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The endocrine disrupting chemical diethylstilbestrol (DES), which has been banned in the U.S. since 1971, may be linked to increased odds of attention-deficit/hyperactivity disorder (ADHD) in grandchildren of the women who used it, a large-scale cohort analysis suggests.

The odds of ADHD were 36% higher in grandchildren of women who had used DES during pregnancy compared to grandchildren of women who did not use it, reported Marianthi-Anna Kioumourtzoglou, ScD, of Columbia University Mailman School of Public Health in New York and colleagues.

This association did not differ by the sex of the grandchildren and the odds of ADHD jumped to 63% if the grandmothers took DES during their first trimester, they reported in .

This is the first study to examine possible links between a potent endocrine disrupting chemical like DES and neurodevelopmental disorders in subsequent generations, Kioumourtzoglou said.

"Despite compelling evidence in animal studies that link exposure to endocrine disruptors to multigenerational neurodevelopmental effects -- such as altered behavior and social interactions in mice -- no study has investigated these associations in humans," she told 口袋女优. "With our study, we addressed this using DES as a case study for endocrine disrupting chemical exposure during pregnancy."

DES, a synthetic estrogen, was prescribed to an estimated 5 to 10 million pregnant women in the U.S. between 1938 and 1971 to prevent pregnancy complications. It was banned in 1971 when a study reported significantly elevated risk of vaginal adenocarcinoma among daughters of women who used DES during pregnancy and linked was later with multiple adverse outcomes among DES daughters.

Since then, studies have reported increased risk for adverse reproductive outcomes like hypospadias and delayed menstrual regularization among grandchildren of women who used DES.

While the literature to date has focused on reproductive tract conditions, estrogen can imprint a host of genes without modifying the gene code, noted Leonardo Trasande, MD, MPP, chief of environmental pediatrics at New York University School of Medicine, who was not involved with the study. The neurodevelopmental finding in this analysis is surprising, "but when you think about it at a deeper level, it makes quite frightening sense," he told 口袋女优: the gametes that would develop into grandchildren were in a very early phase when their mother was exposed to DES in utero.

For this study, researchers studied 47,540 participants from the Nurses' Health Study II (NHSII). They analyzed 3 generations: participants (F1 generation), their mothers (F0 generation), and their children (F2 generation). Participants and their mothers self-reported DES use during F0 pregnancy; physicians diagnosed ADHD in F2 children.

Of the total sample, 861(1.8%) women used diethylstilbestrol while pregnant with F1 participants and 46,679 (98.2%) did not.

Diethylstilbestrol was associated with an increased risk of ADHD among the F2 children: 7.7% versus 5.2%; adjusted OR 1.36 (95% CI 1.10-1.67). The adjusted OR increased to 1.63 (95% CI1.18-2.25) if diethylstilbestrol was used during the first trimester of pregnancy. The researchers found no effect modification by the F2 children's sex.

This finding could be the effect of direct DES exposure of F1's oocytes developing during the F0 pregnancy and does not imply transgenerational epigenetic changes, but animal studies suggest epigenetics may play a role, the authors noted.

And that raises the question of whether psychiatric and neurodevelopmental conditions may be fundamentally epigenetic disorders, Joel Nigg, PhD, of Oregon Health and Science University in Portland noted in an.

"The genetic metaphor for developmental psychopathology has long been considered inadequate for the complex dynamics of human development," he wrote. ADHD is likely a mix of both genes and environment and while the magnitude of gene-by-environment effects is unclear, "it is possible, perhaps even likely, that genotype (liability)-environment (modulation) interplay is fundamental," as the role of environment is increasingly recognized.

Because this is the first study to investigate the association between endocrine disrupting chemical exposure and F2 generation neurodevelopment, these findings should be interpreted with caution, Kioumourtzoglou noted. Several high production volume chemicals in commercial products are known or suspected endocrine disruptors, and population-wide exposure to them is very high. While the potency and levels of DES are much higher than those of any single endocrine disruptor that most humans are exposed to daily, the possibility of cumulative consequences exists.

"With DES, the science has always been the leading edge of a tsunami to come," Trasande observed. "If we don't listen to stories like this about DES and think broadly about the impact of synthetic chemicals and pharmaceuticals, we're missing a grave danger that lies ahead."