How to evaluate endocrine-disrupting chemicals

The use of new approaches and new technologies may enhance the potential to detect effects when undertaking guideline-compliant rodent studies of suspected endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), according to a review article authored by researchers from the Division of Translational Toxicology.

Exposure to EDCs during development may contribute to a variety of health conditions, including infertility, weight gain, behavioral changes in children, early-onset puberty in girls, cancers of the prostate and breast, cardiovascular effects, and diabetes. The evaluation of human health hazards and risks from exposure to such substances relies heavily on results from studies in rodents.

The Consortium Linking Academic and Regulatory Insights on Bisphenol A Toxicity (CLARITY-BPA) is a collaborative research effort to better link academic research with governmental guideline studies. The recent review explored CLARITY-BPA’s secondary goal of identifying endpoints or technologies that may enhance the capacity of rodent toxicity studies to detect EDCs with a focus on the publications from the CLARITY-BPA research program and prior published studies on BPA from the individual investigators participating in CLARITY-BPA.

The analysis revealed that molecular and quantitative morphological approaches are sensitive at detecting alterations in early postnatal development of the brain, ovary, and mammary glands. In addition, studies were effective at detecting increased susceptibility of the prostate to disease when animals were exposed to BPA during development and then challenged in adulthood with sex hormones to mimic human aging.

According to the authors, these insights and others detailed in the report may improve the sensitivity of future rodent toxicology studies to detect potential endocrine disruptors. (JW)

Citation: Howdeshell KL, Beverly BEJ, Blain RB, Goldstone AE, Hartman PA, Lemeris CR, Newbold RR, Rooney AA, Bucher JR. 2023. Evaluating endocrine disrupting chemicals: a perspective on the novel assessments in CLARITY-BPA. Birth Defects Res 115(15):1345–1397.

Uncovering an essential amino acid's unexpected effects on cancer

How the amino acid methionine affects cancer progression depends on the status of the immune system as well as gut microbes, according to NIEHS researchers and their collaborators.

Methionine is a sulfur-containing essential amino acid and a key component of dietary proteins that is important for a variety of cellular functions. Past research had presented conflicting ideas regarding methionine in cancer: Some studies indicated that methionine might bolster antitumor immunity to suppress tumor growth, whereas others suggested that restricting methionine intake could impede cancer growth in animal models.

To resolve these conflicting reports, the researchers investigated the interaction among dietary methionine, immune cells, and cancer cells in mice that either had an intact or deficient immune system. The results showed that methionine restriction inhibited cancer growth in immunocompromised mice. By contrast, this dietary regimen reduced T-cell abundance, exacerbated tumor growth, and impaired tumor response to immunotherapy in mice with intact immune systems.

Further investigation showed that a methionine-restricted diet led to reduced gut microbial production of hydrogen sulfide, which turned out to be critical for the immune cell activation. Consistent with these findings, dietary methionine supplementation enhanced antitumor immunity and suppressed tumor growth partially through the gut microbiota.

According to the authors, the study highlights a delicate balance of pro- and antitumor effects of dietary methionine and suggests that any possible anticancer benefits of methionine restriction require careful consideration of both the microbiota and the immune system. [Read related article.] (JW)

Citation: Ji M, Xu X, Xu Q, Hsiao YC, Martin C, Ukraintseva S, Popov V, Arbeev KG, Randall TA, Wu X, Garcia-Peterson LM, Liu J, Xu X, Andrea Azcarate-Peril M, Wan Y, Yashin AI, Anantharaman K, Lu K, Li JL, Shats I, Li X. 2023. Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota. Nat Metab; doi: 10.1038/s42255-023-00854-3. [Online 3 Aug 2023].

A protein called TRIM28 regulates uterine biology

Tripartite motif-containing 28 (TRIM28) is a protein that modulates steroid hormone signaling to regulate uterine function, according to NIEHS researchers and their collaborators.

Both estrogen and progesterone have important physiological functions, not only in reproductive biology, but also in cardiovascular, metabolic, and immune processes. The receptors for these hormones are targets of environmental endocrine disruptors. These hormones and receptors have been associated with many conditions, including cancers and gynecological, metabolic, and cardiovascular disorders.

