correlation, mainly in patients from the USA, Korea, Iraq, France, and Turkey.

Number of eggs collected. Of the 18 studies that reported on oocyte yield, 50% (9 studies) found a reduction in the total number of mature eggs, which were associated with higher BPA levels in urine, serum, or follicular fluid. This was observed across different infertility diagnoses, including patients with poor ovarian response, tubal factor infertility, or PCOS.

Here are some of the studies referenced in the review:

• Mínguez-Alarcón et al. 2016
• Yenigül et al. 2021
• Mina et al. 2022
• Poormoosavi et al. 2019
• Shen et al. 2020
• Fujimoto et al. 2011
• Souter et al. 2013
• Lin et al. 2021
• Kim et al. 2021

Conclusions

Of the 100+ studies reviewed in this paper, 85% reported negative effects on egg quality from BPA and BPA alternatives.

In vitro studies mainly showed effects on meiotic progression, egg spindle integrity, and egg morphology, while in vivo studies primarily affected follicle counts and spindle integrity.

Human studies showed mixed results, with some linking higher BPA levels to decreased antral follicle counts and number of eggs collected. However, egg quality wasn’t assessed in terms of meiotic progression, egg spindle integrity, and egg morphology, so further research is needed.

The data suggest that BPA alternatives, some of which can be found in BPA-free products, have similar harmful effects, although most research has focused on BPS, highlighting the need for more studies on other alternatives.

Some of the animal studies showed that the negative effects of BPA exposure were multi-generational, where exposure in the mother affected the grandchildren. Studies on BPA and BPA alternatives showed that this may be due to heritable epigenetic changes, or chemical modification of DNA (Trapphoff et al. 2013, Wang et al. 2016, Prokešová et al. 2020).

Many of the animal studies used a “low dose” of BPA (<5 mg/kg/day) that is believed to mimic human exposure, showing adverse effects. The authors note that the FDA has reviewed these studies between 2009 and 2013, but dismissed them due to study design concerns. Since then, multiple studies have also shown adverse effects at these low doses, along with a government-led CLARITY BPA program which represents the largest animal study on BPA and it’s long term effects (Camacho et al., 2019).

This led to researchers recommending new limits that are 20,000-times lower than that in the US, which “might require the elimination of BPA in food contact items in the US” (Vom Saal and Vandenberg, 2021). After 20 years of research and thousands of research papers, Vom Saal and Vandenberg state that “the amount of evidence that is available is overwhelming, and the conclusion is clear: low doses of BPA alter hormone-sensitive organs and are related to a wide range of human noncommunicable diseases based on evidence from human studies; the human data are supported by numerous findings from animal experiments and in vitro mechanistic studies.” Despite this recommendation, and the recommendation of a joint petition submitted by multiple organizations in 2022, the FDA continues to use its 2014 safety limits for BPA (FDA, accessed 9/2024; 2014 pdf report).

Based on this data, the European Food Safety Authority adopted a lower tolerable daily intake limit of 0.2 ng/kg/day (ie. 0.0000002 mg/kg/day) (Lambre et al. 2023). In the US, the daily limit is 0.05 mg/kg/day (EPA’s BPA action plan, 2010), or 50000 ng/kg/day, which is 250,000 times higher than the European TDI. Global average daily intakes of BPA were calculated to be 38.78 ng/kg/day in adults and 51.74 ng/kg/day in children, which both exceed the European FSA recommended tolerable daily intake level.

There is thus an urgent need for the revision of current guidelines by food safety authorities globally, following in the footsteps of the European FSA, to reduce prescribed safe exposure levels of BPA and introduce clear restrictions for the use of BPA analogues.

Peters et al. (2024)

For more information about endocrine disruptors and how to limit their intake, check out my post Endocrine disruptors and their impact on fertility.

Reference

Peters AE, Ford EA, Roman SD, Bromfield EG, Nixon B, Pringle KG, Sutherland JM. Impact of Bisphenol A and its alternatives on oocyte health: a scoping review. Hum Reprod Update. 2024 Sep 14:dmae025. doi: 10.1093/humupd/dmae025. Epub ahead of print. PMID: 39277428.

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About Embryoman

Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.

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