Using cultured human endometrial stroma cells and genetically engineered mouse models, the researchers discovered that TRIM28 plays an essential role in modulating estrogen and progesterone signaling. They found TRIM28 deficiency disrupted uterine cell functions and composition, leading to fertility defects through altered estrogen receptor-alpha (ER-alpha) and progesterone receptor (PR) action. In addition, TRIM28 deletion induced a gene signature resembling that of endometriosis — a condition in which cells typically found in the uterus grow outside the uterus.

Currently, hormone therapy is the main nonsurgical therapy for treating endometriosis, despite its limited long-term efficacy and detrimental effects on fertility. According to the authors, further study of TRIM28 modulation of ER-alpha and PR activity will provide critical insight for developing nonhormonal therapies for uterine diseases as well as obesity, immune disturbances, and muscular conditions. (JW)

Citation: Li R, Wang T, Marquardt RM, Lydon JP, Wu SP, DeMayo FJ. 202. TRIM28 modulates nuclear receptor signaling to regulate uterine function. Nat Commun 14(1):4605.

Bifunctional role of PolG2 in mitochondrial DNA replication

New structures shed light on the dual functions of a mitochondrial protein called PolG2, according to NIEHS and North Carolina State University researchers and their collaborators.

Mitochondria are energy-producing organelles that have their own small, circular DNA called mitochondrial DNA (mtDNA), and they are highly susceptible to damage from toxicants and cellular stress. mtDNA damage can result in mitochondrial disease marked by neurological problems and metabolic disorders. The DNA polymerase-gamma (Pol-gamma) enzyme plays a critical role in copying and maintaining the integrity of mtDNA. PolG2 is one component of that enzyme; however, the structural basis for PolG2 binding to mtDNA, its significance, and how its dysfunction leads to mitochondrial disease remain unknown.

To address this gap, the researchers determined novel 3D X-ray crystal structures of PolG2 bound to DNA. Based on the structures, and Atomic Force Microscopy imaging of PolG2-DNA complexes performed in collaboration with North Carolina State University, the scientists proposed that PolG2 has Pol-gamma-dependent and -independent functions. These functions shed light on the structural and molecular basis for some of the PolG2 clinical disease variants.

Taken together, the data may suggest a role for PolG2 as a possible biological switch between mtDNA replication and maintenance functions. According to the authors, this work lays the groundwork for future investigation of mtDNA in response to cellular or environmental stressors and how PolG2 may be targeted to develop treatments for mitochondrial disorders. (AR)

Citation: Wojtaszek JL, Hoff KE, Longley MJ, Kaur P, Andres SN, Wang H, Williams RS, Copeland WC. 2023. Structure-specific roles for PolG2-DNA complexes in maintenance and replication of mitochondrial DNA. Nucleic Acids Res gkad679.

Phthalate, phenol exposure during pregnancy linked to low infant weight

Gestational phthalate and phenol biomarkers are associated with lower weight and fat mass among male infants, according to NIEHS researchers and their collaborators.

Regular use of phthalates and phenols in consumer products has led to frequent and chronic exposure, including among pregnant women. Gestational exposure — exposure during pregnancy — to these chemicals has been linked to adverse fetal growth outcomes, including reductions in ultrasound measures of fetal weight and birthweight. Although these observations are supported by animal models, much of the evidence in humans remains inconsistent with respect to the direction and magnitude of the effect. In particular, no human studies had explicitly examined the influence of gestational exposure to phthalates and phenols on neonatal or infant body composition. Body composition breaks down total body weight into fat mass (adipose) and lean mass (bones, muscles, and organs). In infants, both extremely high and low measures of fat mass have been linked to obesity development.

To address this knowledge gap, the researchers examined associations between 16 urine biomarkers of phthalate and phenol exposure in mid-pregnancy with the size and body composition of 438 infants. Higher exposure to these chemicals was linked to lower percentage fat mass at birth and at five months among males, but not females. Similar patterns were observed with infant weight.

Taken together, the findings suggest that mid-pregnancy phthalate and phenol exposure may have sex-specific effects, resulting in initial decreases in fat mass, and possibly followed by rapid growth, among male infants. (JW)

Citation: Stevens DR, Starling AP, Bommarito PA, Keil AP, Nakiwala D, Calafat AM, Adgate JL, Dabelea D, Ferguson KK. 2023. Midpregnancy phthalate and phenol biomarkers in relation to infant body composition: the Healthy Start Prospective Cohort. Environ Health Perspect 131(8):87017.